SNPMiner Trials by Shray Alag

L858R (324) T790M (316) V600E (256) T315I (102) L861Q (92) M184V (67) V617F (54) G20210A (53) K65R (52) V600K (51) C282Y (50) V66M (49) G551D (42) P13K (39) C677T (34) A118G (29) I84V (27) V158M (26) H63D (25) V32I (24) S768I (24) I50V (23) I47V (21) K103N (21) Y181C (20) L33F (19) K27M (19) T380A (18) L76V (18) D842V (18) D816V (17) S1251N (17) S1255P (17) G178R (17) G1244E (17) S549R (17) G1349D (17) V82A (16) R117H (16) M41L (16) S549N (16) G12C (16) C3435T (16) G551S (16) Q151M (16) Q12H (15) K219Q (15) I54L (15) G719A (14) K70E (14) C797S (14) L90M (13) L74V (13) E138A (13) D67N (13) K70R (13) L89V (13) L210W (13) Y188L (13) P4503A (12) G11778A (12) L265P (12) M46I (12) I54M (12) G12D (12) V11I (12) R132H (12) G48V (11) D961H (11) T74P (11) R192G (11) E255K (11) V299L (10) K101E (10) G2677T (9) T25W (9) V106A (9) G12V (9) M184I (9) H221Y (9) V30M (9) V600D (9) G1691A (8) F227C (8) T215Y (8) I50L (8) A1298C (8) L100I (8) Y253H (8) F317L (7) N155H (7) S298P (7) G190A (7) M230I (7) C1236T (7) V600R (7) Y188C (7) G2019S (7) P225H (6) Y93H (6) F359C (6) V108I (6) A3243G (6) G73S (6) P12A (6) Y115F (6) E545K (6) Q148H (6) Y537S (6) E542K (6) I10A (6) M230L (6) H1047R (6) N40D (6) D299G (6) D30N (6) M235T (6) D538G (6) Q12W (5) I148M (5) T87Q (5) I47A (5) L74I (5) E92Q (5) N680S (5) G93A (5) A455E (5) M204V (5) D1152H (5) L755S (5) G13D (5) G190S (5) N363S (5) A181V (5) V179L (5) L24I (5) N88S (5) A2143G (5) T399I (5) M36I (5) F53L (5) T315A (5) R263K (5) R132C (5) V777L (5) T1405N (4) D579G (4) G719C (4) N370S (4) R117C (4) Q16W (4) L98H (4) A98G (4) K20M (4) E138G (4) E138K (4) L31M (4) E157Q (4) L10F (4) Q80K (4) C31G (4) L206W (4) P140K (4) I54V (4) K76T (4) Y537C (4) I1314L (4) S945L (4) Y402H (4) P1446A (4) V179D (4) N88D (4) A6986G (4) N236T (4) A1166C (4) G970R (4) Y181I (4) R352Q (4) G2385R (4) S310F (4) P67L (4) R1070W (4) G140A (4) E23K (4) S463P (4) T14484C (3) G719S (3) R206H (3) S1400A (3) S1400I (3) A71V (3) C134W (3) R24W (3) C481S (3) T24H (3) V122I 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(1) I305F (1) N682S (1) T1010I (1) I655V (1) R885H (1) G7444A (1) R776G (1) E354Q (1) A21443C (1) R620W (1) A54T (1) D594G (1) T49A (1) F116Y (1) H870R (1) G205S (1) R535H (1) I767M (1) L55M (1) E571K (1) L55R (1) M2540A (1) E92K (1) G238A (1) L838P (1) E6V (1) L814P (1) K509I (1) V21I (1) G699A (1) V167F (1) L33P (1) M66V (1) D61804R (1) R849W (1) V762A (1) D816H (1) V326L (1) V108M (1) L58H (1) V411L (1) E158K (1) N334K (1) A1067T (1) S1800A (1) G894T (1) G202A (1) C282T (1) I191V (1) G435A (1) K1060T (1) A10H (1) R272G (1) V654A (1) V106T (1) C1091T (1) I638F (1) P317R (1) V433M (1) S230R (1) R4E (1) N550H (1) P1058A (1) N550K (1) E709Q (1) G304A (1) T124A (1) S253N (1) G1316A (1) M552V (1) M552I (1) R182H (1) D835V (1) A871E (1) D835Y (1) A677G (1) C1950G (1) H1505R (1) A893S (1) L597Q (1) S2808A (1) N55H (1) K28M (1) D89E (1) L485W (1) M9346A (1) L159F (1) A437G (1) R92Q (1) V29C (1) L38V (1) G135C (1) A677V (1) C34T (1) G93R (1) R270H (1) V321A (1) C10D (1) R122W (1) G308V (1) 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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation L858R

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 324 clinical trials

Clinical Trials


1 A Multi-center, Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Single-agent Tarceva® (Erlotinib) Following Complete Tumor Resection With or Without Adjuvant Chemotherapy in Patients With Stage IB-IIIA Non-small Cell Lung Carcinoma Who Have EGFR-positive Tumors

This is a study to evaluate the effectiveness of erlotinib compared with a placebo sugar pill following complete surgical removal of the tumor with or without chemotherapy after surgery in Stage IB-IIIA NSCLC patients.

NCT00373425
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Disease-free Survival in Participants With EGFR Mutation - Positive Tumors. --- L858R ---

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Overall Survival in Participants With EGFR Mutation - Positive Tumors. --- L858R ---

Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.. Number of Participants With Adverse Events (AEs). --- L858R ---

Primary Outcomes

Description: DFS is the time from the date of randomization until the first day non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

Measure: Disease Free Survival (DFS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: DFS is the time from the date of randomization until the first day that non-small cell lung cancer (NSCLC) relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date.

Measure: Disease Free Survival (DFS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cutoff date of 11 June 2014 (maximum time on follow-up was 78 months).

Secondary Outcomes

Description: Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

Measure: Overall Survival (OS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: Overall survival was defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive.

Measure: Overall Survival (OS)

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Description: Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Disease-free Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months).

Description: Disease-free survival (DFS) is the time from the date of randomization until the first day NSCLC relapse is documented by radiological exam and/or biopsy, or until death in the absence of relapse. After randomization, NSCLC relapse was based on radiological evidence or biopsy, as determined by the investigator. Participants without a DFS event were censored on the last adequate radiological assessment date. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Disease-free Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months).

Description: Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Overall Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 08 April 2013 (maximum time on follow-up was 64 months)

Description: Overall survival is defined as the time from the date of randomization until the documented date of death. Participants who were still alive were censored on the last day they were known to be alive. Activating EGFR mutation-positive is defined as exon 19 deletion or exon 21 L858R (or both) detected.

Measure: Overall Survival in Participants With EGFR Mutation - Positive Tumors

Time: Every 3 months during active phase and every 6 months during long term follow-up up to 5 years and yearly thereafter until the data cut-off date of 11 June 2014 (maximum time on follow-up was 78 months)

Description: An AE was defined as any untoward medical occurrence in a study participant and did not necessarily have a causal relationship with study treatment. An AE was considered serious if it resulted in death, a life-threatening situation, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a participant, other important medical events, or is on the Astellas Always Serious List. A drug-related AE was any AE with at least a possible relationship to study treatment as assessed by the investigator. Severity was graded by the investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0, where Grade 1=Mild AE; Grade=2 Moderate AE; Grade 3=Severe AE; Grade 4=Life-threatening or disabling; Grade 5=Death related to AE. AEs leading to death include deaths that occurred more than 30 days after the last dose of study drug.

Measure: Number of Participants With Adverse Events (AEs)

Time: From the date of first dose of study drug until 30 days after the last dose. The median time on treatment was 11.9 months for erlotinib and 21.9 months for placebo. Data are based off the 11 June 2014 data cut-off date.

2 A Phase 1, Sequential Cohort, Dose Escalation Trial to Determine the Safety, Tolerability, and Maximum Tolerated Dose of Daily Oral Administration of AV-412 in Patients With Refractory or Relapsed Solid Tumor Malignancies

AV-412 is a new oral therapy developed to inhibit the growth of solid tumors in patients who have not responded to standard therapy or surgical interventions, or who have experienced relapse. This study will test the safety of AV-412 and determine the maximum tolerated dose for the treatment of solid tumors.

NCT00381654
Conditions
  1. Tumor
Interventions
  1. Drug: AV-412
MeSH:Neoplasms
HPO:Neoplasm

Criteria for Inclusion: 1. ≥ 18 year old males or females 2. Documented measurable or evaluable solid tumor malignancy that is relapsed, refractory, locally advanced, or metastatic 3. Patients entered to MTD Cohort B must have: - Histologically or cytologically confirmed NSCLC - No prior therapy with erlotinib, gefitinib, or any other EGFR-kinase inhibitor - Previously documented exon 19 deletion and/or exon 21 L858R mutations - Measurable disease according to RECIST 4. Disease that is currently refractory to, or not amenable to, standard therapy 5. Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor 6. Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months 7. --- L858R ---

Inability to comply with protocol requirements Criteria for Inclusion: 1. ≥ 18 year old males or females 2. Documented measurable or evaluable solid tumor malignancy that is relapsed, refractory, locally advanced, or metastatic 3. Patients entered to MTD Cohort B must have: - Histologically or cytologically confirmed NSCLC - No prior therapy with erlotinib, gefitinib, or any other EGFR-kinase inhibitor - Previously documented exon 19 deletion and/or exon 21 L858R mutations - Measurable disease according to RECIST 4. Disease that is currently refractory to, or not amenable to, standard therapy 5. Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor 6. Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months 7. --- L858R ---

Primary Outcomes

Measure: To evaluate the safety, tolerability, and dose-limiting toxicities (DLT), and determine the maximum tolerated dose (MTD) of AV-412 when administered once daily by the oral route for 4 weeks (4 weeks equals one dosing cycle)

Time: one year

Secondary Outcomes

Measure: To characterize the pharmacokinetic (PK) profile of AV-412 in all patients. Extensive PK collection and assay to be performed in expanded MTD Cohorts

Time: 18 months

Measure: Evaluate potential pharmacodynamic (PD) markers of AV-412 action, in expanded MTD Cohorts ONLY

Time: two years

Measure: Preliminary evaluation of the antineoplastic activity of AV-412 (assessed by evidence and duration of disease stabilization or objective response, and time to disease progression)

Time: two years

3 Sequential Phase I/II Trial of Oral Vorinostat in Combination With Erlotinib in Non-small-cell Lung Cancer Patients With Mutations at Epidermal Growth Factor Receptor With Disease Progression After Erlotinib Treatment

This is an open label, non-randomized, sequential, phase I/II trial in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) with EGFR mutations after progression to Erlotinib. The study will have two parts. The first part (phase I) will be a dose finding (MTD) study to be implemented at three hospitals. The second part of the study (phase II) will asses the safety and efficacy of the combination. In this second part (phase II) patients will be treated with oral Erlotinib 150 mg P.O daily plus oral Vorinostat administered according to the results of the phase I. The study endpoints to be evaluated will include safety and response rate (RR) as primary endpoints and clinical benefit rate (CBR), time to progression, time to response, response duration and progression free survival as secondary endpoints. All the patients (phase I and II) will be treated until progression disease, unacceptable toxicity or withdrawal of the consent, and will be treated at the discretion of the principal investigator.

NCT00503971
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Vorinostat plus Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Have demonstrated mutations at epidermal growth factor receptor (EGFR) at Exon 19 or Exon 21 (Exon 19 mutations characterized by in-frame deletions (747-750), and Exon 21 mutations resulting in L858R substitutions). --- L858R ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Time: First cycle

Secondary Outcomes

Measure: Efficacy: Objective response rate; Time to progression; Time to response Response duration;Progression free survival;Clinical Benefict Rate

Time: Along the study

Measure: Exploratory Endpoints: Molecular analysis (EGFR mutations; thioredoxin; Hsp70; methylation of 14-3-3 sigma and CHFR, EGFR mutation at serum (in blood samples from patients)

Time: baseline, after cycle 3 and at the end of treatment

4 A Phase II Trial of Adjuvant Erlotinib in Patients With Resected, Early Stage Non-Small Cell Lung Cancer (NSCLC) With Confirmed Mutations in the Epidermal Growth Factor Receptor (EGFR)

In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

NCT00567359
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The median amount of time measured from the time of registration until the time of disease recurrence or death.. Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R --- --- T790M --- --- L858R ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung - Erlotinib is a pill taken daily and participants may continue to receive erlotinib for up to two years, as long as the cancer does not return and they do not experience any unacceptable side effects. --- L858R ---

Primary Outcomes

Description: The number of participants alive and free from disease recurrence 2 years after enrollment. Participants were monitored for disease recurrence with the use of surveillance radiographs. When possible and medically appropriate, tissue biopsies were obtained to prove recurrence.

Measure: 2-year Disease-free Survival

Time: 2 years

Secondary Outcomes

Description: Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 3.0) from the start of treatment until 30 days after the end of treatment. Serious adverse events were defined as adverse events that were grade 3 or greater and deemed to be possibly, probably or definitely related to the study treatment.

Measure: Number of Participants With Treat Related Serious Adverse Events

Time: From the start of treatment until 30 days after the end of treatment, up 13 months total

Description: The median amount of time from the time of registration until death due to any cause

Measure: Median Overall Survival

Time: From the time of registration until death, up to approximately 9 years

Description: The median amount of time measured from the time of registration until the time of disease recurrence or death.

Measure: Median Disease Free Survival

Time: From registration to disease recurrence or death, up to approximately 9 years

5 A Phase II Study of Erlotinib and Chemotherapy for Patients With Stage IB-IIIA NSCLC With EGFR Mutations (ECON)

The purpose of this study is to try to improve the odds that your cancer may be cured. Pemetrexed and cisplatin are traditional chemotherapy drugs that have been shown to help some patients with non-small cell lung cancer. Many different types of cancer cells, including your type of lung cancer, have a protein on their surface called the epidermal growth factor receptor (EGFR). Stimulation of these receptors can result in growth of cancer cells and progression of cancer. In addition, your cancer has an EGFR mutation (a specific abnormality in the genetic code for EGFR). Erlotinib (TarcevaTM) is a newer drug which has shown benefit for patients with lung cancers that contain an EGFR mutation. Erlotinib works by blocking this receptor and depriving the cancer cells of this message to grow and multiply. In this research study, we plan to combine erlotinib with traditional chemotherapy drugs to see if the combination works better than chemotherapy alone. The main purpose of this research is to find out the good and bad effects that the combination of these 3 drugs (pemetrexed, cisplatin and erlotinib) has when given to patients with early stage non-small cell lung cancer before surgery. A secondary purpose is to find out the good and bad effects that occur when erlotinib is given to patients after surgery for 2 years.

NCT00577707
Conditions
  1. Non Small Cell Lung Cancer
  2. Lung Cancer
Interventions
  1. Drug: erlotinib
  2. Drug: Pemetrexed
  3. Drug: Cisplatin
  4. Procedure: Resection
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R ---

- Other serious illness or medical condition including unstable cardiac disease requiring treatment, history of significant neurologic or psychiatric disorders (including psychotic disorders, dementia, or seizures), or active uncontrolled infection - Women who are pregnant or breast-feeding - Psychiatric illness or social situation that would limit compliance with study requirements Inclusion Criteria: - Pathologic confirmation of NSCLC - Patients must have previously untreated stage IB-IIIA NSCLC (T1-3N0-2M0) - Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R, L861Q) - Patients must be candidates for resection with curative intent - Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Age greater or equal to 18 years - Karnofsky performance status greater or equal to 70% - Normal marrow function: leukocytes greater than or equal to 3,000/μl, absolute neutrophil count greater than or equal to 1,500/μl, platelets greater than or equal to 100,000/μl, hemoglobin greater than or equal to 9 gm/dl - Adequate renal function, with creatinine less than or equal to 1.3 mg/dl or calculated creatinine clearance greater to or equal to 60ml/min by Cockroft and Gault equation using parameters of age, weight (kg), and baseline serum creatinine (mg/dl) - Adequate hepatic function: Total bilirubin within normal limits, AST < 1.5 X UNL, alkaline phosphatase < 1.5 X UNL - Women of childbearing age must have a negative urine or blood pregnancy test - Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter - Patients must have ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior chemotherapy or radiation therapy, with the exception of chemotherapy for nononcologic conditions (ie, methotrexate for the treatment of rheumatoid arthritis) - Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients must not be receiving any other investigational agents - Any evidence of interstitial lung disease (patients with chronic stable radiographic changes who are asymptomatic need not be excluded) - Patients who report a hearing deficit at baseline, even if it does not require a hearing aid or intervention, or interfere with activities of daily life (CTCAE grade 2 or higher) - Peripheral neuropathy > grade 1 - Known HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with the study drugs. --- L858R ---

Primary Outcomes

Description: Complete Response (CR): Disappearance of all clinical evidence of tumor. Partial Response (PR): A 50% or greater decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Minor Response (MR): A > 25% and < 50% decrease in the sum of the products of measured lesions. No simultaneous increase in the size of any lesion or the appearance of new lesions may occur. Non-measurable lesions must remain stable or regress for this category. Stable Disease (SD): A less than 25% decrease. This includes a decrease of less than 25% in the sum of the products of the measured lesions, and any increase of less than 25% in the sum of the products of the measured lesions. There may be no appearance of new disease sites for this category. Progressive Disease (PD): A ≥25% increase in one or more lesions, or appearance of new lesions.

Measure: Number of Patients With Pathologic Complete Response Rate

Time: Patients will undergo a CT scan of chest every 3 months for year 1 and every 4 months for year 2. In years 3 and 4, a chest CT or chest x-ray every 6 months.

Secondary Outcomes

Measure: Number of Participants With Response After 21 Days of Single Agent Erlotinib for Stage IB-IIIA NSCLC With a Known EGFR Mutation

Time: calculate the response rate after 21 days of single agent erlotinib

Measure: Number of Patients With a Response Rate, 3-year Overall Survival and Median Survival of Patients With a Known EGFR Mutation Receiving Neoadjuvant Chemotherapy and Erlotinib (and Adjuvant Erlotinib).

Time: 3 years

6 Detection of Epithelial Growth Factor Receptor (EGFR) Mutation in Malignant Pleural Effusion of Lung Cancer Patients and Cancer Cell Lines Establishment

1. Detection EGFR mutation of cancer cells from malignant pleural effusion. 2. Established the cancer cell lines with without EGFR mutation from malignant pleural effusion.

NCT00752076
Conditions
  1. NSCLC
Interventions
  1. Other: cancer cell lines establishment
MeSH:Pleural Effusion, Malignant Pleural Effusion
HPO:Pleural effusion

In-frame deletions in exon 19 centered on codons 756 to 750 make up 45~50% of mutations, and another 35~45% consist of the missense mutation leucine to arginine at codon 858 (L858R) in exon 21 (8, 9, 10). --- L858R ---

It is interesting that exon 19 deletion have increased response and survival with TKIs compared with L858R cases (10, 13, 14). --- L858R ---

This is in contrast to the natural history of patients, where those with exon 19 deletions appear to have shorter survival than those with L858R (8). --- L858R ---

Primary Outcomes

Measure: EGFR mutation in malignant pleural effusion of lung cancer patients cancer cell lines establishment

Time: 1 year

7 A Study to Assess the Efficacy of Erlotinib for Leptomeningeal Carcinomatosis in EGFR Mutation Positive Non-small Cell Lung Cancer

To assess the efficacy and safety of erlotinib for non-small cell lung cancer patients with leptomeningeal carcinomatosis

NCT00830245
Conditions
  1. Leptomeningeal Carcinomatosis
  2. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Carcinoma Meningeal Carcinomatosis
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Age >18 2. Histologically or pathologically proven non-small cell lung cancer (NSCLC) 3. Leptomeningeal carcinomatosis confirmed by CSF cytology 4. A patients with EGFR mutation (including exon 19 deletion, L858R) 5. ECOG performance status 0-3 6. Expected life time more than at least 4 weeks 7. --- L858R ---

A patient who refused to sign the informed consent Inclusion Criteria: 1. Age >18 2. Histologically or pathologically proven non-small cell lung cancer (NSCLC) 3. Leptomeningeal carcinomatosis confirmed by CSF cytology 4. A patients with EGFR mutation (including exon 19 deletion, L858R) 5. ECOG performance status 0-3 6. Expected life time more than at least 4 weeks 7. --- L858R ---

Primary Outcomes

Measure: Overall survival

Time: 1 year

Secondary Outcomes

Measure: Cytology negative conversion rate

Time: 1 month, 2 months, 3 months, 4 months

Measure: Neurologic symptom improvement

Time: 1 month, 2 months, 3 months, 4 months

Measure: Response rate (extra-cranial disease)

Time: 2 months, 4 months

Measure: Response rate (brain)

Time: 2 months, 4 months

Measure: Quality of life

Time: 1 month, 2 months, 3 months, 4 months

Measure: Toxicities

Time: 1 month, 2 months, 3 months, 4 months

Measure: Prognostic factors

Time: N-A

8 A Randomized, Open-label, Multi-center Phase III Study of Erlotinib Versus Gemcitabine/Carboplatin in Chemo-naive Stage IIIB/IV Non-Small Cell Lung Cancer Patients With EGFR Exon 19 or 21 Mutation (Optimal)

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) such as erlotinib have proved effective in second or third line therapy for advanced non-small cell lung cancer(NSCLC).It is well tolerated without the side effects usually associated with chemotherapy. The mutations in EGFR exons 19 or 21 have been reported to be associated with efficacy of EGFR TKIs.Based on the encouraging preliminary results from the Spanish lung cancer group' prospective study reported that the efficacy of Tarceva as first line treatment for metastatic NSCLC patients with EGFR mutation would delay disease progression,prolong overall survival and be well tolerated, medium Progression-free survival(PFS) was around 12 months and OS reach 24 months,our study is designed to compare PFS between the patients with mutant EGFR treated by gemcitabine/carboplatin and those by erlotinib in the first-line setting. We assumed 11 months of PFS on Tarceva arm versus 6 months on chemotherapy arm with a=0.025(alpha-spend for an interim analysis), 80% power and 12 months enrolment period, 12 months FU duration to calculate the sample size. The sample size is 69 pairs. Considering about 10% drop-out rate, the final sample size is 152 patients.So, chemo-naive staged IIIb/IV patients with EGFR mutations in exon 19 or 21 will be enrolled into this open-label, randomized,multicenter phase III study.

NCT00874419
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: erlotinib
  2. Drug: gemcitabine/carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. EGFR exon19 deletions or exon 21 L858R mutation by the DNA direct PCR sequencing using fresh tumor sample or paraffin embed tumor sample. --- L858R ---

Primary Outcomes

Measure: Progression free survival

Time: 12 months

Secondary Outcomes

Measure: OS

Time: 24 months

Measure: ORR

Time: 24 months

Measure: Time to Progression

Time: 24 months

Measure: lung cancer symptoms and health-related quality of life (HRQoL)

Time: 24 months

Measure: explore the biological markers (tumor tissue)

Time: 24 months

9 Tailored Second Line Treatment by EGFR Mutation in Patients With Advanced Lung Adenocarcinoma

Currently the investigators have two different classes of second-line treatment options in recurrent non-small Cell Lung Cancer (NSCLC). In chemotherapy, docetaxel and pemetrexed produced similar treatment efficacy outcomes, while pemetrexed had a better tolerability. In recent analysis of pemetrexed clinical studies, a strong treatment-by-histology interaction in overall survival and progression free survival that indicated better efficacy for non-squamous patients treated with pemetrexed. These data supports that pemetrexed could be a preferable chemotherapy drug especially in adenocarcinoma NSCLC patients.

NCT00903292
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: erlotinib (Tarceva)
  2. Drug: pemetrexed (Alimta)
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Since typical EGFR gene mutations (i.e., the deletion of typically five amino acids at codons 746-750 (ELREA) in exon 19 and a leucine-to-arginine mutation at codon 858 (L858R)) are a good predictor for tumor response to tyrosine kinase inhibitor, this present study is to tailor the patient's treatment according to his/her EGFR gene mutation status. --- L858R ---

Primary Outcomes

Measure: The primary analysis will be the overall best response rate, including a 95% confidence interval (Leemis and Trivedi 1996).

Time: 02/2009 - 04/2010

10 Phase II Randomized Assessing Pelvic Irradiation Combined With Cisplatin Alone or Cisplatin Plus Cetuximab in Patients With Carcinoma of the Cervix Stage IB2, II and III

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether radiation therapy given together with cisplatin is more effective with or without cetuximab in treating patients with cervical cancer. PURPOSE: This randomized phase II trial is studying giving radiation therapy together with cisplatin to see how well it works compared with radiation therapy and cisplatin given together with cetuximab in treating patients with stage IB, stage II, or stage IIIB cervical cancer.

NCT00957411
Conditions
  1. Cervical Cancer
Interventions
  1. Biological: cetuximab
  2. Drug: cisplatin
MeSH:Uterine Cervical Neoplasms
HPO:Cervical polyp Cervix cancer

- Study the correlation between treatment response and analysis of EGFR mutations (exons 18-21 of the tyrosine kinase domain including the two hot spots L858R and E746-A750). --- L858R ---

Primary Outcomes

Measure: Recurrence-free survival at 2 years

Secondary Outcomes

Measure: Response as assessed by MRI after radiochemotherapy and before surgery according to RECIST criteria

Measure: Toxicity according to NCI CTCAE v3.0

11 Phase II Study of Erlotinib With or Without Hydroxychloroquine in Patients With Previously Untreated Advanced NSCLC and EGFR Mutations

The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.

NCT00977470
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Hydroxychloroquine
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Specifically, patients harboring the most common mutations, deletions in exon 19 or the L858R mutation in exon 21 are eligible. --- L858R ---

Primary Outcomes

Description: A measure of progression-free survival in patients with advanced non small-cell lung cancer (NSCLC) and EGFR mutations treated with erlotinib as compared with patients treated with erlotinib plus hydroxychloroquine (HCQ). Disease progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, as seen on CT scan, or the appearance of one or more new lesions on CT scan.

Measure: Median Progression Free Survival

Time: From start of treatment until report of disease progression, assessed up to 10 years.

Description: This trial can detect a difference in proportions alive without progression at 9 months from 50% in the erlotinib arm to 77% in the erlotinib plus hydroxychloroquine (HCQ) arm, using an alpha of 0.15 and power of 85%, using the two-sided Likelihood Ratio test. Progression is defined as at least a 20% increase in the size of existing lesions or the appearance of one or more new lesions.

Measure: Nine-month Progression-free Survival Rate

Time: Nine months

Secondary Outcomes

Description: To evaluate the safety of treatment with erlotinib with and without hydroxychloroquine (HCQ). All participants receiving study treatment were evaluated for safety. Parameters included laboratory tests, hematological abnormalities, physical exam findings and spontaneous reports of adverse events reported by participants. Toxicities were evaluated and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = fatal.

Measure: Treatment Related Toxicity, > 10% Frequency, Any Grade

Time: 2 years

Description: Response is assessed via spiral CT scan, done at baseline and after every 2 cycles of study treatment. Standard RECIST (Response Evaluation Criteria in Solid Tumors) was used. Complete Response (CR) = disappearance of all target lesions; Partial Response (PR) = at least a 30% decrease in the size of target lesions, as compared to baseline; Progressive Disease (PD) = at least at 20% increase in the size of target lesions, or the appearance of one or more new lesions; Stable Disease (SD) = neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Response rate = CR + PR. Disease control rate = CR + PR + SD

Measure: Objective Tumor Response Rate Following Treatment With Erlotinib and With Erlotinib/HCQ.

Time: 2 years

Measure: Overall Survival of Patients Treated With Erlotinib and With Erlotinib/HCQ

Time: Until death

Other Outcomes

Description: Serial circulating tumor cell (CTC) analyses will be performed on peripheral blood and correlated with disease response.

Measure: Circulating Tumor Cell Quantification

Time: Until disease progression (median of 10.8 months)

Description: Correlation of molecular and genetic tumor characteristics with disease response. Genomic DNA will be extracted from tumor tissue and direct sequencing analysis will be performed to identify additional mutations.

Measure: EGFR Mutational Status

Time: 2 years

Description: [18F]-FMISO-PET/CT was performed on a 64-slice PET/CT scanner and tracer uptake was assessed using SUV (standardized uptake value), normalizing the radioactivity measured in tissue by the injected dose and the body weight of the patient. Mean and maximum SUV and threshold volume of FMISO uptake were measured to quantify the extent of hypoxia in the primary tumor. Imaging was performed before and after initiation of therapy with erlotinib.

Measure: Percent of Participants in Which FMISO-PET ([18F]-Fluoromisonidazole-positron Emission Tomography) is Able to Detect and Quantify Changes in Tumor Hypoxia After Erlotinib.

Time: 12 weeks

12 A Phase Ib Open-label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Cetuximab (Erbitux®) in Patients With Non-small Cell Lung Cancer With Progression Following Prior Erlotinib (Tarceva®) or Gefitinib (Iressa®)

The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.

NCT01090011
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Cetuximab
  2. Drug: Cetuximab
  3. Drug: BIBW 2992
  4. Drug: BIBW 2992
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.. Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R ---

Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnancy or breast-feeding Inclusion criteria: 1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment 2. Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. --- L858R ---

Primary Outcomes

Description: A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: CTCAE Grade 2 or higher decrease in cardiac left ventricular function CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days CTCAE Grade ≥3 rash despite standard medical management CTCAE Grade ≥3 fatigue lasting for more than 7 days CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.

Measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).

Time: from day 1 treatment until progression or undue toxicity, up to 28 days

Secondary Outcomes

Description: Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0

Measure: Highest CTCAE Grade

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Dose Reduction

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with adverse events leading to treatment discontinuation

Measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Death

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with drug-related serious adverse events

Measure: Frequency (%) of Patients With Related Serious Adverse Events

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy

Measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).

Measure: Concentration of Afatinib in Plasma for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.

Measure: Peak-trough Fluctuation (PTF)

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)

Measure: t1/2,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days

Measure: MRTpo,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)

Measure: CL/F,ss,15

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days

Measure: Vz/F,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.

Measure: Predose Plasma Concentrations of Afatinib for the Combination Arm

Time: Up to 57 days

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.

Measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.

Measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).

Measure: Duration of Objective Response (According to RECIST v1.1)

Time: up to 116 weeks

Description: Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.

Measure: Duration of Disease Control (According to RECIST v1.1)

Time: up to 116 weeks

Description: Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.

Measure: Progression-Free Survival (PFS) Time

Time: up to 116 weeks

13 Development of Circulating Tumour Cell Molecular Diagnostics Using a Novel Microfluidic Device

1. To compare EGFR mutations between primary non-small cell lung cancer (NSCLC) tumours and corresponding CTCs isolated by a label-free microfluidic device-based system 2. To characterize the association between clinical response in NSCLC patients treated with gefitinib and serial changes in CTC EGFR mutations detected by a label-free microfluidic device-based system The investigators recently developed a label-free, microfluidic device for capturing circulating tumour cells (CTCs) and acquired a Fluidigm Biomark digital PCR instrument for reliable low-level DNA quantification. The overall aim of this study is to test the feasibility of using these state-of-the-art devices to reliably detect clinically relevant EGFR mutations in CTCs.

NCT01193829
Conditions
  1. Patients With Non-small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

DNA will be extracted from the retrieved CTCs and tumour samples, and analyzed exon 19 deletion, L858R and T790M mutations by digital PCR on the Fluidigm Biomark according to methods described previously.23 --- L858R ---


14 A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors

Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.

NCT01259089
Conditions
  1. Adenocarcinoma of the Lung
  2. Non-small Cell Lung Cancer
Interventions
  1. Drug: erlotinib hydrochloride
  2. Drug: Hsp90 inhibitor AUY922
  3. Other: laboratory biomarker analysis
  4. Procedure: needle biopsy
  5. Genetic: mutation analysis
  6. Other: pharmacological study
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.. Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- T790M --- --- L858R ---

Gilbert's syndrome) Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- L858R ---

Primary Outcomes

Description: To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.

Measure: Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)

Time: During the first 4 weeks of treatment for each patient.

Description: Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions

Measure: Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922

Time: At 8 weeks from treatment initiation

Secondary Outcomes

Description: To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years

Description: Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Incidence of Reported Adverse Events in Phase I

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years

Description: Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Progression-free Survival (Phase II)

Time: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment

Description: Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.

Measure: Overall Survival (Phase II)

Time: From the time of first treatment with AUY922 to death, followed up to 2 years post treatment

Description: Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.

Measure: Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)

Time: From the time of first treatment with AUY922 to death, followed for up to 2 years

15 Phase II, Open-Label Study of Erlotinib (Tarceva®) Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Present Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor

This single arm, open-label study will evaluate the efficacy and safety of erlotinib (Tarceva) in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations.

NCT01260181
Conditions
  1. Non-Squamous Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.. Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator. --- L858R ---

Primary Outcomes

Description: Objective response (OR) was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of complete response (CR) and partial response (PR) four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response (Complete Response [CR]/Partial Response [PR]) Based on Computer Tomography (CT) or Magnetic Resonance Imaging (MRI) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

Secondary Outcomes

Description: Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Patients who had not died or progressed at the time of the final analysis were censored at the date of last contact.

Measure: Progression Free Survival (PFS) Based on CT or MRI According to RECIST v 1.1

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

Description: Overall Survival (OS) was defined as the time between the date of randomization and the date of death due to any cause.

Measure: Overall Survival

Time: Baseline up to 5 years

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Measure: Percentage of Participants With Adverse Events

Time: Baseline up to 5 years

Description: Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.

Measure: Percentage of Participants With Epidermal Growth Factor Receptor (EGFR) Mutation in Study Population

Time: Screening (21 days prior to Day 1)

Description: The response duration was defined as the time of initial response (complete response (CR) /partial response (PR) whichever is first recorded) until documented disease progression. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Disease progression was defined as At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

Measure: Median Time Taken From the First Response Until Disease Progression Based on RECIST v 1.1 as Determined by the Investigator

Time: Baseline up to 5 years (assessed at Baseline, every 8 weeks until disease progression or death or end of treatment period [up to 5 years])

16 A Randomized Phase III Study of TaxoteRe Plus Cisplatin Versus AlImta Plus Cisplatin in 1st Line Non-squamous Cell Type Lung Cancer

This study is: - A multicenter, prospective, randomized, phase 3 trial. - To prove non-inferiority of Taxotere/Cisplatin compared to Pemetrexed/Cisplatin as a front line treatment of patients with non-squamous cell lung cancer. - 276 patients will be recruited.

NCT01282151
Conditions
  1. Carcinoma, Non Small Cell Lung
Interventions
  1. Drug: Taxotere
  2. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Inclusion Criteria: - Age >= 18 years old - ECOG performance status 0-2 - Non-squamous cell type non-small cell lung cancer (NSCLC) - Stage IV, Stage IIIB cannot be treated with curative intent or Relapsed after surgery or radiation therapy - No prior chemotherapy except adjuvant chemotherapy and concurrent chemoradiation treatment. --- L858R ---

Platelet >=100,000/uL, neutrophil >=1,500 /uL Creatinine <=1.5 x upper normal limit or creatinine clearance >=60 mL/min Bilirubin <=1.5 x upper normal limit, Transaminases <=2 x upper normal limit Alkaline phosphatase <=2 x upper normal limit - Written informed consent Exclusion Criteria: - Pregnancy, Lactating woman - Woman in child bearing age who refuses to do pregnancy test - Moderate or greater than grade 1 motor or sensory neurotoxicity - Hypersensitivity to taxane - Comorbidity or poor medical conditions - Other malignancy (except cured basal cell carcinoma or uterine cervical carcinoma in situ) - Concurrent treatment with other investigational drugs within 30 days before randomization - Active treatment with other anticancer chemotherapy - EGFR mutation (exon 19 deletion, L858R, L861Q, G719A/C/S) Carcinoma, Non Small Cell Lung Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung Docetaxel is being used in 60mg/m2 3 weekly dosage in Japan and several east Asian institutions. --- L858R ---

Primary Outcomes

Description: months after beginning of first cycle chemotherapy

Measure: Progression Free Survival

Time: one year

Secondary Outcomes

Description: months from the beginning of first cycle chemotherapy

Measure: Overall Survival (months from the beginning of first cycle chemotherapy)

Time: three years

Description: Toxicity using CTCAE version 4.0

Measure: Safety Profile

Time: four months

Description: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

Measure: Response rate

Time: 6-7th week

17 A Phase 1, Open-Label, Multiple-Ascending-Dose Study of DS-2248, an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Subjects With Advanced Solid Tumors

This phase 1 clinical trial is intended to understand the safety and tolerability of a new anticancer drug in subjects with advanced solid tumors. The patients who qualify for the study will receive a once daily dose of the drug taken by mouth and will undergo several tests to measure the drug in the blood and to understand the safety, tolerability and any effect of the drug on the tumor. The antitumor effect of the drug is not known in human.

NCT01288430
Conditions
  1. Solid Tumors
  2. Non-small Cell Lung Carcinoma
Interventions
  1. Drug: DS-2248
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

- Either of the following: A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) -OR- Prior objective clinical benefit from EGFR-TKI, as evidenced by complete response (CR), partial response (PR), or stable disease (SD) ≥6 months as defined by RECIST or World Health Organization criteria. --- L858R ---

Primary Outcomes

Description: Objective response rate was defined as the sum of complete response (CR) and partial response (PR) rates. CR was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Summary of Objective Response Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Secondary Outcomes

Description: Complete response (CR) was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to <10 mm. Partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Objective response rate (ORR) was defined as the sum of CR and PR rates.

Measure: Summary of Best Overall Response Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Description: Disease control rate (DCR) was defined as the sum of complete response (CR) and partial response (PR) rates, and stable disease (SD) rate for a minimum of 12 weeks. Complete response (CR) was defined as a disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to <10 mm. Partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (at least a 20% increase in the sum of diameters of target lesions), taking as reference the smallest sum diameters while on study.

Measure: Summary of Disease Control Rate Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Description: Duration of response measured from the time at which criteria were first met for complete (CR) or partial response (PR) until the first date that progressive disease (PD) was objectively documented. Participants who had not progressed at the data cut-off date were censored at their last evaluable tumor assessment date. Duration of stable disease (SD) measured from the date of enrollment until the first date that criteria for disease progression were met. The minimum time interval for the duration of SD was 6 weeks. Participants who had not progressed at the data cut-off date were censored at their last evaluable tumor assessment date.

Measure: Duration of Stable Disease Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Description: Progression-free survival (PFS) defined as the time from the date of enrollment to the earlier of the dates of the first objective documentation of radiographic disease progression (as per RECIST V1.1) or death due to any cause. Participants who were alive with no objective documentation of (radiographic) disease progression by the data cut-off date were censored at the date of their last evaluable tumor assessment. Participants who were lost to follow-up or withdrew early from the study with no documented disease progression were censored at the last evaluable tumor assessment.

Measure: Summary of Progression-free Survival Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to disease progression, discontinuation of study, or death, up to 2 years 11 months

Measure: Summary of Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Infinity Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Maximum Concentration Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Time at Maximum Concentration Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Terminal Half-life Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Measure: Summary of Pharmacokinetic Parameter Total Body Clearance Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Cycle 1, Day 1 predose, 0.5, 1, 2, 3, 4, 6, and 8 h postdose; Cycle 1, Day 2 and Day 15; Cycle 1, Day 8 predose, 1 and 6 h postdose; Cycle 2 and 3, Day 1, 8, and 15

Description: A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during treatment, having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the AE is continuous. A DS-2248-related TEAE is an TEAE that is related to DS-2248 in the relationship.

Measure: Summary of Drug Related Treatment Emergent Adverse Events Following Oral Administration of DS-2248 in Participants With Advanced Solid Tumors

Time: Baseline up to 30 days post last dose, up to 2 years 11 months

18 An Open-Label Multicenter Study of Erlotinib (Tarceva®) as First Line Therapy Until and Beyond RECIST Progression in NSCLC Patients Who Harbour EGFR Mutations

This open-label, single arm study will evaluate the safety and efficacy of Tarceva (erlotinib) as first-line therapy in participants with stage IV or recurrent non-small cell lung cancer who harbour epidermal growth factor receptor (EGFR) mutations. All participants will receive Tarceva 150 mg daily orally until disease progression or unacceptable toxicity occurs. At the investigator's discretion, participants may receive Tarceva beyond disease progression.

NCT01310036
Conditions
  1. Non-Squamous Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.. Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.. Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.. Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1). --- L858R ---

PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.. Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R. --- L858R ---

Primary Outcomes

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Secondary Outcomes

Description: PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.

Measure: Progression-free Survival Per Investigator (PFS2)

Time: Approximately 68 months

Description: ORR was defined as the occurrence of either a confirmed complete (CR) or a partial response (PR, as a best overall response), as determined by RECIST, v. 1.1 criteria. CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: DCR was defined as CR + PR + Stable disease (SD). CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Description: OS was defined as the time from baseline to the date of death from any cause.

Measure: Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug.

Measure: Number of Participants With Adverse Events

Time: Approximately 68 months

Description: This outcome measure was not assessed.

Measure: Correlation Between EGFR Mutations in Plasma and Clinical Outcome (ORR/PFS/OS)

Time: Approximately 68 months

19 A Phase II Trial of Gefitinib Monotherapy in Pretreated Patients With Advanced Non-small Cell Lung Cancer Not Harboring Active EGFR Mutations

The investigators will examine efficacy and toxicity of gefitinib in Korean patients with EGFR wild tumors diagnosed with direct sequence test.

NCT01312337
Conditions
  1. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: salvage iressa
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Nonsmall Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Inclusion Criteria: - Pathologically proven NSCLC - Ineligibile for curative treatment (namely, stage IIIb or IV) - History of one to three prior systemic chemotherapy tumors without active EGFR mutations (exon 19 deletion, L858R mutation in exon 21) - At least one lesion that was unidimensionally measurable by computed tomography (by RECIST 1.1) - 18 years old or older - Performance status ECOG 0-2 - Adequate organ function as evidenced by the following: - Absolute neutrophil count > 1.0 x 109/L - Platelets > 75 x 109/L - Total bilirubin ≤ 1.5 UNL - AST and/or ALT < 5 UNL - Creatinine clearance ≥ 45mL/min Exclusion Criteria: - Previous EGFR TKI therapy history - Systemic anticancer therapy within the previous 3 weeks - Other invasive malignancy within the past 2 years except non-melanoma skin cancer, in situ cervix cancer, or papillary thyroid cancer - Other concurrent illness that would preclude study participation (severe heart disease) - Other concurrent physical condition (e.g., infectious disease) that would preclude study participation - Pregnant or nursing Nonsmall Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L858R ---

Primary Outcomes

Measure: To determine disease control rate at 8 weeks will be 35% or higher in the the study group

Time: 6 months after the enrollment of the last patients

Secondary Outcomes

Measure: The number of patients who live longer than 6 months after enrollment

Time: 6 months after the enrollment of the last patients

20 e- Ab Sensor-based Real-time Detection of Mutant EGFR in Clinical Specimens From Patients of Non-small Cell Lung Cancer

The purpose of this study is to develop a real-time diagnostic technique with e- Ab sensor for specific EGFR mutation detection in clinical specimens of NSCLC patients, the investigators conduct a prospective clinical study. In comparison with results from direct sequencing of EGFR, the investigators evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). The potential factors which may interfere with the results would be investigated. With such technique, the investigators can obtain EGFR mutation information of NSCLC patients in cost-saving and time-saving way and can offer more individualized treatment for the investigators patients.

NCT01359436
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Device: Electrosensing antibody probing system (e- Ab sensing)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

In comparison with results from direct sequencing of EGFR, the investigators evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

However, only some EGFR mutations are associated with sensitivity to tyrosine kinase inhibitor treatment, especially deletion in exon 19 and L858R mutation in exon 21.4-5 Two recent phase III randomized clinical trials evaluated gefitinib treatment and chemotherapy in patients of advanced NSCLC with sensitive EGFR mutaions.6-7 --- L858R ---

8 For detection for specific EGFR mutations, mutation-specific monoclonal antibodies were developed to detect E746-A750 deletion in exon 19 and L858R in exon 21. --- L858R ---

In the study by Akhiko Kawahara et al, IHC assay of NSCLC tumor specimens with anti-delE746-A750 antibody showed a sensitivity of 79%, which was 83% by IHC assay with anti-L858R antibody.10 --- L858R ---

IHC assay with anti-L858R antibody also showed high specificity but low sensitivity (97% and 36%, respectively). --- L858R ---

For anti-L858R antibody, the sensitivity was 76%-95% and the positive predicted value was 99%-100%. --- L858R ---

Electrosensing antibody probing system (e- Ab sensor), which was developed for the rapid and sensitive detection of hapten, proteins, or viral antigen in medical samples, will be used for analyzing the interaction kinetics between mutation specific anti-EGFR and its antigen (EGFR with E746-A750 deletion or L858R mutation) present in the specimens of patients with lung cancer. --- L858R ---

In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750). --- L858R ---

Primary Outcomes

Description: In comparison with results from direct sequencing of EGFR, we evaluate the performance of e- Ab sensor, including reproducibility, sensitivity, specificity, and cross-reaction (such as detection of EGFR mutations other than L858R and DelL746-A750)

Measure: The performance of e- Ab sensor

Time: 1 day

21 A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Study of ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects With Locally Advanced or Metastatic, Non-Squamous, Non-Small-Cell Lung Cancer With Wild-type Epidermal Growth Factor Receptor

The primary objective of this study is to determine if the combination regimen of ARQ 197 with erlotinib will improve overall survival (OS) compared to erlotinib monotherapy in subjects with locally advanced or metastatic non-squamous NSCLC with wild-type EGFR who have received 1 or 2 prior systemic anti-cancer therapies in the Intent-to-Treat (ITT) population.

NCT01377376
Conditions
  1. Non-small-cell Lung Cancer
Interventions
  1. Drug: ARQ 197 and Erlotinib
  2. Drug: Placebo and Erlotinib
MeSH:Lun Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria 1. Male or female at least 20 years of age with life expectancy ≥ 3 months 2. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC with wild-type (excluding major activating mutation (exon 19 deletion and/or exon 21 L858R mutation)) EGFR gene status confirmed by a highly sensitive PCR assay 3. Evaluable disease according to RECIST, Version 1.1 4. Received one or two prior lines of systemic anti-cancer therapy for advanced or metastatic disease, one of which must be a platinum-based therapy 5. ECOG performance status of 0 or 1 6. --- L858R ---

Any other significant co-morbid condition that, in opinion of the investigator/sub-investigator, would impair study participation or cooperation Inclusion Criteria 1. Male or female at least 20 years of age with life expectancy ≥ 3 months 2. Histologically or cytologically confirmed surgically unresectable locally advanced or metastatic (stage IIIB/IV) non-squamous NSCLC with wild-type (excluding major activating mutation (exon 19 deletion and/or exon 21 L858R mutation)) EGFR gene status confirmed by a highly sensitive PCR assay 3. Evaluable disease according to RECIST, Version 1.1 4. Received one or two prior lines of systemic anti-cancer therapy for advanced or metastatic disease, one of which must be a platinum-based therapy 5. ECOG performance status of 0 or 1 6. --- L858R ---

Primary Outcomes

Measure: Overall survival

Secondary Outcomes

Measure: Progression free survival

Description: Each assessment will be determined based on RECIST criteria version 1.1 by investigator

Measure: Objective response rate

Measure: Number of patients with adverse events

22 Molecular Analysis of Thoracic Malignancies

A research study to learn about the biologic features of cancer development, growth, and spread. We are studying components of blood, tumor tissue, normal tissue, and other fluids, such as urine, cerebrospinal fluid, abdominal or chest fluid in patients with cancer. Our analyses of blood, tissue, and/or fluids may lead to improved diagnosis and treatment of cancer by the identification of markers that predict clinical outcome, markers that predict response to specific therapies, and the identification of targets for new therapies.

NCT01385722
Conditions
  1. Thymus Cancer
  2. Thymoma
  3. Thymic Carcinoma
  4. Lung Cancer
  5. Carcinoma, Non-Small-Cell Lung
  6. Mesothelioma
MeSH:Carcinoma Mesothelioma Carcinoma, Non-Small-Cell Lung Thymoma Thymus Neoplasms
HPO:Carcinoma Neoplasm of the thymus Non-small cell lung carcinoma Thymoma

Over 90% of EGFR tyrosine kinase domain mutations associated with sensitivity to EGFR Tyrosine kinase inhibitor (TKI) therapy fall into two categories, in-frame deletions in exon 19, and the L858R point mutation in exon 21. --- L858R ---

Primary Outcomes

Measure: Collect detailed clinical information on patients with thoracic malignancies via the electronic medical record and a detailed patient questionnaire

Time: 20 years

23 A Phase II Trial of Radiation Therapy Combined With Iressa in Patients With Locally Advanced Non-small Cell Lung Cancer With Harboring Active EGFR Mutations

The purpose of this study is to access the effect and safety of radiotherapy combined whth Iressa for patients with locally advanced non-small cell lung cancer with harboring active EGFR mutations.

NCT01391260
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Other: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically confirmed diagnosis of non-squamous NSCLC; Stage ⅢA-ⅢB(not suitable for surgery) or stage Ⅳ(only single-site single transfer ); - Untreated patients, or who completed ≤ 2 cycles of first-line chemotherapy (chemotherapy regimen: paclitaxel, docetaxel + cisplatin) within the previous month; - Patients with tumor EGFR mutation positive (exon 19 deletion mutation or exon 21 L858R substitution mutation); - Patients must be informed of the investigational nature of the study and must sign an informed consent form; - Presence of at least one measurable/evaluable according to RECIST criteria. --- L858R ---

Primary Outcomes

Measure: Response rate (RR)

Time: 1 year

Secondary Outcomes

Measure: Progression free survival (PFS)

Time: 2 years

Measure: Overall survival (OS)

Time: 2 years

Measure: Quality of life (MD-Anderson questionnaire)

Time: 1 year

24 A Randomized, Open-label Trial of Gefitinib Versus Combination of Vinorelbine Plus Platinum as Adjuvant Treatment in Pathological Stage II-IIIA(N1-N2) Non-small Cell Lung Cancer With EGFR Mutation

Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been characterized in a subset of patients with advanced NSCLC.The EGFR mutation rate was 30% in Chinese Non-small Cell Lung Cancer(NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This randomized phase III trial is studying gefitinib to see how well it works compared to cisplatin-based chemotherapy in treating patients who have undergone surgery for stage II-IIIA(N1-N2) NSCLC with EGFR activating mutation in Asian population.

NCT01405079
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Vinorelbine+Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Target population is completely resected pathological stage II-IIIA(N1-N2) NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation. --- L858R ---

Primary Outcomes

Description: To evaluate the disease free survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for pathological stage II-IIIA(N1-N2) NSCLC with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Secondary Outcomes

Description: To evaluate the overall survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for stage II-IIIA(N1-N2) NSCLC with EGFR mutation.

Measure: Overall survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: To compare the randomized treatment arms in terms of 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate.

Measure: 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: The Total Score and TOI of FACT-L to Measure Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

25 Trial of Afatinib (BIBW 2992) in Suspected or Confirmed Mutant EGFR Lung Cancer Patients Unfit for Chemotherapy

The purpose of this study is to examine the efficacy and safety of using afatinib (BIBW 2992) to treat non-small cell lung cancer patients considered unfit for chemotherapy and have either suspected or confirmed Epidermal Growth Factor Receptor (EGFR) mutation.

NCT01415011
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Afatinib (BIBW 2992)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

L858R, exon 19 deletions, exon 20 insertions, T790M, list is not exhaustive), and WHO PS 0-3 Or No tissue suitable for EGFR genotyping, failed genotype, or EGFR genotyping unavailable, and NSCLC Adenocarcinoma sub-type, and Eligible smoking history: Never smoker (<100 cigarettes in lifetime), or Former smoker (stopped >1year ago and ≤10 pack-years) and WHO PS 0-2 - Unsuitable for or patient declining chemotherapy due to significant co-morbidity - Measurable disease according to RECIST version 1.1 - Adequate haematopoietic, hepatic and renal function defined as follows: Absolute neutrophil count (ANC) ≤1.5 x 109/L and platelet count ≤100 x 109/L - Bilirubin ≤1.5 x ULN, ALT (SGPT) ≤3 x ULN (or ≤ 5 x ULN in cases of liver metastases) - Serum creatinine clearance ≥45 ml/min - Palliative radiotherapy allowed unless to a solitary target lesion - Age 18 or over (no upper age limit) - Written informed consent that is consistent with ICH-GCP guidelines Exclusion Criteria: - Previous treatment with afatinib (BIBW 2992), or any EGFR-directed inhibitor - Any concurrent anticancer systemic therapy - Prior chemotherapy for relapsed and/or metastatic NSCLC - Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and registration - Suitable for radical radiotherapy - Palliative radiotherapy within 2 weeks prior to registration - Palliative radiotherapy to a solitary target lesion - Surgery (other than biopsy) within 4 weeks prior to registration - Inability to take oral medication, requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption, any medical co- morbidity affecting gastrointestinal absorption - Patients with current or pre-existing interstitial lung disease - Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient's participation in the trial - Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE version 4.0 Grade ≥3 diarrhoea of any etiology at baseline - Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants and/or leptomeningeal disease). --- L858R ---

Primary Outcomes

Description: Progression free survival will be determined by measurement of tumour size using RECIST version 1.1 at progression or date of patient death.

Measure: Progression free survival

Time: At 6 months

Secondary Outcomes

Measure: Overall response

Time: CT scan of chest & abdomen 4 weeks after registartion, then every 8 calender weeks until disease progression. CT scans every 12 weeks if patient is still on BIBW 2992 after 1 year of treatment.

Measure: Overall survival

Time: This will be measured in days, from the first day of treatment to the day of death.

Measure: Change in performance status

Time: At 1 month

Description: For each type of adverse event, the maximum toxicity grade will be obtained for each patient using CTCAE version 4.0 to closely monitor tolerability to BIBW 2992. Focus will be on those with a grade 3 or 4 BIBW 2992 related toxicities. The proportion of patients with any grade 3 or 4 event will also be examined.

Measure: Safety

Time: To be assessed at every timepoint i.e. baseline, fortnightly for the first 2 cycles and then monthly for 12 months and 2 monthly thereafter

Measure: Progression free survival in patients aged 70 and over

Time: At progression or patient death

Measure: Treatment compliance

Time: Compliance will be examined based on the time between starting treatment and stopping it completely

26 Phase I/II Clinical Trial Combining TUSC2-nanoparticles and Erlotinib in Stage IV Lung Cancer

The goal of phase 1 of this clinical research study is to find the highest dose of DOTAP:Chol-TUSC2 that can be safely given in combination with Tarceva (erlotinib hydrochloride) to patients with NSCLC. The goal of phase 2 of this clinical research study is to learn if the combination of DOTAP:Chol-TUSC2 and erlotinib hydrochloride can help to control NSCLC. The safety of this drug combination will also be studied in both phases. DOTAP:Chol-TUSC2 (previously FUS1) is a drug that helps transfer a gene called TUSC2 into cancer cells. Researchers think that cells without this gene may be involved in the development of lung cancer tumors. They want to find out if replacing the gene in these cells may keep the tissue from forming cancer cells. Erlotinib hydrochloride is designed to block a protein on tumor cells that may control tumor growth and survival. This may stop tumors from growing.

NCT01455389
Conditions
  1. Lung Cancer
Interventions
  1. Drug: DOTAP:Chol-TUSC2
  2. Drug: Erlotinib
  3. Drug: Dexamethasone
  4. Drug: Diphenhydramine
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Subjects must have specimens adequate for analysis of EGFR mutations (and other clinically relevant biomarkers) 4. All subjects with an activating EGFR mutation (exon 19 deletion or exon 21 L858R mutation) are eligible IF they have progressed following treatment with a first, second, or third generation EGFR inhibitor. --- L858R ---

Primary Outcomes

Description: MTD defined as dose level at which less than 2 participants experience dose-limiting toxicity (DLT). Toxicity graded according to National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Version 4. DLT will be grade > 3 toxicity occurring during the first cycle of therapy (i.e., within the first 3 weeks).

Measure: Maximum Tolerated Dose (MTD) Level for Drug Treatment Combination

Time: First 21 day cycle

Secondary Outcomes

Description: Responses determined by RECIST criteria. Responses will include only complete response (CR) + partial response (PR). Participants considered as non-responders when tumor progression by RECIST is observed. Measurable disease is defined as tumor masses with identifiable diameters measurable in two dimensions by computed tomography. Best overall response is best response designation recorded from the start of treatment until disease progression. Complete and partial responses have to be confirmed by two evaluations of the disease taken at least four weeks apart.

Measure: Response Rate

Time: After two, 21 day cycles

27 LUX-Lung 7: A Randomised, Open-label Phase IIb Trial of Afatinib Versus Gefitinib as First-line Treatment of Patients With EGFR Mutation Positive Advanced Adenocarcinoma of the Lung

This is a randomised, open-label, phase IIb trial of afatinib to compare to gefitinib in first-line treatment setting with patients who are having epidermal growth factor receptor mutation positive advanced adenocarcinoma of the lung.

NCT01466660
Conditions
  1. Lung Neoplasms
Interventions
  1. Drug: Afatinib
  2. Drug: gefitinib
MeSH:Adenocarcinoma Lung Neoplasms Adenocarcinoma of Lung
HPO:Neoplasm of the lung

2. Documented activating epidermal growth factor receptor mutation (Del19 and/or L858R) with tumour tissues. --- L858R ---

Primary Outcomes

Description: Progression-free survival (PFS) defined as the time from date of randomisation to date of disease progression, or date of death if a patient died earlier. Participants with no event (Disease progression (PD) or death) were censored. PD was primarily evaluated for the primary analysis by an independent central imaging review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): PD, At least a 20% increase in the sum of the longest diameter (SoD) of target lesions taking as reference the smallest SoD of target lesions recorded since the treatment started, together with an absolute increase in the SoD of target lesions of at least 5 millimetre (mm) or the appearance of one or more new lesions. For the final analysis (analysis cut-off date 12 April 2019) status and date of PD were determined by investigator assessment.

Measure: Progression-free Survival

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Description: Time to Treatment Failure (TTF) which was the time from the date of randomisation to the date of i.e. permanent treatment discontinuation for any reason.

Measure: Time to Treatment Failure (TTF) (Main Overall Survival Analysis Cut-off Date, 08 April 2016)

Time: From first drug administration until last drug administration, up to 1482 days

Description: Overall survival (OS) which was defined as the time from the date of randomisation to the date of death. Participants for whom there is no evidence of death at the time of the analysis will be censored at the date that they were last known to be alive.

Measure: Overall Survival

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on death, up to 2465 days.

Secondary Outcomes

Description: Objective response rate (ORR) which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

Measure: Objective Response Rate

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Description: Number of participants with objective response (best overall response of complete response or partial response) to study treatment over time, cumulative number of participants is displayed. Time to objective response was defined as the time from randomisation to the first recorded objective response. For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

Measure: Time to Objective Response

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Description: Duration of objective response defined as the time of first objective response (best overall response of complete response or partial response) to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) objective response was determined by investigator assessment.

Measure: Duration of Objective Response

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression, further anti-cancer treatment and death, up to 2465 days.

Description: Percentage of participants with disease control which was defined as the number of participants with best overall response of complete response (CR) or partial response (PR) or stable disease (SD) as assessed by central independent review according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. divided by the total number of participants who received treatment. Per RECIST version 1.1. for target lesions and assessed by Computed Tomography (CT)-scan or Magnetic Resonance Imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Responses of SD were only considered if they occur ≥42 days from date of randomisation. For the final analysis (analysis cut-off date 12 April 2019) disease control was determined by investigator assessment.

Measure: Disease Control

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Description: Duration of disease control defined as the time from randomisation to the time of progression or death, whichever occurred first (or date of censoring for progression free survival). For the final analysis (analysis cut-off date 12 April 2019) the status and date of disease progression were determined by investigator assessment.

Measure: Duration of Disease Control

Time: From first drug administration until 28 days after last drug administration + Follow-Up period for collecting information on disease progression or death, up to 2465 days.

Description: Tumour shrinkage assessed by minimum sum of post-baseline target lesion diameters recorded after randomisation. A positive value shows a decrease in tumour size.

Measure: Tumour Shrinkage (Main Overall Survival Analysis Cut-off Date, 08 April 2016)

Time: From first drug administration until last drug administration, up to 1482 days

Description: Health-related quality of life (HRQoL) measured using European Quality of life - 5 Dimensions (EQ-5D) score for United Kingdom (UK) and Belgium and European European Quality Visual Analogue Scale (EQ-VAS). EQ-5D utility scores range from 0 (worst health) to 1 (full health). EQ-VAS scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). Results display the mean score up to 56 weeks.

Measure: Health-related Quality of Life (Primary Analysis Cut-off Date, 21 August 2015)

Time: Every 8 weeks, up to 56 weeks

28 Phase II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Preclinical data in lung cancer cell lines showed that EGFR mutation can potentially be a positive predictor for sensitivity to BKM120. Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). Therefore, combining BKM120 with erlotinib could potentially down-modulate PI3K-Akt activity resulting in a synergistic effect on cell growth inhibition and enhancing the response to erlotinib.

NCT01487265
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: BKM120 and Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

These include, but are not limited to mutations in L858R (Exon 21); Exon 19 deletion; G719S, G719A, G719C mutations (Exon 19);or L861Q (laboratory report required at enrollment). --- L858R ---

Primary Outcomes

Description: Percentage of patients who are alive and progression-free at 3 months (APF3) from first treatment.

Measure: Progression Free Survival at 3 Months

Time: 3 months

Secondary Outcomes

Description: Defined as the time from first treatment until death from any cause.

Measure: Overall Survival

Time: every 3 months after study treatment, projected 24 months

Description: Defined as the time from complete or partial response (CR or PR) until objective tumor progression. Tumor measurements will be obtained using CT scans of chest, abdomen and pelvis and assessed per RECIST v 1.1. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Duration of Response

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Defined as the percentage of complete and partial responses (CR + PR) among all patients. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Objective Response Rate

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Adverse events will be graded using CTCAE v4.3. and will be collected until 30 days after the discontinuation of study treatment for each participant. A non-serious adverse event is any untoward medical occurrence. A serious adverse event (SAE) is an event that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; requires intervention to prevent permanent impairment or damage. Specific AE and SAE terms are provided in the Adverse event module.

Measure: Number of Participants With Serious and Non-serious Adverse Events as a Measure of Safety.

Time: Every 2 weeks for 8 weeks, then every 8 weeks thereafter, estimated 24 months

29 A Phase 2A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Immune Response, Safety and Efficacy of HS-110 in Combination With Erlotinib vs. Erlotinib as a Single Agent in Patients With Advanced, Non-EGFR Mutated Non-Small Cell Lung Cancer (NSCLC)

This study will enroll patients with locally advanced or metastatic non-EGFR mutated Non-Small Cell Lung Cancer (NSCLC) lung cancer after failure of at least one but no more than two prior approved treatment regimens. Patients will be randomized to receive one of two doses of vaccine or placebo to be dosed twice weekly for 18 weeks (36 doses total) and patients will also receive erlotinib 150mg taken orally once daily for the duration of the trial. The study will examine the immune effects, safety and efficacy of two different doses of HS110 vaccine in combination with erlotinib versus erlotinib alone.

NCT01504542
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Biological: HS110 vaccine
  2. Biological: Placebo
  3. Biological: HS110 vaccine
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This multicenter, randomized, double-blind, placebo-controlled study will enroll patients with advanced NSCLC (squamous cell or non-squamous cell) without EGFR mutations (either L858R or 746-750 deletions) who have had progression or recurrence of their disease following at least one but no more than two prior regimens (adjuvant therapy excluded) of approved therapy that did not include immunomodulating or anti-EGFR targeted therapy for their disease. --- L858R ---

Primary Outcomes

Description: Immune response will be evalulated by ELISPOT assays and change will be assessed from baseline.

Measure: Immunologic Response (defined as production of IFNƴ from CD8+ T cells as evaluated by ELISPOT assay)

Time: Week 18

Secondary Outcomes

Description: Incidence and severity of adverse events, changes in laboratory measures, physical exams and evaluation of autoimmune phenomena.

Measure: Safety of the combination of HS110 vaccine and erlotinib

Time: Up to 1 year

Description: Patients will have a CT scan performed at baseline, Week 12 and Week 22 or at the end of study visit in the case of early termination from study. Investigators will assess the disease response using irRC for overall response, CR, PR, SD or PD.

Measure: Tumor assessment by immunologic response criteria (irRC)

Time: Baseline, Week 12 and Week 22

Description: Analysis via a semiautomated, epithelial cell adhesion molecule-based immunomagnetic technique.

Measure: Exploratory Immunologic endpoint - evaluation of circulating tumor cells

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

Description: Analysis of cell surfance molecules by flow cytometry

Measure: Exploratory immunologic endpoint - immune function

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

Description: Examination of protein expression utilizing western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA) or mass spectrometry

Measure: Exploratory immunologic endpoint - proteomic profile

Time: Baseline, Week 1, Week 2, Week 3, Week 4, Week 6, Week 9, Week 12 and Week 18

30 Multicenter, Randomized, Phase Ib/IIb Study to Evaluate the Efficacy and Tolerability of Gefitinib in Combination With Olaparib (AZD2281) Versus Gefitinib Alone, in Patients With EGFR Mutation Positive Advanced Non-small-cell Lung Cancer

This is a study of gefitinib plus olaparib gefitinib in combination with olaparib (AZD2281) versus gefitinib alone, in patients with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced non-small-cell lung cancer.

NCT01513174
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Gefitinib plus olaparib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Tumor tissue available (according to the criterion of the specimen-processing laboratory) for EGFR mutation assessment: to be included in the study patients should present at least one EGFR mutation (exon 19 deletion or L858R with or without T790M). --- L858R ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose) defined as the highest dose level at which < 2 out of 6 patients experience a DLT

Time: 5 weeks

Secondary Outcomes

Measure: Progression-free survival

Time: An expected average of 2 years

Measure: Overall response rate

Time: An expected average of 2 years

Measure: Overall survival

Time: An expected average of 2 years

Measure: Peak Plasma Concentration

Time: Predose, half an hour, 1, 2, 4, 6 and 12 hours post-dose

31 A Phase I Dose-Escalation Study of Erlotinib in Combination With Pralatrexate in Subjects With Advanced Cancer

The goal of this clinical research study is to find the highest tolerable dose of the combination of erlotinib and pralatrexate that can be given to patients with advanced cancer. The safety of the drug combination will also be studied. Pralatrexate is designed to block the body's ability to make folic acid, a protein that may help cancer tissue to develop and spread. Erlotinib hydrochloride is designed to block proteins that are thought to cause cancer cells to grow. Erlotinib may help slow the growth of tumors.

NCT01532011
Conditions
  1. Advanced Cancers
  2. Solid Tumors
Interventions
  1. Drug: Erlotinib
  2. Drug: Pralatrexate
MeSH:Neoplasms
HPO:Neoplasm

For the MTD expansion cohort, patients will be eligible if they meet one of the following criteria: I. Have an epidermal growth factor receptor (EGFR)-sensitive mutation (as G719C in exon 18, E746-A750 in exon 90, L858R in exon 21) and have been previously treated with EGFR inhibitor therapy but have subsequently developed resistance, OR II. --- G719C --- --- L858R ---

Primary Outcomes

Description: MTD defined by dose limiting toxicities (DLTs) that occur in the first cycle. DLT defined as any Grade 3 or 4 non-hematologic toxicity as defined in the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. Grade 4 hematologic toxicity lasting 2 weeks or longer despite supportive care. Grade 4 nausea or vomiting > 5 days despite maximum anti-nausea regimens, and any other Grade 3 non-hematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in NCI-CTCAE as attributable to therapy.

Measure: Maximum Tolerated Dose (MTD) of Erlotinib with Pralatrexate

Time: 8 weeks

Secondary Outcomes

Description: Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured in Hounsfield units (HU), by more than or equal to 15% (28).

Measure: Tumor Response

Time: 8 weeks

32 A Randomized Phase II Trial of Erlotinib Alone or in Combination With Bevacizumab in Patients With Non-Small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating patients with NSCLC.

NCT01532089
Conditions
  1. EGFR Exon 19 Deletion Mutation
  2. EGFR NP_005219.2:p.L858R
  3. Lung Non-Squamous Non-Small Cell Carcinoma
  4. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Bevacizumab
  2. Drug: Erlotinib
  3. Drug: Erlotinib Hydrochloride
  4. Other: Laboratory Biomarker Analysis
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

(CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).. Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R). --- L858R ---

Evaluated using time-dependent receiver operating characteristic curve and area under curve.. Inclusion Criteria: - Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. --- L858R ---

Genzyme, Response Genetics, etc); the laboratory report from the commercial laboratories report the specific mutations detected, and the method of detecting the exon 19 and exon 21 L858R point mutations must be available - Stage IV disease according to the 7th Edition of the American Joint Committee on Cancer staging system - Measurable disease - Life expectancy of >= 12 months - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 - Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 14 days prior to randomization - Platelet count >= 100,000/mm^3 obtained =< 14 days prior to randomization - Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to randomization - Total bilirubin =< 1.5 x upper limit of normal (ULN) obtained =< 14 days prior to randomization - Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or bone metastases obtained =< 14 days prior to randomization - Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x ULN obtained =< 14 days prior to randomization - Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0 obtained =< 14 days prior to randomization - Note: patients discovered to have >= 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate =< 1 g of protein in 24 hours - Negative pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only - Provide informed written consent - Willing to return to Academic and Community Cancer Research United (ACCRU) enrolling institution for follow-up - Willing to provide tissue and blood samples for correlative research purposes Exclusion Criteria: - Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component - Prior chemotherapy or treatment for metastatic non-small cell lung cancer - Any of the following: - Pregnant women - Nursing women - Men or women of childbearing potential who are unwilling to employ adequate contraception - Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens - Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive, per medical doctor (MD) discretion - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations, or any other medical condition that would limit compliance with study requirements - Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm - Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: non melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment (i.e. --- L858R ---

aortic aneurysm surgical repair or recent peripheral arterial thrombosis) =< 6 months prior to randomization - Radiotherapy to any site for any reason =< 14 days prior to randomization - Receiving any medications or substances that are strong or moderate inhibitors of CYP3A4; use of the following strong or moderate inhibitors are prohibited =< 7 days prior to randomization: - Strong inhibitors of CYP3A4: indinavir (Crixivan), nelfinavir (Viracept), atazanavir (Reyataz), ritonavir (Norvir), clarithromycin (Biaxin, Biaxin XL), itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), saquinavir (Fortovase, Invirase), telithromycin (Ketek) - Moderate inhibitors of CYP3A4: aprepitant (Emend), erythromycin (Erythrocin, E.E.S, Ery-Tab, Eryc, EryPed, PCE, fluconazole (Diflucan), grapefruit juice, verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM), diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Taztia XT, Tiazac) - Receiving any medications or substances that are strong or moderate inducers of CYP3A4; use of the following inducers are prohibited =< 7 days prior to randomization: efavirenz (Sustiva), nevirapine (Viramune), carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR), modafinil (Provigil), phenobarbital (Luminal), phenytoin (Dilantin, Phenytek), pioglitazone (Actos), rifabutin (Mycobutin), rifampin (Rifadin), St. John?s wort Inclusion Criteria: - Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. --- L858R ---

To investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R point mutations. --- L858R ---

Primary Outcomes

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Progression Free Survival (PFS)

Time: Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years

Secondary Outcomes

Description: Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Overall Survival

Time: Time from randomization to death of any causes, assessed up to 6 years

Description: The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).

Measure: Response Rate (Complete or Partial) to Each Treatment, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guidelines (Version 1.1)

Time: Up to 6 years

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator by mutation type.

Measure: Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R)

Time: From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years

Description: The number of patients experiencing toxicity defined as grade 3 or higher adverse events (using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) considered at least possibly related to treatment is reported below.

Measure: Number of Patients Experiencing Toxicity

Time: Up to 42 days after treatment discontinuation

Other Outcomes

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Plasma Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Tumor Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods

Time: Baseline

Description: Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: EGFR T790M Mutations

Time: Up to 6 years

Description: Evaluated using time-dependent receiver operating characteristic curve and area under curve.

Measure: Predictive Value of Plasma VEGF-A Levels on Progression Free Survival in Patients Treated With Erlotinib Hydrochloride Alone or in Combination With Bevacizumab

Time: Baseline

33 Randomized, Double-Blind, Multicenter, Phase 2 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Metastatic or Advanced Non-Small Cell Lung Cancer (NSCLC)

A Randomized, Double-Blind, Multicenter, Phase 2 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Metastatic or Advanced Non-Small-Cell Lung Cancer (NSCLC).

NCT01560104
Conditions
  1. Non-Small -Cell Lung Cancer
Interventions
  1. Drug: Veliparib
  2. Drug: Carboplatin
  3. Drug: paclitaxel
  4. Drug: placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Subjects with peripheral neuropathy ≥ grade 2. - Subjects with a known epidermal growth factor receptor (EGFR) mutation of exon 19 deletion or L858R mutation in exon 21. (Subjects with wild type epidermal growth factor receptor (EGFR), unknown status or other type of epidermal growth factor receptor (EGFR) mutation will be considered eligible). --- L858R ---

Primary Outcomes

Measure: Progression Free Survival (PFS)

Time: Radiographic evaluation starting from the third day of study treatment and on average every 6 weeks until documented progression or date of death from any cause, whichever came first, until patient is registered as off study.

Secondary Outcomes

Description: Continuously from date of randomization until date of death from any cause or until patient is registered as off study, whichever came first.

Measure: Overall Survival (OS)

Time: Monthly after patient is registered off study up to 36 months or until date of death from any cause, whichever came first.

Measure: Objective Response Rate (ORR)

Time: Radiographic evaluation starting from the third day of study treatment and on average every 6 weeks until documented progression or date of death from any cause, whichever came first, until patient is registered as off study.

Measure: Chemotherapy Induced Peripheral Neuropathy (CIPN)

Time: From date of screening, first day of study treatment and then every cycle (about every 3 weeks) until date of death from any cause or patient is registered as off study, whichever came first.

34 An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

NCT01562028
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

BELIEF (Bevacizumab and ErLotinib In EGFR Mut+ NSCLC) Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. --- L858R ---

- Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R) Exclusion Criteria: - Patients with increased risk of bleeding - Patients with clinically significant cardiovascular diseases - Patients with a history of thrombosis or thromboembolism in the 6 months prior to treatment - Patients with gastrointestinal problems - Patients with neurologic problems - Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. --- L858R ---

Primary Outcomes

Description: Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first. Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Progression Free Survival

Time: From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.

Secondary Outcomes

Description: Time from the date of enrollment until death from any cause.

Measure: Overall Survival

Time: From the date of enrollment until death, assessed up to 48 months.

Description: Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death.

Measure: Time to Treatment Failure

Time: From the date of enrollment until discontinuation of treatment, assessed up to 48 months.

Description: Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Objective Response

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Disease Control

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Duration of Response

Time: Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).

Description: Adverse events graded according to NCI CTCAE V4.

Measure: Adverse Events

Time: Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).

35 Randomized, Open Label, Positive Controlled, Multicenter Trial to Evaluate Icotinib as First-line and Maintenance Treatment in EGFR Mutated Patients With Lung Adenocarcinoma

This study is designed to compare the efficacy and safety of first-line icotinib treatment and first-line chemotherapy followed by maintenance treatment with icotinib.

NCT01665417
Conditions
  1. EGFR Positive Non-small Cell Lung Cancer
  2. Adenocarcinoma
Interventions
  1. Drug: Experimental
  2. Drug: Chemotherapy
  3. Drug: Chemotherapy
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Adverse events assessed by CTCAE4.0.. Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT); Patients must have previously untreated locally advanced or metastatic NSCLC; Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R). --- L858R ---

Exclusion Criteria: - Prior chemotherapy Prior treatment with gefitinib, erlotinib, or other drugs that target EGFR Patients must not be receiving any other investigational agents Any evidence of interstitial lung disease Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT); Patients must have previously untreated locally advanced or metastatic NSCLC; Patients must have lung cancer with a documented EGFR activating mutation (exon 19 deletion, L858R). --- L858R ---

Primary Outcomes

Description: PFS was defined as the time from the date of first dose of study medication to the date of first documentation of tumor progression or death due to any cause, whichever occurred first.

Measure: Progression-free survival

Time: 8 months

Secondary Outcomes

Description: OS was assessed via calculation of the time to death due to any cause from the date of randomization. A patient was censored at the last date they were known to be alive.

Measure: Overall survival

Time: 24 months

Description: TTP was defined as the time from the date of first dose of study medication to first documentation of objective tumor progression. If tumor progression data included more than 1 date, the first date was used. TTP (in weeks) was calculated as (first event date minus first dose date +1)/7. Kaplan-Meier method was used.

Measure: Time to Tumor Progression

Time: 8 months

Description: Number of Subjects With Overall Confirmed Objective Disease Response According to the Response Evaluation Criteria in Solid Tumors(RECIST)1.1.

Measure: Objective response rate

Time: 3 months

Description: Adverse events assessed by CTCAE4.0.

Measure: Number of participants with adverse events

Time: 24 months

36 Phase IIIb, Open-Label Study of Erlotinib (Tarceva®) Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Present Activating Mutations in the Tyrosine Kinase Domain of the Epidermal Growth Factor Receptor

This open-label, multi-center study will evaluate the progression-free survival and safety of erlotinib in participants with locally advanced or metastatic non-small cell lung cancer with activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Participants will receive daily oral doses of erlotinib until disease progression or unacceptable toxicity.

NCT01667562
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.. Percentage of Participants With Adverse Events. --- L858R ---

Primary Outcomes

Description: Kaplan Meier estimate of the median PFS was defined as the time at which half of the participants have progressed (progressive disease [PD]) based on RECIST tumor response criteria or died from any cause, whichever occurred first. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Patients who had not died or progressed at the time of the final analysis were censored at the date of last contact.

Measure: Progression-Free Survival as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v 1.1)

Time: Baseline until disease progression, or death, whichever occurs first (approximately up to 4 years and 9 months)

Secondary Outcomes

Description: Objective response (OR) was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of complete response (CR) and partial response (PR) four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Proportion of Participants With Objective Response as Assessed by RECIST v 1.1

Time: Baseline until disease progression, or death, whichever occurs first (approximately up to 4 years and 9 months)

Description: Disease control was defined as objective response or stable disease (SD) for at least 6 weeks. OR was based on criteria related to changes in size of target lesions according to modified RECIST. Target lesions were selected on the basis of their size (lesions with the longest diameter) as well as the feasibility of reproducible repeated measurements. OR was the sum of CR and PR four at least 4 weeks during treatment. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Proportion of Participants With Disease Control as Assessed by RECIST v 1.1

Time: Baseline until disease progression, or death, whichever occurs first (approximately up to 4 years and 9 months)

Description: Mutations in the EGFR included exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21.

Measure: Proportion of Participants With Epidermal Growth Factor Receptor (EGFR) Mutations

Time: Screening up to approximately 7 days

Description: An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

Measure: Percentage of Participants With Adverse Events

Time: Baseline up to approximately 4 years and 9 months

Description: The domains in the Quality of life score using the Functional Assessment of Cancer Therapy Lung (FACT-L) include physical, social/family, emotional, and functional well-being, and a lung cancer subscale include symptoms, cognitive function and regret of smoking. Minimum and maximum value of the scale is 0 and 4, respectively. Higher score indicate better health state.

Measure: Change From Baseline to End of Study in Quality of Life Score Using The Functional Assessment of Cancer Therapy Lung (FACT-L)

Time: Baseline and end of study (approximately 4 years and 9 months)

37 A Prospective, Open-labelled, Randomized, Multicenter Phase II Study to Evaluate Efficacy and Safety of Erlotinib vs NP Chemotherapy as Adjuvant Therapy in Post Radical Operation NSCLC Patients With EGFR19 or 21 Exon Mutation

This study is to compare 2-year Disease Free Survival Rate (DFSR) in post radical operation IIIA Non-Small Cell Lung Cancer (NSCLC) patients with Epidermal Growth Factor Receptor (EGFR) 19 or 21 exon mutation treated Erlotinib vs NP chemotherapy as adjuvant therapy.

NCT01683175
Conditions
  1. Non-small Cell Lung Cancer Stage III
Interventions
  1. Drug: Erlotinib
  2. Drug: cis-platinum
  3. Drug: Vinorelbine
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - IIIA NSCLC patients according to TMN-staging of Lung Staging Standard version 7 2009, confirmed by histopathology or cytology after radical operation, and having EGFR exon 19 deletion mutation or exon 21 L858R single base substitution; - Accept study adjuvant therapy within 6 weeks post radical operation; - ECOP PS 0-1; Life expectancy ≥12 weeks; - Hematology: absolute neutrophil count (ANC) ≥1.5×10^9/L; platelet count ≥100×10^9/L; hemoglobin concentration ≥ 9.0 g/dL (permit to maintain hematologic criteria by blood transfusion); - Liver Function: TBil ≤1.5xULN; ALT and AST ≤2.5xULN; - Renal Function: Cr ≤1.25xULN, and Ccr ≥60ml/min; - Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days before study treatment; - Signed inform consent form by patient or his/her legal representative; - Comply with study protocol and procedure, and be able to take oral medication; Aged ≥18 years and ≦75 years; - Eligible patients of reproductive potential (both sexes) must agree to use a reliable method of birth control before enrollment, during the study period and for at least 30 days after their last dose of study therapy; Exclusion Criteria: - Having treated by Her-Target therapy, i.e. erlotinib, gefitinib, cetuximab, trastuzumab; - Having treated by any systemic anti-tumor therapy of NSCLC, including cytotoxic therapy, target medication treatment (i.e. --- L858R ---

Primary Outcomes

Description: 2-year disease free survival rate is defined as the estimation percentage of disease free survival patients with study treatment at 2-year.

Measure: 2-year disease free survival rate (DFSR)

Time: 2 years

Secondary Outcomes

Description: Disease free survival is defined as the time from randomization to disease recurrence or death which comes first.

Measure: disease free survival

Time: 5 years

Description: Overall survival is defined as the time from randomization to death.

Measure: overall survival (OS)

Time: 5 years

Description: The score of Functional Assessment of Cancer Therapy - Lung (FACT-L) subscale and Lung Cancer Symptom Scale (LCSS)

Measure: Quality of Life

Time: 5 years

Description: frequency of Adverse Event

Measure: Adverse Event (AE)

Time: 5 years

Description: Frequency of Serious Adverse Event (SAE)

Measure: Serious Adverse Event (SAE)

Time: 5 years

38 Pilot Study to Identify the Mechanism of De Novo Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) in NSCLC With EGFR Mutation.

This study is based on the following hypothesis "De novo resistance to EGFR-TKI in EGFR mutation positive patients is related with mutations in EGFR downstream genes". Investigators will prospectively collect genomic DNA and clinical data regarding treatment outcomes to EGFR-TKI in NSCLC patients with activating EGFR mutations. Investigators will sequence candidate mutations of EGFR downstream genes and analyze c-met gene amplification and protein expression in PTEN, HGF, and IGFR. To identify genetic mutations, amplification, and protein over expression as predictive markers of treatment outcomes, investigators analyzed the association of treatment outcomes with the presence of genetic alteration or protein over expression. Investigators will attempt to identify biomarkers that are able to predict de novo resistance to EGFR-TKI in EGFR mutated NSCLC.

NCT01697163
Conditions
  1. NSCLC

Inclusion Criteria: 1. Pathologically proven unresectable NSCLC 2. 20 years of age or older 3. Planned treatment with Iressa® 4. Patients with activating EGFR mutation (del 19, L858R) 5. Available detailed smoking history 6. Available tissue samples (archival tissue) for mutational or molecular analysis (representative paraffin block or unstained sections from tumor diagnostic specimen are mandatory) 7. Available blood sample 8. --- L858R ---

Primary Outcomes

Description: The primary objective is to compare hazard rates of PFS in patients treated with Iressa between with and without any molecular aberrancy in EGFR-downstream genes/proteins.

Measure: hazard rates of PFS

Time: 1year

Other Outcomes

Description: Overall survival (OS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Disease control rate (DCR) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification) Progression-free survival (PFS) of EGFR-TKI according to each biomarker (i.e. PIK3CA, AKT, PTEN, and STK11 mutation and HGF, c-met, and IGFR amplification)

Measure: OS

Time: 2years

39 A Randomized Phase II Trial of Erlotinib, Cabozantinib, or Erlotinib Plus Cabozantinib as 2nd or 3rd Line Therapy in Patients With EGFR Wild-Type NSCLC

This randomized phase II trial studies how well giving erlotinib hydrochloride and cabozantinib-s-malate alone or in combination works as second or third line therapy in treating patient with stage IV non-small cell lung cancer. Erlotinib hydrochloride and cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving erlotinib hydrochloride together with cabozantinib-s-malate is more effective than erlotinib hydrochloride or cabozantinib-s-malate alone in treating non-small cell lung cancer.

NCT01708954
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Cabozantinib S-malate
  2. Drug: Erlotinib Hydrochloride
  3. Other: Laboratory Biomarker Analysis
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Criteria: - Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined as follows: - EGFR mutation testing of tumor has been performed and did not demonstrate an EGFR tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for EGFR exon 19 deletion and exon 21 L858R mutations must have been included; OR - EGFR mutation testing has been attempted and is inconclusive (for example, due to lack of sufficient deoxyribonucleic acid [DNA] yield); OR - EGFR mutation status is unknown but tumor is positive for at least one alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation, human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene (RET) rearrangement/fusion, or one not listed following approval by the study chair prior to registration Inclusion Criteria: - INCLUSION CRITERIA STEP 1: - Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC) - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer TNM classification system - Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation of all sites of disease must be obtained within 4 weeks prior to registration - Prior to registration, the investigator/site must confirm that sufficient pathology material representative of patient's cancer is available for submission for MET immunohistochemical (IHC) testing - Patients must have received one or two lines of prior chemotherapy (first line platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one line of therapy); prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the time frames specified in the protocol - Patients must have discontinued treatment with any other type of investigational agent >= 4 weeks prior to registration - Patients must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs) - Patients with no known brain metastasis at baseline must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases; patients with brain metastases at baseline must have baseline brain imagining within 4 weeks prior to study registration and meet all of the specific criteria for brain mets listed in the protocol - Radiation related toxicities must have resolved to =< grade 1 prior to registration - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 - Patients must have an anticipated life expectancy greater than 3 months - Acceptable bone marrow, renal and hepatic function within 2 weeks prior to registration as defined in the protocol - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - INCLUSION CRITERIA STEP 2: - Patients must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2 - Patients must have radiographic progressive disease per RECIST v1.1 criteria after >= 2 courses of therapy on Arm A or Arm B - Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1 - Patients must have an ECOG performance status between 0-2 - Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 <= grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs Exclusion Criteria: - EXCLUSION CRITERIA STEP 1: - Patients without sufficient pathology material representative of the patient's cancer (tumor block or 10 unstained slides) - Prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor therapy, Met tyrosine kinase inhibitor therapy, or Met monoclonal antibody (MetMAb); prior antibody therapy such as bevacizumab or cetuximab is allowed with a washout period depending on dosing interval and investigational nature - Prior radiation therapy to the thoracic cavity, abdomen, or pelvis within 3 months prior to registration, to bone or brain metastasis within 14 days prior to registration, or to any other site within 28 days prior to registration - History of the following: Clinically-significant gastrointestinal (GI) bleeding within 6 months prior to registration; Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to registration; Any other signs indicative of pulmonary hemorrhage within 3 months prior to registration - Radiographic or other evidence of the following within 28 days prior to registration: • Tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor; Cavitating pulmonary lesion(s); Tumor in contact with, invading or encasing any major blood vessels - Psychiatric illness/social situations that would limit compliance with study requirements - History of major thrombotic events (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months prior to registration - Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). --- L858R ---

(low dose aspirin [=< 81 mg/day] and prophylactic LMWH are permitted) - Concomitant treatment of strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort) - Cardiovascular disorders including: Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening; - Concurrent uncontrolled hypertension; Any history of congenital long QT syndrome; Any of the following within 6 months prior to registration: - Unstable angina pectoris - Clinically-significant cardiac arrhythmias - Stroke (including transient ischemic attack [TIA], or other ischemic event) - Myocardial infarction - GI disorders particularly those associated with a high risk of perforation or fistula formation specified in the protocol - Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to registration - Uncontrolled, significant, intercurrent or recent illness - Prior malignancy within 2 years prior to registration which required systemic treatment or is currently active - Pregnant or breast-feeding - Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral therapy - Known chronic active hepatitis B - EXCLUSION CRITERIA (STEP 2): - Intervening anticancer treatment or major surgical procedure(s) between Step 1 and Step 2, except palliative radiation to the bone finishing >= 2 weeks prior to registration to Step 2 - Central nervous system (CNS) progression; patients with stable CNS disease are allowed - Intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of erlotinib and cabozantinib Criteria: - Tumor with a sensitizing mutation in epidermal growth factor receptor (EGFR), defined as follows: - EGFR mutation testing of tumor has been performed and did not demonstrate an EGFR tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for EGFR exon 19 deletion and exon 21 L858R mutations must have been included; OR - EGFR mutation testing has been attempted and is inconclusive (for example, due to lack of sufficient deoxyribonucleic acid [DNA] yield); OR - EGFR mutation status is unknown but tumor is positive for at least one alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation, human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene (RET) rearrangement/fusion, or one not listed following approval by the study chair prior to registration Inclusion Criteria: - INCLUSION CRITERIA STEP 1: - Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC) - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer TNM classification system - Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation of all sites of disease must be obtained within 4 weeks prior to registration - Prior to registration, the investigator/site must confirm that sufficient pathology material representative of patient's cancer is available for submission for MET immunohistochemical (IHC) testing - Patients must have received one or two lines of prior chemotherapy (first line platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one line of therapy); prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the time frames specified in the protocol - Patients must have discontinued treatment with any other type of investigational agent >= 4 weeks prior to registration - Patients must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs) - Patients with no known brain metastasis at baseline must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases; patients with brain metastases at baseline must have baseline brain imagining within 4 weeks prior to study registration and meet all of the specific criteria for brain mets listed in the protocol - Radiation related toxicities must have resolved to =< grade 1 prior to registration - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 - Patients must have an anticipated life expectancy greater than 3 months - Acceptable bone marrow, renal and hepatic function within 2 weeks prior to registration as defined in the protocol - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - INCLUSION CRITERIA STEP 2: - Patients must have met all eligibility requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2 - Patients must have radiographic progressive disease per RECIST v1.1 criteria after >= 2 courses of therapy on Arm A or Arm B - Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1 - Patients must have an ECOG performance status between 0-2 - Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 <= grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs Exclusion Criteria: - EXCLUSION CRITERIA STEP 1: - Patients without sufficient pathology material representative of the patient's cancer (tumor block or 10 unstained slides) - Prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor therapy, Met tyrosine kinase inhibitor therapy, or Met monoclonal antibody (MetMAb); prior antibody therapy such as bevacizumab or cetuximab is allowed with a washout period depending on dosing interval and investigational nature - Prior radiation therapy to the thoracic cavity, abdomen, or pelvis within 3 months prior to registration, to bone or brain metastasis within 14 days prior to registration, or to any other site within 28 days prior to registration - History of the following: Clinically-significant gastrointestinal (GI) bleeding within 6 months prior to registration; Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to registration; Any other signs indicative of pulmonary hemorrhage within 3 months prior to registration - Radiographic or other evidence of the following within 28 days prior to registration: • Tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor; Cavitating pulmonary lesion(s); Tumor in contact with, invading or encasing any major blood vessels - Psychiatric illness/social situations that would limit compliance with study requirements - History of major thrombotic events (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months prior to registration - Concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from randomization to documented disease progression or death from any cause, whichever occurred first. Patients who had not experienced an event of interest by the time of analysis were censored at the date of last disease assessment.

Measure: Progression-free Survival (PFS)

Time: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years

Secondary Outcomes

Description: OS is defined as the time from randomization to death from any cause or date of last known alive.

Measure: Overall Survival (OS)

Time: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years

Description: Objective response is defined as complete response (CR) or partial response (PR) evaluated using RECIST v 1.1. CR is defined as disappearance of all lesions and any pathological lymph nodes must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions and persistence of one or more non-target lesion(s).

Measure: Proportion of Patients With Objective Response

Time: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry, up to 5 years

Description: Submission of archival tissue for central MET IHC testing was required for this study, and total MET IHC testing was conducted at the Brigham and Women's Hospital using the c-Met clone CVD13 (arabbit polyclonal). Membranous and cytoplasmic staining were individually scored, and positivity was declared if MET was expressed in either the membrane or cytoplasm.

Measure: Proportion of Patients With MET Positivity

Time: Assessed at baseline

Measure: Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher

Time: Assessed every 4 weeks while on treatment and for 30 days after the end of treatment

40 Observational Post-authorization Prospective Study to Characterize the Incidence of Epidermal Growth Factor Receptor (EGFR) Mutation Positive and Advanced Non-small Cell Lung Cancer Patients and Their Clinical Management in Galicia

The present study has been designed in order to characterize the incidence of patients with advanced non-small cell lung cancer (NSCLC) carrying epidermal growth factor receptor (EGFR) positive mutations and their clinical management in Galicia.

NCT01717105
Conditions
  1. Metastatic Non-Small-Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Type of epidermal growth factor receptor (EGFR) mutations: deletion in exon 19, point mutation at codon 858 (L858R) or other (only for EGFR M+ patients). --- L858R ---

Primary Outcomes

Measure: Number of patients with epidermal growth factor receptor (EGFR) positive mutation among advanced or metastatic non-small-cell lung cancer (NSCLC) patients in Galicia

Time: 10 months (recruitment period)

Secondary Outcomes

Measure: Epidermal growth factor receptor (EGFR) mutational status in tumor tissue (primary tumor or metastatic samples) and plasma samples at screening

Time: 1 day (Screening Visit)

Measure: Type of epidermal growth factor receptor (EGFR) mutations: deletion in exon 19, point mutation at codon 858 (L858R) or other (only for EGFR M+ patients)

Time: 1 day (Screening Visit)

Measure: Prescribed first line treatment (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: 1 day (First study visit)

Measure: Tumor response (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: From inclusion until disease progression, death or until 9 months from the inclusion of the last patient in the study have elapsed, whichever is earlier.

Measure: Disease control (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: From inclusion until the end of the study (9 months subsequent to the last patient's inclusion or until lost of follow-up)

Measure: Prescribed second-line treatment after progression (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: 1 day (Progression Visit)

Measure: Progression-free survival and overall survival (only for epidermal growth factor receptor (EGFR) M+ patients)

Time: 1 day (at the end of the study 9 months subsequent to the last patient's inclusion or until lost of follow-up

Measure: Epidermal growth factor receptor (EGFR) mutational status at disease progression in tumor tissue (primary tumor or metastatic samples) and plasma samples (only for EGFR M+ patients)

Time: 1 day (Progresion Visit)

41 Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) in Lung Adenocarcinoma Patients With Acquired Resistance to 1st Generation EGFR Tyrosine Kinase Inhibitors

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a 2nd line monotherapy agent in lung adenocarcinoma patients with acquired resistance to prior EGFR tyrosine kinase inhibitors (TKIs).

NCT01718847
Conditions
  1. Increased Drug Resistance
Interventions
  1. Drug: NOV120101 (Poziotinib)

Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R ---

Patients who cannot participate in this trial by investigator's judgment Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarinoma 3. Patients who have 1 or more than 1 measurable or evaluable but unmeasurable lesions according to RECIST ver1.1 4. Patients who received prior 1st generation EGFR TKIs (gefitinib or erlotinib) monotherapy and meet the following criteria: 1. Patients with EGFR mutation (e.g., G719X, exon 19 deletion, L858R, L861Q, etc) known to be associated with sensitivity to TKIs 2. Patients who showed objective clinical benefit from treatment with an EGFR TKI as defined by either: - Patients who showed complete (CR) or partial response (PR), or - Patients who maintained stable disease (SD) status ≥ 6 months 3. Patients who showed progressive disease (PD, RECIST ver1.1) while on continuous treatment with gefitinib or erlotinib within the last 30 days (However, patients whose progressive disease is limited in the brain cannot participate in this trial.) --- L858R ---

Primary Outcomes

Description: The length of time during and after medication or treatment during which the disease being treated (usually cancer) does not get worse.

Measure: Progression free survival (PFS)

Time: By 1 year after enrollment of the last subject

Secondary Outcomes

Description: The proportion of Patients maintaining progress-free status at 16 weeks

Measure: PFS rate at 16 weeks

Time: 16 weeks

Description: The proportion of patients with partial response or complete response at their best tumor treatment evaluation

Measure: Objective response rate (ORR)

Time: By 1 year after enrollment of the last subject

Description: The proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: By 1 year after enrollment of the last subject

Measure: Overall survival (OS)

Time: By 1 year after enrollment of the last subject

Measure: Time to progression (TTP)

Time: By 1 year after enrollment of the last subject

Measure: Time to objective response

Time: By 1 year after enrollment of the last subject

Measure: Duration of objective response

Time: By 1 year after enrollment of the last subject

Measure: Duration of disease control

Time: By 1 year after enrollment of the last subject

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: baseline and the end of treatment, by 1 year after enrollment of the last subject

Other Outcomes

Description: The study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a study drug. Certain patient demographic, pathophysiological, and therapeutical features, such as body weight, excretory and metabolic functions, and the presence of other therapies, can regularly alter dose-concentration relationships.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: By 3 months after enrollment of the last subject

Description: Subgroup analysis, in the context of design and analysis of study drug, refers to looking for pattern in a subset of the subjects according to genotype

Measure: Subgroup analyses with the genetic information

Time: by 1 year after enrollment of the last patient

42 A Phase Ⅱ Randomized Controlled Trial to Compare Chemotherapy Sequenced by EGFR-TKIs and Chemotherapy Combined With EGFR-TKIs for Advanced or Metastatic NSCLC Patients Failed to EGFR-TKIs Therapy

There are two different treatment modes for NSCLC patients who failed to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) after initially responding to EGFR-TKI. One is EGFR-TKI combined with chemotherapy and the other is chemotherapy followed by EGFR-TKI. It is unclear which one is more suitable to this group of lung cancer patients. So this phase Ⅱclinical trial is designed to compare the efficiency and safety of these two different treatment modes.

NCT01746277
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: combined group
  2. Drug: Sequenced group
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria(version3.0) (NCI-CTC).. Inclusion Criteria: - age ≥ 18 years - histologically and cytologically proven non-small cell bronchogenic carcinoma (sputum cytology alone was not acceptable) - clinical stages ⅢB or Ⅳ - recurrent or refractory disease following previous first-line chemotherapy regimens containing platinum and second-line EGFR-TKIs therapy - partial remission (PR) or stable disease (SD) at least for 6 months during previous EGFR-TKI treatment - at least one bidimensionally measurable or radiographically assessable lesion - Eastern cooperative oncology group performance status (ECOG PS) ≤ 2 - life expectancy ≥ 12 weeks - adequate hematological, renal, and hepatic functions Exclusion Criteria: - additional malignancies - uncontrolled systemic disease - any evidence of clinically active interstitial lung disease - newly diagnosed central nervous system (CNS) metastasis and not treated by radiotherapy or surgery - pregnancy or breast feeding phase Inclusion Criteria: - age ≥ 18 years - histologically and cytologically proven non-small cell bronchogenic carcinoma (sputum cytology alone was not acceptable) - clinical stages ⅢB or Ⅳ - recurrent or refractory disease following previous first-line chemotherapy regimens containing platinum and second-line EGFR-TKIs therapy - partial remission (PR) or stable disease (SD) at least for 6 months during previous EGFR-TKI treatment - at least one bidimensionally measurable or radiographically assessable lesion - Eastern cooperative oncology group performance status (ECOG PS) ≤ 2 - life expectancy ≥ 12 weeks - adequate hematological, renal, and hepatic functions Exclusion Criteria: - additional malignancies - uncontrolled systemic disease - any evidence of clinically active interstitial lung disease - newly diagnosed central nervous system (CNS) metastasis and not treated by radiotherapy or surgery - pregnancy or breast feeding phase Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Responses to EGFR-TKIs are quiet dramatic and durable, especially in patients with EGFR gene classic mutations, such as 19 deletion or 21 leucine 858 arginine(L858R). --- L858R ---

Primary Outcomes

Description: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 52 weeks.

Measure: progression free survival

Time: up to 52 weeks (about one year)

Secondary Outcomes

Description: From date of randomization until the date of death from any cause, assessed up to 100 weeks.

Measure: overall survival

Time: up to 100 weeks

Description: The objective response rate includes the complete remission and partial remission rate.

Measure: objective response rate

Time: up to 9 weeks

Description: FACL-L is assessed at different time points.(Date of randomization,1 week after chemotherapy,every cycle of chemotherapy,every month of EGFR-TKI maintain treatment,up to 100 weeks)

Measure: the score of functional assessment of cancer treatment-lung(FACT-L)

Time: up to 100weeks

Description: The adverse events are assessed by National Cancer Institute-Common Toxicity Criteria(version3.0) (NCI-CTC).

Measure: Number of participants with adverse events

Time: Participants will be followed for the duration of treatment, an expected average of 52 weeks.

43 Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of Simotinib Hydrochloride in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

The primary objective is to assess the safety and tolerability of multiple doses of Simotinib Hydrochloride in NSCLC patients. The secondary objective is to determine the pharmacokinetic (PK) profile and explore the preliminary anti-tumor activity.

NCT01772732
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Simotinib Hydrochloride
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC, who were previously treated with at least one platinum-based chemotherapy regimen, but had disease relapse; - Patients have ended their chemotherapy or radiotherapy at least 4 weeks prior to study entry and have recovered from any previous toxicity; - EGFR mutation positive (such as E19del, L858R, L861Q, G719X, etc.); - Patients with at least one measurable lesion meeting RECIST; - ECOG performance status 0-2; - Life expectancy ≥12 weeks; - Adequate bone marrow function: ANC ≥1.5 × 109/L, PLT≥80 ×109/L, HB ≥90 g/L; - Adequate hepatic function: serum bilirubin ≤ 2 × ULN, AST and ALT ≤ 2.5 × ULN, and ≤ 5 × ULN are acceptable if the liver has tumor involvement; - Adequate renal function: endogenous creatinine clearance rate (CrCl) ≥ 60 mL/min or serum creatinine ≤ 1.5 × ULN; - Females with childbearing potential must have a negative pregnancy test within 7 days prior to treatment and use an approved contraceptive method during the study; - Males must be surgically sterile or use an approved contraceptive method during the study. --- L858R ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD)

Time: 28 days

Secondary Outcomes

Measure: The maximum plasma concentration (Cmax)

Time: d1,d8,d9,d10,d15

Measure: The time to Cmax (tmax)

Time: d1,d8,d9,d10,d15

Measure: Area under the plasma concentration-time curve (AUC)

Time: d1,d8,d9,d10,d15

Measure: Overall Response Rate (ORR)

Time: 1 year

Measure: Progression-free Survival (PFS)

Time: 1 year

44 ARCHER 1050: A Randomized, Open-Label Phase 3 Efficacy and Safety Study Of Dacomitinib (PF-00299804) Vs. Gefitinib For The First-Line Treatment Of Locally Advanced or Metastatic NSCLC In Subjects With EGFR-Activating Mutations

This is a multinational, multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of treatment with dacomitinib (PF-00299804) to treatment with gefitinib in patients with locally advanced or metastatic non-small cell lung cancer, with epidermal growth factor receptor EGFR-activating mutation (s). Analyses of primary objective (Progression Free Survival) will be done as defined in the protocol.

NCT01774721
Conditions
  1. Non-small Cell Lung Cancer With EGFR-Activating Mutations
Interventions
  1. Drug: Dacomitinib (PF-00299804)
  2. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration).. Inclusion Criteria: - Evidence of histo or cytopathology confirmed, advanced NSCLC (with known histology) with the presence of EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21). --- L858R ---

- It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study - Minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC - Adequate tissue sample must be available for central analyses. --- T790M --- --- L858R ---

- Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R ---

Inclusion Criteria: - Evidence of histo or cytopathology confirmed, advanced NSCLC (with known histology) with the presence of EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21). --- L858R ---

Primary Outcomes

Description: PFS: time from randomization to date of progression of disease (PD) as determined by IRC review as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Secondary Outcomes

Description: PFS: time from randomization to date of PD as determined by investigator assessment as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: Number of participants with BOR based on IRC review(complete response[CR] or confirmed partial response[PR]) was recorded from randomization until disease progression based on RECISTv1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Number of participants with BOR based on investigator assessment (CR or confirmed PR) was recorded from randomization until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on IRC review recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on investigator assessment recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: DoR was defined as time from first documentation of objective response(CR or PR, whichever occurred first)to date of PD or death from any cause, whichever occurred first. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter used in sum for target nodes, longest diameter used in sum for all other target lesions. PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed(over baseline if no decrease in sum is observed),with a minimum absolute increase of 5 mm. DoR was recorded based on IRC review and investigator's assessment.

Measure: Duration of Response (DoR)

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to 28-35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non- serious adverse events.

Measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Laboratory parameters included haematological and biochemistry parameters. Haematology parameters included anaemia, activated partial thromboplastin time, haemoglobin, international normalized ratio, lymphocyte count, lymphopenia, neutrophils (absolute), platelets, prothrombin time and white blood cells. Biochemistry parameters included alanine aminotransferase (increased), alkaline phosphatase (increased), aspartate aminotransferase (increased), bilirubin (total), creatinine (increased), hypercalcaemia, hyperglycaemia, hyperkalaemia, hypermagnesaemia, hypernatraemia, hypoalbuminaemia, hypocalcaemia, hypoglycaemia, hypokalaemia, hypomagnesaemia, hyponatraemia. Test abnormalities were graded by AEs according to the Common Terminology Criteria for Adverse Events(NCI CTCAE) version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Urinalysis parameter included urine protein, urine blood/haemoglobin, urine glucose and urine sediment. Test abnormalities was defined as deviation from normal range (higher or lower). Normal range of 24-hour urine protein test: less than 150 mg of protein per day, urine glucose: 0 to 0.8 mmol/L (millimole per liter), urine protein: 0 to 20 mg/dL (milligrams per deciliter). Urine blood/haemoglobin abnormality was defined as presence and absence of blood/haemoglobin in urine of participants. Urine sediment abnormality was defined as the presence of any bacteria, casts, crystals, and epithelial cells. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities: Urinalysis

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Criteria for vital signs abnormalities: systolic pulse rate less than (<) 50 beats per minute (bpm) or greater than (>)130 bpm and maximum increase or decrease from baseline in pulse rate of 30 bpm. Systolic blood pressure of maximum increase from baseline (MIB) >=40 millimeters of mercury (mmHg), maximum decrease from baseline (MDB) in systolic blood pressure =<60 mmHg. Diastolic blood pressure of MIB >=20 mmHg and MDB in diastolic blood pressure >40 and =<20 mm Hg. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: ECG parameters included corrected QT interval using Bazett's formula (QTcB) and corrected QT interval using Fridericia's formula (QTcF). ECG criteria for abnormality: absolute value 450 - <480 msec, 480 - <500 msec >=500. The number of participants with potentially clinically significant ECG findings at any visit were reported.

Measure: Number of Participants With Clinically Significant Abnormality in Electrocardiogram (ECG)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: An ejection fraction (EF) was the volumetric fraction of blood ejected from a ventricle of the heart with each heartbeat; it was a measure of the pumping efficiency of the heart. The EF of the left heart, known as the left ventricular ejection fraction, was a measure of the efficiency of pumping into the body's systemic circulation.

Measure: Number of Participants With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

Time: From baseline up to 7 days of Cycle 4 (up to 91 days)

Description: HRQOL was measured by standardized questionnaires (European Organization for Research and Treatment of Cancer (EORTC)) quality of life questionnaires (OLQ-C30) and its lung cancer module (QLQ-LC13). TTD in pain (chest, arm/shoulder), dyspnea, fatigue or cough was defined as time between baseline and first occurrence of increase in score of 10 points or greater from baseline in any of these 4 symptoms for at least two consecutive cycles. For those who had not shown deterioration, the data was censored at the last date when the participants completed an assessment for pain, dyspnea, fatigue or cough.

Measure: Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

Time: Baseline until the end of treatment (up to 48 months)

Description: The Euro Quality of Life-5 dimension (EQ-5D) is a brief self-administered, validated reliable generic health status instrument. EQ-5D general health status can also be measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Measure: Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

Time: From Cycle 1 to 41 (up to 48 months)

Measure: Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Fluctuation coefficient between trough and peak plasma concentration was determined as Cmax-Ctrough divided by Cavg, where Cmax was the maximum observed concentration within the dosing interval, Ctrough was the observed concentration prior to dose administration and Cavg was averaged plasma concentration at steady state.

Measure: Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes).

Measure: Apparent Clearance (CL) of Dacomitinib

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration).

Measure: Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose on Day 1 of Cycle 2, 3, 4, 5 and 6

45 Efficacy of EGFR Tyrosine Kinase Inhibitors (EGFR TKIs) in Patients With EGFR-mutated Non-small Cell Lung Cancer Except Both Exon 19 Deletion and Exon 21 L859R: A Retrospective Analysis

Lung cancer is the leading cause of cancer-related death worldwide and is well known to remain a major health problem. Non-small-cell lung cancer (NSCLC) constitutes more than 80% of all the cases of lung cancer. Today, NSCLC can be defined by various molecular criteria. Especially, somatic mutations within the epidermal growth factor receptor (EGFR) gene itself were discovered in a subset of NSCLC patients. Two activating EGFR mutations are in-frame deletion in exon 19 and the substitutions for L858R in exon 21, which account for 85% of all clinically important mutations related to EGFR TKI sensitivity. Besides two activating EGFR mutations, other EGFR mutations in NSCLC have been discovered. G719 and L861 are reported to have intermediate sensitivity to EGFR TKI. And in-frame insertions within exon 20 and T790, which are known to be resistant to EGFR TKIs. However, there are still other EGFR mutations such as E709 and S768 as well as doublet EGFR mutations are also observed. These rare mutations have not been fully described and data on their correlation with response to EGFR-TKIs are still unclear. Research hypothesis Rare EGFR mutations of unknown clinical significance in NSCLC patients, which are distinguish from mutations such as deletion in exon 19, L858 and insertion in exon 20, have some possibility of EGFR TKI sensitivity. Rationale for conducting this study It has an opportunity to be shown the efficacy of EGFR TKIs in patients with rare EGFR mutation in large number of patients in Korea (Asia) during the short period.

NCT01775943
Conditions
  1. Lung Neoplasms
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Two activating EGFR mutations are in-frame deletion in exon 19 and the substitutions for L858R in exon 21, which account for 85% of all clinically important mutations related to EGFR TKI sensitivity. --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R --- --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R --- --- L858R --- --- L858R ---

Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Inclusion Criteria: 1. Histological confirmed non-small cell lung cancer (NSCLC), Stage IIIB or stage IV, between January 1, 2008 to December 31, 2011 2. Confirmed EGFR rare mutations (EGFR mutation except both exon 19 deletion and exon 21 L858R) using direct DNA sequencing 3. Experiences of treatment with EGFR TKIs. 4. at least one measurable and/or evaluable lesion according to RECIST criteria (version 1.1) Exclusion Criteria:Subjects should not enter the study if any of the following exclusion criteria are fulfilled: EGFR wild type, EGFR exon 19 deletion alone, EGFR L858R alone Lung Neoplasms Lung Neoplasms null --- L858R --- --- L858R --- --- L858R --- --- L858R ---

Primary Outcomes

Measure: the efficacy of EGFR TKIs as defined by objective response rate

Time: up to 1 year

Secondary Outcomes

Measure: the incidence of patients with rare EGFR mutated NSCLC

Time: up to 1 year

Other Outcomes

Measure: the clinical characteristics of patients with rare EGFR mutated NSCLC

Time: up to 1 year

Measure: the efficacy of EGFR TKIs as defined by disease control rate, progression-free survival and overall survival in the patients with rare EGFR mutated NSCLC

Time: up to 1 year

46 Detection of Resistance Genes From Serially Collected Plasma DNA in Non-small Cell Lung Cancer Patients Harboring EGFR Activating Mutation Who Are Being Treated With EGFR TKIs

To detect resistance gene from serially collected plasma DNA in non-small cell lung cancer harbouring EGFR activating mutation who are being treated with EGFR TKIs by using castPCR method.

NCT01776684
Conditions
  1. EGFR Mutation Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: EGFR TKIs (gefitinib, erlotinib, afatinib, et al)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding EGFR Mutation Positive Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding Inclusion Criteria: - 1. Histologically confirmed NSCLC 2. Aged of or older than 20 years 3. ECOG performance status 0-2 4. Adequate hematological, renal, hepatic function 5. Patients with tumors harboring EGFR mutation (del 19 or L858R mutation) 6. Patient who are about to be treated with EGFR TKI (gefitinib, erlotinib or other EGFR TKI) 7. At least more than one measurable disease 8. Informed consent Exclusion Criteria: - 1. Active infection 2. Active bleeding EGFR Mutation Positive Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L858R ---

Primary Outcomes

Description: To evaluate the efficiency of castPCR method for detection of resistance genes, especially, T790M mutation from serially collected plasma DNA in non-small cell lung cancer patients harboring EGFR activating mutation who are being treated with EGFR TKIs

Measure: detection of resistant gene

Time: 24 months

47 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.

NCT01802632
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Advanced (Inoperable) Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients (with the exception of 1st line expansion cohort) must fulfil one of the following: - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR - Must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (Jackman et al 2010) followed by systemic objective progression (RECIST or WHO) while on continuous treatment with EGFR TKI. - Previous treatment with a single-agent EGFR TKI (e.g. --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for Dose Escalation Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for 80mg AZD9291 Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

48 A Prospective, Open-label, Single Arm, Multi-center, Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) as the First-line Treatment Medication in Patients With Harboring EGFR Mutations

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation.

NCT01819428
Conditions
  1. Adenocarcinoma of Lung Stage IIIB
  2. Adenocarcinoma of Lung Stage IV
Interventions
  1. Drug: NOV120101 (Poziotinib)
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarcinoma 3. Documented EGFR mutation (e.g., exon 19 deletion, exon 21 L858R, etc.) with tumor tissue 4. Patients who have 1 or more measurable lesions according to RECIST version 1.1 5. ECOG performance status 2 or less 6. --- L858R ---

Patients who cannot participate in this trial by investigator's judgment Inclusion Criteria: 1. Male or female patients aged 20 years or older 2. Pathologically confirmed stage IIIB (unresectable) or IV lung adenocarcinoma 3. Documented EGFR mutation (e.g., exon 19 deletion, exon 21 L858R, etc.) with tumor tissue 4. Patients who have 1 or more measurable lesions according to RECIST version 1.1 5. ECOG performance status 2 or less 6. --- L858R ---

Primary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR)

Measure: Objective response rate (ORR)

Time: about 3 years

Secondary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR) at 12 months following start of study drug administration.

Measure: Progression free survival (PFS) rate at 12 months

Time: 12 months after enrollment of the last subject

Description: the proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: 3 years

Description: The length of time during and after medication or treatment during which the disease being treated (usually cnacer) does not get worse.

Measure: Progression free survival (PFS)

Time: 3 years

Description: the time from study drug administration until death from any cause

Measure: Overall survival (OS)

Time: 3 years

Description: Change means the end of treatment minus baseline in each patient

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: 3 years

Other Outcomes

Description: to observe pharmacokinetic parameter, inter-individual variability and intra-individual variability considering covariates, demographic factors, influencing PK profile.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: 3 months after enrollment of the last subject

Description: to observe HGF expression status in plasma and T790M mutation induction status from plasma DNA

Measure: Subgroup analyses according to the genetic information

Time: 3 years

49 A Phase Ib Study of Afatinib Plus Nimotuzumab in Non-small Cell Lung Cancer Patients Who Progressed With Reversible EGFR TKI

To find the optimal dose of afatinib and nimotuzumab in patients who acquired resistance to gefitinib or erlotinib.

NCT01861223
Conditions
  1. NSCLC
Interventions
  1. Drug: afatinib (30 or 40mg) + nimotuzumab (100 or 200mg)

Inclusion Criteria: - Histologically confirmed diagnosis of stage IIIB or IV NSCLC - Presence of EGFR sensitizing mutations (L858R mutation in exon 21 or exon 19 deletion) or response by RECIST on prior gefitinib or erlotinib or stable disease on prior gefitinib or erlotinib for at least 6 months - Disease progression on treatemtn with gefitinib or erlotinib within 30 days - Biopsy on disease progression - Age ≥20 years - ECOG performance status of 0, 1, or 2 - Measurable disease by the criteria of RECIST 1.1 - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL; creatinine clearance ≥ 45 mL/min Exclusion Criteria: - Known interstitial lung disease - Prior treatment with EGFR targeting antibodies or BIBW 2992 - Prior three or more lines of chemotherapy for advanced NSCLC - Significant bowel disease impairing drug absorption - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Have symptomatic, untreated, or uncontrolled central nervous system (CNS) metastases. --- L858R ---

Primary Outcomes

Description: To establish maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) for BIBW 2992 and nimotuzumab in patients with acquired resistance to erlotinib or gefitinib

Measure: Maximal tolerated dose

Time: 4 weeks

50 A Randomized, Controlled Phase 2 Study Evaluating LY2875358 Plus Erlotinib Versus Erlotinib as First-Line Treatment in Metastatic Non-Small Cell Lung Cancer Patients With Activating EGFR Mutations Who Have Disease Control After an 8-Week Lead-In Treatment With Erlotinib

The primary purpose of this study is to compare the efficacy of the study drug LY2875358, given together with erlotinib, against erlotinib, alone. Participants will have Non-Small Cell Lung Cancer (NSCLC) that has advanced to Stage IV. Participants should not have been treated with drugs for Stage IV NSCLC, previously. All participants will get erlotinib alone, for approximately 8 weeks. Participants with radiographic disease control at the end of the erlotinib lead-in study period will be randomly assigned to receive LY2875358 plus erlotinib or erlotinib alone. Participants, who were chosen to receive erlotinib, alone, may cross over to the combination treatment at the time of progression.

NCT01897480
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Biological: LY2875358
  2. Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of metastatic Stage IV NSCLC - Have at least 1 measurable lesion whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) - Have molecular evidence of an epidermal growth factor receptor mutation (EGFRmt) known to be associated with EGFR tyrosine kinase inhibitor (TKI) drug sensitivity (G719X, exon 19 deletion, L858R, L861Q) - Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 - Haven't received any prior systemic chemotherapy for Stage IV NSCLC (unless received as neoadjuvant or adjuvant therapy for early-stage NSCLC disease and completed therapy at least 6 months prior to enrollment) - Availability of adequate tumor material (block or slides) Exclusion Criteria: - Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device - Have previously completed or withdrawn from this study or any other study investigating LY2875358 - Have a serious concomitant systemic disorder or significant cardiac disease - Have interstitial pneumonia or interstitial fibrosis of the lung or have pleural effusion, pericardial fluids or ascites, requiring drainage every other week or more frequently - Have a history of another malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to the study - Have major surgery less than 2 weeks prior to the initiation of study treatment therapy - Pregnant or lactating women Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- L858R ---

Primary Outcomes

Measure: Progression Free Survival (PFS)

Time: Randomization to Objective Disease Progression or Death Due to Any Cause (Estimated 3 Years)

Secondary Outcomes

Measure: Change in Tumor Size (CTS)

Time: Baseline to Measurement with Smallest Tumor Size (Estimated 3 Years)

Measure: Proportion of Participants Exhibiting a Confirmed Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR])

Time: Baseline to Objective Disease Progression or Start of New Anticancer Therapy (Estimated 3 Years)

Measure: Duration of Response (DoR)

Time: Date of CR or PR to Date of Objective Disease Progression or Death Due to Any Cause (Estimated 3 Years)

Measure: Time to Progressive Disease (TTPD)

Time: Randomization to Objective Disease Progression (Estimated 3 Years)

Measure: Proportion of Participants Exhibiting a Stable Disease (SD) or a confirmed CR or PR (Disease Control Rate [DCR])

Time: Baseline to Objective Disease Progression or Participant Stops Study (Estimated 3 Years)

Measure: Overall Survival (OS)

Time: Randomization to Death Due to Any Cause (Estimated 5 Years)

Measure: Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ) C30 (QLQ-C30) and Lung Cancer 13 (QLQ-LC13)

Time: Baseline, Objective Disease Progression or Participants Stops Study (Estimated 3 Years)

Measure: Pharmacokinetics (PK): Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) of LY2875358 and Erlotinib

Time: Baseline through Cycle 4 (28 Day Cycle)

Measure: Proportion of Participants with Anti-LY2875358 Antibody Response

Time: Baseline through 30 Day Follow Up (Estimated 3 Years)

51 Phase I Study of INC280 Plus Erlotinib in Patients With C-Met Expressing Non-Small Cell Lung Cancer

This phase I trial studies the side effects and best dose of c-Met inhibitor INCB028060 and erlotinib hydrochloride when given together in treating patients with previously treated non-small cell lung cancer. C-Met inhibitor INCB028060 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01911507
Conditions
  1. Recurrent Non-small Cell Lung Cancer
Interventions
  1. Drug: INC280
  2. Drug: erlotinib hydrochloride
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

G719X, exon 19 deletion, L858R, L861Q) - Systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] or World Health Organization [WHO]) while on continuous treatment with gefitinib or erlotinib - Patients must have measurable disease; disease in previously irradiated sites is considered measurable if there is clear disease progression following radiation therapy - Failed 1-2 prior chemotherapies for advanced disease; prior erlotinib is allowed in the dose finding phase and expansion cohort A (Patients in expansion cohort B must be erlotinib naïve and have v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS] wild type tumor) - Patients must be willing to be off therapy for a minimum of two weeks (In expansion cohort A patients on erlotinib do not have to discontinue treatment) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Life expectancy greater than 3 months - Hemoglobin > 9 g/dL (International System [SI] units: 90 g/L) without transfusion support or growth factors within 10 days of starting INC280 - Platelet count >= 75 x 10^9/L - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L without growth factor support - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) - Serum creatinine =< 2 x ULN - Serum amylase =< ULN - Serum lipase =< ULN - Fasting serum triglyceride level =< 500 mg/dL Exclusion Criteria: - Patients who have had major surgery within 4 weeks of initiation of study medication, excluding the placement of vascular access - Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data - Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia - Severely impaired lung function - Active (acute or chronic) or uncontrolled infection - Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy - Liver disease (i.e. --- L858R ---

Primary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Maximum tolerated dose (MTD) of c-Met inhibitor INCB028060 and erlotinib, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V4

Time: Up to 28 days after a full course of therapy

Secondary Outcomes

Description: The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by nadir or maximum values for the laboratory measures), time of onset (i.e. course number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by course. Baseline information (e.g. the extent of prior therapy) and demographic information will be presented.

Measure: Toxicities as measured by NCI CTCAE V4

Time: Up to 30 days

Description: Response rate among patients with measurable disease will be summarized by exact binomial confidence intervals.

Measure: Overall response rate among patients with measurable disease, measured by RECIST 1.1

Time: Up to 30 days

Measure: Disease control rate, measured by RECIST 1.1

Time: Up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Progression-free survival

Time: Duration of time from start of treatment to time of progression or death, assessed up to 30 days

Description: Summarized with Kaplan-Meier plots. Median time to progression will be estimated using standard life table methods.

Measure: Overall survival

Time: Duration of time from the start of treatment to death from any cause, assessed up to 30 days

Measure: Concentrations of c-Met inhibitor INCB028060 in plasma, measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay

Time: Days 15-16 of course 1, days 1 and 15 of course 2, and day 1 of courses 3-4

52 A Randomized Open-Label Phase II Trial of Pemetrexed and a Platinum (Carboplatin or Cisplatin) With or Without Erlotinib in Patients With Non-Small Cell Lung Cancer Harboring Activating Epidermal Growth Factor Receptor Mutations and Acquired Resistance to First-Line EGFR TKIs, Erlotinib or Gefitinib

This randomized phase II trial studies how well pemetrexed disodium and carboplatin or cisplatin with or without erlotinib hydrochloride work in treating patients with epidermal growth factor receptor (EGFR) mutant positive stage IV non-small cell lung cancer and acquired resistance to first-line therapy with erlotinib hydrochloride or gefitinib. In patients that develop resistance to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs) the drug is usually stopped and the patient is switched to chemotherapy. Drugs used in chemotherapy, such as pemetrexed disodium, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pemetrexed disodium and carboplatin or cisplatin is more effective with or without erlotinib hydrochloride in treating patients with EGFR mutant non-small cell lung cancer and acquired resistance to EGFR TKIs.

NCT01928160
Conditions
  1. Recurrent Non-small Cell Lung Cancer
  2. Stage IV Non-small Cell Lung Cancer
Interventions
  1. Drug: pemetrexed disodium
  2. Drug: carboplatin
  3. Drug: cisplatin
  4. Drug: erlotinib hydrochloride
  5. Other: laboratory biomarker analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Age > 18 years - Able and willing to comply with the protocol - Histologically- or cytologically-confirmed Stage IV NSCLC with an EGFR exon-19 deletion or L858R mutation - Must have received at least 6 months of first-line therapy with erlotinib or gefitinib - Clinical evidence of progression on first-line EGFR TKI therapy - Adequate hematological function within 7 days of study treatment initiation: 1. Absolute neutrophil count (ANC) > 1.5 x 109/L AND 2. Platelet count > 100 x 109/L AND 3. Hemoglobin > 9 g/dL (may be transfused to maintain or exceed this level) - Adequate liver function within 7 days of study treatment initiation: 1. --- L858R ---

Primary Outcomes

Description: The Kaplan-Meier approach will be used to estimate the time-to-PFS distribution (and median PFS times) for each treatment arm. The stratified log-rank test will be used to compare the PFS distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Progression free survival using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

Time: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs earlier, assessed up to 1 year

Secondary Outcomes

Description: The Kaplan-Meier approach will be used. The stratified log-rank test will be used to compare the Overall Survival (OS) distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Overall survival

Time: From the date of randomization to the date of death from any cause, assessed up to 1 year

Description: An estimate of the objective response rate and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment arm. The Mantel-Haenszel chi-squared test stratified according to the factors specified by EGFR activating mutation type (exon 19 deletion vs. exon 21 single point mutation), time to progression on first-line EGFR TKI (≤ 1 year vs. > 1 year), and ECOG performance status (0 vs. 1) will be used to compare the response rates between the two treatment arms. An unadjusted Fisher's exact test result will also be provided.

Measure: Objective response rate defined as partial response (PR) and complete response (CR) using RECIST version 1.1

Time: Up to 1 year

Description: Safety will be assessed through summaries of Adverse Events (AEs), Serious Adverse Events (SAEs), deaths, grade 3 or 4 AEs, AEs with incidence rates greater than 10% (all grades), AE of grade 3 or 4 with incidence rates greater 2%, and changes in laboratory test results. Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms

Measure: Number of patients with each worst grade toxicity grades 3-5 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4

Time: Up to 45 days post-treatment

53 Third-line Treatment of Gefitinib in NSCLC Patients Who Had Received First-line Gefitinib With EGFR 19del/L858R Mutation and Tumor Progression After the Second-line Chemotherapy: a Single-arm, Prospective and Multi-center Study

The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy

NCT01933347
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Third-line Treatment of Gefitinib in NSCLC Patients Who Had Received First-line Gefitinib With EGFR 19del/L858R Mutation and Tumor Progression After the Second-line Chemotherapy: a Single-arm, Prospective and Multi-center Study. --- L858R ---

Third-line Treatment of Gefitinib in NSCLC Patients The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy Disease Control Rate (DCR). --- L858R ---

Third-line Treatment of Gefitinib in NSCLC Patients The purpose of this study is to evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy Disease Control Rate (DCR). --- L858R --- --- L858R ---

2. Male or female aged 18 years or older; 3. Subjects were diagnosed with stage IIIB or IV NSCLC before starting the first dose of gefitinib third-line treatment; 4. EGFR exon 19 deletion or exon 21 L858R substitution mutation confirmed; 5. ECOG performance status 0-2; 6. Life expectancy of at least 12 weeks or longer; 7. Has at least one measureable lesion by RECIST 1.1; 8. NSCLC of enrolled subjects previously progressed after first-line gefitinib treatment (PFS ≥ 6 months) and progressed again after second-line chemotherapy (not limited for chemotherapy regimen, ≥ 4 cycles of chemotherapy). --- L858R ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung - Primary Study Objective: To evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy - Secondary Study Objectives: To evaluate objective response rate (ORR), progressive-free survival (PFS), overall survival(OS) and quality of life (QoL) of gefitinib as third-line retreatment in NSCLC patients To evaluate the safety of gefitinib as third-line treatment in NSCLC patients - Exploratory analyses: To dynamically monitor EGFR mutation status and explore the relationship with clinical outcome --- L858R ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung - Primary Study Objective: To evaluate the disease control rate (DCR) of gefitinib as third-line retreatment in stage IIIB/IV NSCLC with EGFR 19del/L858R positive mutation patients who had benefited from first-line gefitinib treatment with EGFR 19del/L858R positive mutation and tumor progression after the second-line chemotherapy - Secondary Study Objectives: To evaluate objective response rate (ORR), progressive-free survival (PFS), overall survival(OS) and quality of life (QoL) of gefitinib as third-line retreatment in NSCLC patients To evaluate the safety of gefitinib as third-line treatment in NSCLC patients - Exploratory analyses: To dynamically monitor EGFR mutation status and explore the relationship with clinical outcome --- L858R --- --- L858R ---

Primary Outcomes

Measure: Disease Control Rate (DCR)

Time: week 8

Secondary Outcomes

Measure: objective response rate (ORR), progressive-free survival (PFS), overall survival(OS)

Time: until the death of last subject or 2 years after enrollment

54 A Single-arm Phase II Study to Determine the Efficacy of Preemptive Local Ablative Therapy to Residual Metabolic Active Oligo-metastases in Those EGFR Mutation Positive Non-small Cell Lung Cancer Patients Who Have Achieved a Good Partial Response With First-line EGFR TKI (ATOM)

To determine the efficacy of preemptive local ablative therapy in NSCLC patients with activating EGFR mutation who have oligometastatic residual metabolic-active disease after first-line EGFR TKI, as measured by PFS rate at 1 year from the trial enrollment.

NCT01941654
Conditions
  1. NSCLC
  2. Activating EGFR Mutation
Interventions
  1. Radiation: preemptive local ablative therapy
  2. Drug: Oral TKI

Inclusion Criteria: 1. Pathologically confirmed UICC 7th edition Stage IIIB (not amenable for curative intent local radiotherapy)/IV (metastatic or recurrent) non-small cell carcinoma of lung 2. Documented activating EGFR mutation (exon 19 deletion or exon 21 L858R only) in tumor tissues 3. Treated with first-line EGFR TKI for 3 months and achieved good radiological partial response that was documented with a CT scan 4. --- L858R ---

Non-compliance to the study procedure Inclusion Criteria: 1. Pathologically confirmed UICC 7th edition Stage IIIB (not amenable for curative intent local radiotherapy)/IV (metastatic or recurrent) non-small cell carcinoma of lung 2. Documented activating EGFR mutation (exon 19 deletion or exon 21 L858R only) in tumor tissues 3. Treated with first-line EGFR TKI for 3 months and achieved good radiological partial response that was documented with a CT scan 4. --- L858R ---

Primary Outcomes

Measure: PFS rate at 1 year

Time: 2 years

Secondary Outcomes

Measure: Overall survival

Time: 2 years

Measure: Progression-free survival

Time: 2 years

Measure: radiologic change on PET-CT scan 3 months after SABR

Time: 3 months

Measure: Number of Participants with Adverse Events as a Measure of safety

Time: 2 years

55 A Randomized, Open-label Phase II Trial of Erlotinib 100mg Daily Versus Gefitinib 250mg Daily in Patients With Advanced Non-small Cell Lung Cancer Who Harbor EGFR Mutations.

This study is a multicenter, randomized, open-label Phase II trial that compares reduced dose erlotinib 100mg daily and standard dose gefitinib 250mg daily in patients with advanced non-small cell lung cancer who harbor EGFR mutations. The primary endpoint is disease control rate (DCR) and the key secondary endpoint is progression free survival (PFS). A total of 224 eligible patients will be randomized to receive either erlotinib 100mg daily or gefitinib 250mg daily in a 1:1 ratio until patients experience disease progression. Independent assessment of the major endpoints will be completed in a treatment-blinded manner. Randomization will be stratified based on treatment-lines (first-line vs. maintenance vs. second-line therapy). Tumor response and progression will be assessed according to RECIST 1.1.

NCT01955421
Conditions
  1. Advanced Stage Non Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib 100mg qd
  2. Drug: Gefitinib 250mg qd
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Harboring a PCR-confirmed activating mutation of EGFR, including an exon 19 deletion or an exon 21 L858R point mutation. --- L858R ---

Primary Outcomes

Measure: disease control rate

Time: 2 years

Secondary Outcomes

Measure: progression free survival

Time: 2 years

Description: rash, diarrhea, ILD, etc.

Measure: adverse events

Time: 2 years

56 A Phase IB/II, Open Label, Multicenter Study of Selumetinib Administered Orally in Combination With Gefitinib in Patients With EGFR-mutated Non-small Cell Lung Cancer Who Have Developed Acquired Resistance of EGFR Inhibitor Treatment

This is an open-label, non-randomized, multicenter phase Ib/II study, which is composed of a phase Ib dose escalation part and a phase II dose expansion part. Patients will receive selumetinib in combination with gefitinib 250mg daily. This study will enroll EGFR-mutated NSCLC patients who have developed acquired resistance to EGFR TKI treatment.

NCT02025114
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: selumetinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A tumor harboring an EGFR mutation known to be associated with drug sensitivity (ie, exon 19 deletion , L858R, L861Q, G719X etc.). --- L858R ---

Primary Outcomes

Description: Frequency and characteristics of DLTs to the selumetinib and gefitinib combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. (an expected average of 18 weeks) If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, then dose escalation may occur.

Measure: To determine the MTD and/or RP2D

Time: an expected average of 18 weeks

Secondary Outcomes

Description: to estimate overall clinical activity of selumetinib combined with gefitinib in EGFR-mutated NSCLC patients who have acquired resistance to EGFR TKIs

Measure: Overall Response Rate (ORR)

Time: Patients will be followed up for 2 years(post disease progression)

57 An Open-label, Randomized, Phase II Study of Erlotinib Monotherapy Versus Docetaxel and Cisplatin as Neoadjuvant Therapy in Patients of Stage IIIA Lung Adenocarcinoma With Epidermal Growth Factor Receptor Gene Mutation.

To compare clinical response (complete response and partial response) by RECIST) rates by RECIST between erlotinib monotherapy and docetaxel plus cisplatin chemotherapy

NCT02036359
Conditions
  1. Non-small Cell Lung Cancer(NSCLC)
Interventions
  1. Drug: erlotinib
  2. Drug: docetaxel
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Life expectancy > 12 weeks - Tumor specimen with EGFR gene mutation of exon 19 deletion and L858R, G719X, L861Q mutation - Adequate hematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL - Data of INR and PTT should be available in patients taking anticoagulants concomitantly, with INR ≤ 1.5 and PTT ≤ 1.5 times the upper limit of normal (x ULN ) within 7 days prior to starting study treatment - Adequate liver function: serum bilirubin ≤ 1.5 x ULN; transaminases ≤ 2.5 x ULN - Adequate renal function: 24-hour urine creatinine clearance or creatinine clearance measured and calculated according to the formula of Cockroft and Gault ≥ 60ml/min - Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women - Written informed consent. --- L858R ---

Those with exon 19 deletion and L858R, G719X, L861Q mutation were randomized as erlotinib monotherapy or docetaxel plus cisplatin chemotherapy. --- L858R ---

Primary Outcomes

Measure: Number of Adverse Event

Time: Within 28 days of last study dose

58 Phase I, Open-label, Safety, Tolerability and Preliminary Efficacy Study of Tremelimumab in Combination With Gefitinib in EGFR Mutant NSCLC Patients

This is an open-label phase 1, safety, PK, and preliminary efficacy study of oral Gefitinib and IV Tremelimumab in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as Erlotinib or Gefitinib. The primary objective of this phase I, is to determine the safety and tolerability of oral Gefitinib in combination with escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Secondary objectives include evaluation of, pharmacokinetics, immunogenicity, antitumor activity of Gefitinib and Tremelimumab combination. The exploratory objectives are to evaluate biomarkers that may correlate with activity or prospectively identify patients likely to respond to Tremelimumab and Gefitinib. The biological rationale for such a study is that even though the disease is progressing it is likely that EGFR sensitive clones, although diminished under the pressure from the EGFR TKI, are still present. Therefore, withdrawing the inhibitory pressure of the EGFR TKI can potentially allow regrowth of the EGFR sensitive cells. On the other hand, the proliferation of EGFR resistant clones needs to be suppressed by another therapeutic approach. Until today no association of chemotherapy and TKI EGFR has demonstrated clinical benefit. Moreover, patients may have received chemotherapy and the likelihood of chemosensitivity is very low. So, the association of Gefitinib with immune checkpoint blockade is very attractive and may result in clinical benefit in NSCLC with EGFRmut.

NCT02040064
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Tremelimumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R ---

- Previous allogenic bone marrow transplant Inclusion Criteria: 1. Provision of written informed consent ; 2. Female or male patients aged 18 years or over at the time of consent ; 3. World Health Organisation (WHO) Performance Status 0 to 1 (Appendix C) ; 4. Cytologically or histologically confirmed NSCLC with an activating EGFR TK mutations known to be associated with EGFR TKI sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) as determined locally using a well-validated and robust methodology ; 5. Prior objective clinical benefit defined by either partial, complete or SD (>/= 4months) after initiation of EGFR TKI treatment ; 6. Patients could have received first line chemotherapy or chemotherapy between the EGFR TKI and inclusion in the study but must present a systemic objective progression ; 7. A washout period is not required for patients who are being treated with Gefitinib at the time of study entry. --- L858R ---

Primary Outcomes

Description: The primary objective of this phase 1 study is to determine the safety and tolerability of oral Gefitinib in combination with three escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Overall safety profile will be characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCICTCAE] Version 4.03), timing of adverse events and laboratory abnormalities in the first and in the following cycles

Measure: safety and tolerability of the association between Gefitinib (fixed dose) and Tremelimumab (dose escalation)

Time: Up to 42 days

Secondary Outcomes

Description: To obtain a preliminary assessment of the anti-tumour activity of Gefitinib + Tremelimumab by evaluation of tumour response using modified Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and evaluation of Disease control rate and PFS

Measure: Anti-tumour activity of Gefitinib + Tremelimumab

Time: From day 1 cycle 1 every 8 weeks for 24 weeks and then every 6 weeks until progression or death whichever comes first assessed up to 30 months

Description: Immunogenicity results will be analyzed descriptively by summarizing the number and percentage of subjects who develop detectable anti-Tremelimumab antibodies. The immunogenicity titer will be reported for samples confirmed positive for the presence of anti-Tremelimumab antibodies.

Measure: Immunogenicity of Tremelimumab in combination with Gefitinib

Time: At day 1 cycle 1 and then every 8 weeks from day 1 cycle 2 until progression or death whichever comes first assessed up to 30 months

Description: Gefitinib pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)

Measure: Pharmacokinetics of Gefitinib

Time: At first Tremelimumab administration and then every 4 weeks until progression or death whichever comes first assessed up to 30 months

Description: Tremelimumab pharmacokinetic parameters comprise the area under the curve from time t0 to t (AUC0-t), AUC from time t0 to the infini (AUC0-∞) and maximal concentration (Cmax)

Measure: Pharmacokinetics of Tremelimumab

Time: Before and after injection of Tremelimumab at day 1 cycle 1 and at day 8 and day 15 of cycle 1 and then before and after injection at day 1 for every cycle (4 weeks) until progression or death whichever comes first assessed up to 30 months

59 Erlotinib Treatment Beyond Progression in EGFR Mutant or Patients Who Have Responded EGFR TKI in Stage IIIB/IV NSCLC

The purpose of this study is to determine whether continuing erlotinib beyond disease progression in combination with chemotherapy is beneficial for NSCLC patients who have EGFR mutant disease or who have responded to EGFR TKI.

NCT02064491
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Chemotherapy
MeSH:Carcinoma, Non-Small-Cell Lung Disease Progression
HPO:Non-small cell lung carcinoma

- Investigator confirmed progression according RECIST 1.1 during EGFR TKI treatment within 28 days of the randomization - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Performance status: WHO 0-2 - Measurable disease according to RECIST 1.1 - Patients must be able to comply with study treatments - Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study - Neutrophils ≥ 1'000/μl, Platelets ≥ 100'000/μl, Alanine amino transferase ≤ 2.5 × Upper limit of normal (ULN) (< 5 × ULN if liver metastases), Alkaline phosphatase ≤ 2.5 × ULN (< 5 × ULN if liver metastases), Serum bilirubin ≤ 1.5 × ULN, Serum Creatinine ≤ 1.5 × ULN. - Patient must be able to comply with the protocol Exclusion Criteria: - RECIST 1.1 defined disease progression for more than 28 days while on previous EGFR TKI treatment. --- G719A --- --- L858R ---

Primary Outcomes

Measure: Progression-free survival of the whole study population and in the strata 1-2

Time: An expected average of 36 weeks after last subject enrolled into our study

Secondary Outcomes

Measure: Overall Survival

Time: An expected average of 52 weeks after last subject enrolled into our study

Measure: Overall Response Rate

Time: An expected average of 36 weeks after last subject enrolled into our study

Measure: Rate of non-progression at 9 and 18 weeks

Time: 18 weeks after date of randomization of a last patient

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety and toxicity

Time: An expected average of 52 weeks after last subject enrolled into our study

60 A Multi-center, Open-labeled Phase 2 Study of First Line Intermittent and Maintenance of Erlotinib in Combination With Pemetrexed/Carboplatin in ⅢB/IV Non Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Mutation

EGFR-tyrosine kinase inhibitor(TKI)- ie, erlotinib, gefitinib, has been recommended as the first option for EGFR-mutated IIIb/IV NSCLC by serial trials as it prolonged patients' progression-free survival. The OPTIMAl trial indicated that those who received TKI and chemotherapy during the whole treatment window survived longest. Unfortunately, previous studies(INTACT, TRIBUTE et al) that concurrently combined TKI and cytotoxic regimens failed to improve survival in unselected patients. To avoid the potential synergistic antagonism, the FAST-ACT II trial committed a sequential strategy and find a superiority in the combination arm upon chemotherapy even in EGFR-mutated group. However, pharmaceutically, the continuous administration of an EGFR-TKI before subsequent chemotherapy in FAST-ACT II could obviate the effects of cytotoxic agents due to the erlotinib-induced G1 arrest. On the basis of these and other studies, the investigators hypothesized that a better sequential combination strategy of EGFR-TKI and chemotherapy (adding a EGFR-TKI wash-out window before chemotherapy) would be more efficacious than chemotherapy alone. In this study, the investigators investigate the efficacy(PFS:progression free survival), safety, and adverse-event profile of chemotherapy plus intermittent and maintenance of erlotinib, when these drugs were used as first-line treatment in who had non-squamous lung carcinoma with EGFR gene mutation in China.

NCT02066038
Conditions
  1. Lung, Carcinoma
Interventions
  1. Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmed activating mutation of EGFR-ie, an exon 19 deletion or an exon 21 L858R point mutation. --- L858R ---

Primary Outcomes

Description: Patients were imaged with computed tomography (CT) scan

Measure: Response Evaluation Criteria in Solid Tumors(RECIST) 1.1

Time: eight weeks

61 A Phase IIIb/IV Safety Trial of Nivolumab (BMS-936558) in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed During or After Receiving At Least One Prior Systemic Regimen

The purpose of this study is to estimate the incidence and characterize the outcome of high grade, select adverse events in subjects with advanced or metastatic NSCLC treated with Nivolumab.

NCT02066636
Conditions
  1. Non Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: Nivolumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A switch of an agent within a regimen in order to manage toxicity does not define the start of a new line of therapy - Maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate regimen of therapy - Subjects who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible - Subjects with recurrent disease >6 months after platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, who also subsequently progressed during or after a platinum doublet-based regimen given to treat the recurrence are eligible - Subjects with non-squamous histology must be tested for Epithelial Growth Factor Receptor (EGFR) mutations (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution) and Anaplastic Lymphoma Kinase (ALK) rearrangement if tests have not been previously performed. --- L858R ---

Primary Outcomes

Measure: Incidence for high grade (Grade 3-4 and Grade 5) treatment related select adverse events (AEs)

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

Secondary Outcomes

Measure: Incidence for high grade (Grade 3-4 and Grade 5) select AEs

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

Measure: Median time to onset and median time to resolution (Grade 3-4)

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

Description: Immune modulating medication (e.g. corticosteroids, Infliximab, Cyclophosphamide, intravenous immune globulin (IVIG), and Mycophenolate Mofetil)

Measure: Percentage of subjects who received immune modulating medication or hormonal replacement therapy, percentage of subjects who received ≥40 mg Prednisone equivalents, total duration of all immune modulating medications given for select event

Time: Up to 100 days after last dose date (approximately up to 6.5 years)

62 My Pathway: An Open-Label Phase IIa Study Evaluating Trastuzumab/Pertuzumab, Erlotinib, Vemurafenib/Cobimetinib, Vismodegib, Alectinib, and Atezolizumab in Patients Who Have Advanced Solid Tumors With Mutations or Gene Expression Abnormalities Predictive of Response to One of These Agents

This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.

NCT02091141
Conditions
  1. Neoplasms
  2. Solid Tumors
  3. Biliary Cancer
  4. Salivary Cancer
  5. Bladder Cancer
Interventions
  1. Drug: Trastuzumab
  2. Drug: Pertuzumab
  3. Drug: Erlotinib
  4. Drug: Vemurafenib
  5. Drug: Cobimetinib
  6. Drug: Vismodegib
  7. Drug: Alectinib
  8. Drug: Atezolizumab

The tissue sample must be submitted within 4 weeks after enrollment General Exclusion Criteria: - Participants with hematologic malignancies - Concurrent administration of any other anti-cancer therapy (except male participants with prostate cancer receiving androgen blockade): Bisphosphonates and denosumab are allowed; Most recent anti-cancer therapy ≤28 days and have not recovered from the side effects, excluding alopecia; Radiation therapy within ≤14 days - Active or untreated brain metastases - History of carcinomatous meningitis - Uncontrolled concurrent malignancy (early stage is allowed if not requiring active therapy or intervention) - Pregnant or breastfeeding women, or intending to become pregnant during the study - Any significant cardiovascular events within 6 months prior to study entry - Pulmonary embolism within 30 days prior to study entry - History or presence of clinically significant ventricular or atrial dysrhythmia >Grade 2 per NCI CTCAE v4.0 - Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results - Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol Study-Drug Specific Exclusion Criteria: Trastuzumab plus Pertuzumab - Previous treatment with any HER2-targeted therapy Erlotinib - Non-small cell lung cancer (NSCLC) or pancreatic cancer identified by exon 19 deletions or exon 21 L858R substitution mutations - EGFR amplifications in the absence of EGFR-activating mutations - Cancers with exon 20 mutations - Previous treatment with erlotinib or any other EGFR inhibitor - Inability to swallow pills - Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of erlotinib Vemurafenib plus Cobimetinib - Malignant melanoma, papillary thyroid cancer, colorectal cancer, or hematologic malignancy including multiple myeloma - LVEF below institutional lower level of normal (LLN) or below 50%, whichever is lower - History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration - Presence of any of the following conditions, which are risk factors for RVO: Uncontrolled glaucoma with intraocular pressure >21 millimetres of mercury (mm Hg); Serum cholesterol ≥Grade 2; Hypertriglyceridemia ≥Grade 2; Hyperglycemia (fasting) ≥Grade 2; Grade ≥2 uncontrolled hypertension (participants with a history of hypertension controlled with anti-hypertensive medication to Grade L858R ---

Primary Outcomes

Description: Tumor response will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for all arms.

Measure: Percentage of Participants in All Tumor-Pathway Cohorts With Overall Response, as Assessed by the Investigator

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants With Tissue Tumor Mutational Burden (tTMB) ≥16 Mutations/Mb With Overall Response, as Assessed by the Independent Review Committee (IRC)

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Secondary Outcomes

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Percentage of Participants With Disease Control

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Progression-Free Survival (PFS)

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Measure: Percentage of Participants who are Alive at Year 1

Time: 1 year

Description: Tumor response will be assessed using RECIST version 1.1 for all arms.

Measure: Duration of Response

Time: From the date of first documented response (complete response [CR] or partial response [PR]) to the time of disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants with tTMB ≥10 Mutations/Mb and <16 Mutations/Mb With Overall Response, as Assessed by the Investigator

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Description: Tumor response will be assessed using RECIST version 1.1.

Measure: Percentage of Atezolizumab-Treated Participants with Blood Tumor Mutational Burden (bTMB) ≥16 Mutations With Overall Response, as Assessed by the IRC

Time: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (up to approximately 5 years)

Measure: Percentage of Participants With Adverse Events

Time: From first study treatment administration to 30 days (45 days for vismodegib, 90 days for atezolizumab) after the last dose (up to approximately 5 years)

63 Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

NCT02094261
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

64 Intercalated Combination of Chemotherapy and Erlotinib in 1st Line Setting for Patients Advanced Stage Non-small-cell Lung Cancer With Low Abundant Activating EGFR Mutation(INNOVATE)

This is a single arm phase II clinical trial, which aims to evaluate the effectiveness of intercalated combination of doublet chemotherapy of paclitaxel plus carboplatin and erlotinib on patients with advanced stage non-small-cell lung cancer with low abundant activating EGFR mutation.

NCT02095782
Conditions
  1. Non-small-cell Lung Cancer
Interventions
  1. Drug: Intercalated combination of chemotherapy and erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Low abundant activating EGFR mutation: EGFR exon 19 deletion or exon 21 L858R, which are positive by real-time PCR methods and negative by standard sequencing methods. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy untill progression or death

Measure: Progression free survival defined by imagery methods

Time: 8 weeks

Secondary Outcomes

Description: From start of anti-cancer therapy till progression of death

Measure: Toxicities related to anti-cancer therapy

Time: 8 weeks

65 Second Line Erlitinib Combination With Gemcitabine Cisplatinum in Non-small Cell Lung Cancer Patients Who Harbored EGFR Sensitive Mutation Developed Resistance After First Line TKI Treatment

Numerous evidences verified that erlotinib could dramatically improve the PFS and OS of non-small cell lung cancers who harbor EGFR sensitive mutations, however, primary or secondary resistance will be developed after TKI treatment, doctors do plenty of researches to overcome TKI resistance. FAST ACT-2 study present that, first line erlotinib combined with chemotherapy could improved mOS to more than 30 months in NSCLCs who harbor EGFR sensitive mutations, several study shows that sensitive mutations still exist after TKI resistance, because of the next generation TKIs(such as BIBW2992) are not avaliable at present, agents for met amplification(such as Crizotinib) are so expensive that many Chinese patients could not support. Thus, the investigators hypothesis that, after first line TKI treatment, the patients who developed TKI resistance could still benefit from second line TKI combined with chemotherapy.

NCT02098954
Conditions
  1. Carcinoma, Non-Small Cell Lung
  2. EGFR Gene Mutation
Interventions
  1. Drug: Gemcitabine platinum combined with erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Carcinoma, Non-Small-Cell Lung The investigators will enroll patients diagnosed with advanced non-squamous,non-small cell lung cancer, patients with EGFR TKI sensitive mutations and developed TKI resistance in first line treatment. --- L858R ---

Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Inclusion Criteria: - advanced non-small cell lung cancer, stage IIIB/IV - non-squamous - EGFR sensitive mutations, such as exon 19 del, or exon 21 L858R - received first line TKIs treatment and developed TKI resistance - ECOG 0-2 Exclusion Criteria: - squamous non-small cell lung cancer - patients have unstable brain metastasis, predict survival less than 8 weeks - spinal-cord compression without evidence of stabilisation or treatment - women who were pregnant or lactating; women with a positive or no available pregnancy test result at baseline - patients have any unstable illness that could not receive further treatment Carcinoma, Non-Small Cell Lung EGFR Gene Mutation Carcinoma, Non-Small-Cell Lung The investigators will enroll patients diagnosed with advanced non-squamous,non-small cell lung cancer, patients with EGFR TKI sensitive mutations and developed TKI resistance in first line treatment. --- L858R --- --- L858R ---

Primary Outcomes

Description: mean progression free survival(mPFS) will be recorded in enroll patients who received second line gemcitabine platinum combined with erlotinib. mPFS should be measured before second line treatment, before the third combined chemotherapy, after the fourth combined chemotherapy, every 3 months during erlotinib treatment, mPFS should be measured up to two years or every time progression disease occurs within two years.

Measure: mean progression free survival(mPFS)

Time: after patients receive treatment, mPFS should be measured before the third cycle of chemotherapy, after the fourth cycle, mPFS should be measured every 3 months up to two years

Secondary Outcomes

Description: mOS should be measured since enrollment, every 3 months we will contact patients to find out detail survival data of each patient until 3 years, or within 3 years if all survival data is obtained.

Measure: mean overall survival(mOS)

Time: every 3 months up to 3 years, or until all the survival data is obtained

Description: 8 week ORR should be measured after enrollment, after combined chemotherapy for 8 weeks, the exact time point should be the ninth week during combined chemotherapy. CR, PR, SD shoud be measured according to RESICT 1.1

Measure: 8 week overall response rate(8 week ORR)

Time: 8 week ORR should be measured after enrollment, the exact time point should be the ninth week after combined chemotherapy

66 A Multicenter, Phase 1/1b, Open-Label, Dose-Escalation Study of ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors

This is a Phase 1/1b open-label study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of ABBV-399 as monotherapy and in combination with osimertinib, erlotinib, and nivolumab in participants with advanced solid tumors likely to express c-Met. Enrollment is closed for the monotherapy arms, Arm A, and Arm D.

NCT02099058
Conditions
  1. Advanced Solid Tumors Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Nivolumab
  3. Drug: Telisotuzumab vedotin
  4. Drug: Telisotuzumab vedotin
  5. Drug: Erlotinib
MeSH:Neoplasms
HPO:Neoplasm

- Participant must have metastatic/locally advanced nonsquamous NSCLC with documented Epidermal Growth Factor Receptor (EGFR) mutation(s) del19 or L858R, with or without T790M mutation, and none of the EGFR mutations known to be resistant to osimertinib. --- L858R ---

Primary Outcomes

Description: An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

Measure: Number of Participants with Adverse Events

Time: Up to 24 Months

Description: The RPTD of ABBV-399 when administered as monotherapy and in combination with osimertinib, erlotinib or nivolumab will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data.

Measure: Recommended Phase 2 Dose (RPTD) of ABBV-399 when Administered as Monotherapy and in Combination with Osimertinib, Erlotinib or Nivolumab

Time: Up to 24 Months

Description: AUC (0-t) = Area under the serum concentration versus time curve from time zero (pre-dose) to the time of the last measurable concentration.

Measure: Area under the curve (AUC) from time zero to the last measurable concentration AUC (0-t)

Time: Up to 24 months

Description: Maximum observed plasma concentration (Cmax).

Measure: Maximum observed plasma concentration (Cmax)

Time: Up to 24 months

Description: Time to Cmax (Tmax).

Measure: Time to Cmax (Tmax)

Time: Up to 24 months

Description: Terminal elimination half life.

Measure: Terminal elimination half life

Time: Up to 24 months

67 Sequential Icotinib Plus Chemotherapy Versus Icotinib Alone as First-line Treatment in Stage IIIB/IV Lung Adenocarcinoma: a Randomized, Open-label, Multicenter Study

This randomised, controlled, multicentre trial is designed to assess the efficacy and safety of sequential icotinib plus chemotherapy versus single icotinib as first-line treatment in stage IIIB/IV lung adenocarcinoma patients with EGFR mutation.

NCT02103257
Conditions
  1. EGFR Positive Non-small Cell Lung Cancer
  2. Adenocarcinoma
Interventions
  1. Drug: Sequential Icotinib Plus Chemotherapy
  2. Drug: Icotinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

The number of patients who suffered adverse events, which is graded by NCI CTCAE version 4.0.. Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease EGFR Positive Non-small Cell Lung Cancer Adenocarcinoma Adenocarcinoma Adenocarcinoma of Lung null --- L858R ---

The number of patients who suffered adverse events, which is graded by NCI CTCAE version 4.0.. Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease Inclusion Criteria: - Pathologic confirmation of lung adenocarcinoma with measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded on CT) - Patients must have previously untreated locally advanced or metastatic NSCLC - EGFR activating mutation (exon 19 deletion, L858R) is required - Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1 Exclusion Criteria: - Prior chemotherapy or treatment with gefitinib, erlotinib, or other drugs that target EGFR - Patients with wild-type EGFR - Any other investigational agents are not permitted - Any evidence of interstitial lung disease EGFR Positive Non-small Cell Lung Cancer Adenocarcinoma Adenocarcinoma Adenocarcinoma of Lung null --- L858R --- --- L858R ---

Primary Outcomes

Description: A duration from randomization date to disease progression(as defined by RECIST) or death. If a participant are known to have progressed, the time to progression is defined as the time from the date of randomization to the date of progression. Otherwise, a participant will be censored at the last date they are known not to be progressed.

Measure: Progression Free Survival

Time: 15 months

Secondary Outcomes

Description: Overall Survival is assessed via calculation of the time to death due to any cause. If a participant is known to have died, the time to death is defined as the time from the date of randomization to the date of death. Otherwise, a participant will be censored at the last date they are known to be alive.

Measure: Overall survival

Time: 24 months

Description: Number of subjects with confirmed objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Measure: Objective response rate

Time: 15 months

Description: The number of patients who suffered adverse events, which is graded by NCI CTCAE version 4.0.

Measure: Adverse events

Time: 24 months

68 Randomized, Double-Blind, Multicenter, Phase 3 Study Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus Carboplatin and Paclitaxel in Previously Untreated Advanced or Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)

This is a 2 arm Phase 3 study to evaluate the safety and efficacy of the addition of veliparib plus carboplatin and paclitaxel versus the addition of placebo plus carboplatin and paclitaxel in subjects with advanced or metastatic squamous NSCLC.

NCT02106546
Conditions
  1. Squamous Non-Small Cell Lung Cancer
Interventions
  1. Drug: carboplatin
  2. Drug: veliparib
  3. Drug: paclitaxel
  4. Drug: placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Subject has peripheral neuropathy >= grade 2. 4. Subject has non-squamous NSCLC, or a known Epidermal Growth Factor Receptor (EGFR) mutation of exon 19 deletion or L858R mutation in exon 21, or a known Anaplastic Lymphoma Kinase (ALK) gene rearrangement. --- L858R ---

Primary Outcomes

Description: Time to death for a given subject will be defined as the number of days from the date that the subject was randomized to the date of the subject's death.

Measure: Overall Survival (OS) in current smokers

Time: Up to 3 years from first dose of study drug

Secondary Outcomes

Description: Time to death for a given subject will be defined as the number of days from the date that the subject was randomized to the date of the subject's death.

Measure: Overall Survival (OS) in all subjects

Time: Up to 3 years from first dose of study drug

Description: Defined as the number of days from the date that the subject was randomized to the date the subject experiences an event of disease progression or to the date of death (all causes of mortality) if disease progression is not reached.

Measure: Progressive-Free Survival (PFS) in current smokers and in all subjects

Time: Up to 3 years from first dose of study drug

Description: Objective response rate is defined as the proportion of subjects with complete or partial response as determined by the investigator per RECIST (version 1.1)

Measure: Objective Response Rate (ORR) in current smokers and in all subjects

Time: Up to 3 years from first dose of study drug

Other Outcomes

Measure: Change in Quality of Life: European Organisation for Research and Treatment of Cancer Quality of Life Core 30 Question Questionnaire (EORTC-QLQ-C30).

Time: From Screening (prior to dosing) up to 2 years

Measure: Change in Quality of Life: European Organisation for Research and Treatment of Cancer Quality of Life Lung Cancer 13 Question Questionnaire (EORTC-LC13).

Time: From Screening (prior to dosing) up to 2 years

Measure: Change in Eastern Cooperative Oncology Group (ECOG) Performance Status

Time: From Screening (prior to dosing) up to 2 years

Measure: Change in Quality of Life: European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L)

Time: From Screening (prior to dosing) up to 2 years

Description: The duration of overall response for a given subject will be defined as the number of days from the day the criteria are met for Complete or Partial Response (whichever is recorded first) to the date that Progressive Disease (PD) is objectively documented.

Measure: Duration of Response

Time: From complete or partial response to disease progression (up to 3 years from randomization).

69 An Open-label, Phase 1 Dose Escalation Study of Oral ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations

The purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.

NCT02113813
Conditions
  1. Non-Small-Cell Lung Cancer (NSCLC)
  2. Epidermal Growth Factor Receptor Mutations
Interventions
  1. Drug: naquotinib
  2. Drug: midazolam
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.. Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R ---

Exclusion Criteria: - Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment - Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days - Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV) - Symptomatic Central Nervous System (CNS) metastasis - Active infection requiring systemic therapy within 14 days - Severe or uncontrolled systemic diseases including uncontrolled hypertension - History of or active interstitial lung disease - Screening QTcF >450 msec or current medication known to prolong QT - ≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months - History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction - Concurrent corneal disorder or ophthalmologic condition making subject unsuitable - RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days - Any other malignancy requiring treatment Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03.

Measure: Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)

Time: up to 18 months

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Measure: Safety and tolerability as assessed by adverse events (AEs)

Time: up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.

Measure: Safety and tolerability as assessed by laboratory tests

Time: up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature.

Measure: Safety and tolerability as assessed by vital signs

Time: up to 18 months

Measure: Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)

Time: up to 18 months

Secondary Outcomes

Description: Maximum concentration (Cmax), the time after dosing when Cmax occurs (tmax), area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast), area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf), apparent terminal elimination half-life (t1/2), apparent oral systemic clearance (CL/F), Apparent volume of distribution (Vz/F)

Measure: Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3

Measure: Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2

Description: Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.

Measure: Best overall response rate

Time: Up to 18 months

Description: Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.

Measure: Disease control rate

Time: Up to 18 months

Description: Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.

Measure: Progression free survival

Time: Up to 18 months

70 A Single-Arm Phase II Clinical Trial of Cabozantinib (XL184) in Patients With Previously Treated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases With and Without C Met Amplification

This is an open-label phase II clinical trial designed to allow a preliminary assessment of the efficacy and safety of cabozantinib in unselected Non-Small Cell Lung Cancer (NSCLC) patients with metastases to the brain and in the subset of patients with c-MET amplified Non-Small Cell Lung Cancer with metastases to the brain. Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial. Patients with clinically asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating investigator. Patients who have undergone treatment for their brain metastases with Whole-Brain Radiation Therapy (WBRT), stereotactic radiosurgery (SRS) or surgery must be clinically stable and recovered from all procedures at the time of study enrollment.

NCT02132598
Conditions
  1. Non Small Cell Lung Cancer (NSCLC)
  2. Metastases to the Brain
Interventions
  1. Drug: cabozantinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients must agree to submission of these specimens as defined in Section 9. - c-MET amplification will be determined by FISH ratio (c-MET/CEP7) > 2.0, based on testing of the primary tumor and/or site of metastatic disease - Patients' tumors must undergo testing for Epidermal Growth Factor Receptor (EGFR) exon 19 deletion, EGFR exon 21 L858R substitution, and anaplastic lymphoma kinase (ALK) rearrangements. --- L858R ---

Primary Outcomes

Description: The proportion of response-evaluable patients who achieve Complete Response (CR) or Partial Response (PR) as best response by RECIST v1.1 criteria. Per RECIST v1.1, Complete Response (CR) is defined as disappearance of all target lesions; disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD.

Measure: Overall Response

Time: Up to 12 months

Secondary Outcomes

Description: Proportion of response-evaluable patients that experienced Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) as best response (RECIST v1.1 criteria) per the total study population criteria. Per RECIST v1.1, Complete Response (CR) is defined as disappearance of all target lesions; disappearance of all non-target lesions and normalization of tumor marker level. Partial Response (PR) is defined as at least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD. Stable Disease (SD) is defined as, neither sufficient shrinkage (compared to baseline) to qualify for partial or complete response (CR or PR) nor sufficient increase (taking as reference the smallest sum of diameters at baseline or while on study, whichever is smallest) to qualify for progressive disease (PD).

Measure: Disease Control Rate (DCR)

Time: Up to 16 weeks

Description: Progression-free survival is the time measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression), whichever occurs first, with progression defined by RECIST v 1.1. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Measure: Progression-free Survival (PFS)

Time: Up to 12 months

Description: The length of time from the start of treatment that patients remain alive, until death from any cause.

Measure: Overall Survival (OS)

Time: Up to 24 months

Description: Time from initiation of study treatment to disease progression per RECIST v1.1, excluding death from causes unrelated to the disease. As defined by RECIST v 1.1. Progressive disease (PD) is defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Measure: Time to Progression (TTP)

Time: Until disease progression; Up to 2 years

Description: Worst Grade of Adverse Events Reported as assessed by the investigator. Severity/grade defined by the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Subjects monitored continuously for Adverse Events (AE's) throughout the study and for 30 days after the last dose of study treatment.

Measure: Worst Grade of Adverse Events Reported

Time: From baseline up to 20 weeks

Description: Worst Grade of Adverse Events Reported as assessed by the investigator. Severity/grade defined by the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Subjects monitored continuously for Adverse Events (AE's) throughout the study and for 30 days after the last dose of study treatment.

Measure: Worst Grade of AE at Least Possibly Related to Treatment Reported

Time: From baseline up to 20 weeks

Description: Worst Grade of Adverse Events Reported as assessed by the investigator. Severity/grade defined by the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Subjects monitored continuously for Adverse Events (AE's) throughout the study and for 30 days after the last dose of study treatment.

Measure: Worst Grade of AE at Least Probably Related to Treatment Reported

Time: From baseline up to 20 weeks

Description: Worst Grade of Adverse Events Reported as assessed by the investigator. Severity/grade defined by the Cancer Therapy Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Subjects monitored continuously for Adverse Events (AE's) throughout the study and for 30 days after the last dose of study treatment.

Measure: Worst Grade of AE Definitely Related to Treatment Reported:

Time: From baseline up to 20 weeks

71 Phase 3, Randomized, Placebo-Controlled, Double-Blind, Multi-Center, Two-Part Study of Patritumab (U3-1287) In Combination With Erlotinib in EGFR Wild-type Subjects With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Who Have Progressed on at Least One Prior Systemic Therapy

1. Part A: Subjects will receive Patritumab or placebo with erlotinib. Progression-free survival will be the primary outcome. Subjects will need to have Epidermal Growth Factor Receptor (EGFR) wild-type, locally advance or metastatic NSCLC and have their cancer progressed after at least one prior systemic anti-cancer therapy, available recent or archival tumor specimen and may not have had previous EGFR-targeted regimen, anti-HER2 (Human Epidermal Growth Factor Receptor 2), anti-HER3, or anti-HER4 therapy. Subjects may have high heregulin or low heregulin. 2. Part B: Subjects will receive Patritumab or placebo with erlotinib. Overall survival will be the primary outcome. Subjects will need to have EGFR wild-type, locally advance or metastatic NSCLC and have their cancer progressed after at least one prior systemic anti-cancer therapy, available recent or archival tumor specimen and may not have had previous EGFR-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy. Only subjects with high heregulin will be enrolled.

NCT02134015
Conditions
  1. Lung Cancer
  2. Non-small Cell Lung Cancer
Interventions
  1. Drug: Patritumab
  2. Drug: Erlotinib
  3. Drug: Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

If tumor histology is adenocarcinoma, must have wild-type EGFR genotype as assessed by a validated assay that includes exon 19 deletion and exon 21 (L858R) substitution. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table.

Measure: Part A: Progression Free Survival (PFS) in Heregulin-high Participants

Time: by trial termination (at 20 months)

Description: PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause. Kaplan-Meier Estimate. Confidence interval (CI) for median was computed using the Brookmeyer-Crowley method. 80% confidence interval is included in the data table.

Measure: Part A: Progression Free Survival (PFS) in Heregulin-low Participants

Time: by trial termination (at 20 months)

Description: Percentage of participants still alive at the end of Part B

Measure: Part B: Overall Survival

Time: 4 years

Secondary Outcomes

Description: Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial

Measure: Part A: Overall Survival in HRG High Participants

Time: by trial termination (at 20 months)

Description: Key secondary efficacy endpoint: Percentage of participants who survived for the length of the trial

Measure: Part A: Key Secondary Efficacy Endpoint: Overall Survival in HRG Low Participants

Time: by trial termination (at 20 months)

Description: PFS is defined as the time from the date of randomization to the earlier of the dates of first objective documentation of radiographic disease progression (TTD, as per RECIST Version 1.1 per investigator assessment) or death resulting from any cause.

Measure: Part B: Key Secondary Efficacy Endpoint: PFS, TTD

Time: 4 years

Description: Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response (CR) or partial response (PR) Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response [in the order of CR, PR, stable disease (SD), and progressive disease (PD)] among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable.

Measure: Part A: Objective Response Rate (ORR) in HRG High Participants

Time: by trial termination (at 20 months)

Description: Key secondary efficacy endpoint: Objective response is defined as percentage of participants achieving complete response or partial response Denominator for percentages is the number of subjects with measurable disease in the full analysis set. The best overall response is the best response (in the order of CR, PR, SD, and PD) among all overall responses recorded from the start of treatment until the subject withdraws from the study. If there is no post-baseline tumor assessment or all post-baseline tumor assessments with overall response being Inevaluable captured in the CRF, the best overall response is classified as Inevaluable.

Measure: Part A: Objective Response Rate (ORR) in HRG Low Participants

Time: by trial termination (at 20 months)

72 Phase 3 Study of Erlotinib 100mg or 150mg in Treating EGFR Mutated Patients With Non-small Cell Lung Cancer

The purpose of this study is to determine whether 100mg erlotinib had similar effect compared with 150mg erlotinib in NSCLC patients with EGFR mutation in China.

NCT02140333
Conditions
  1. NSCLC
  2. EGFR Mutation
Interventions
  1. Drug: Erlotinib

Inclusion Criteria: 1. Histological diagnosis of NSCLC with phase IIIB or IV disease; 2. Sensitive mutation EGFR gene (18, 19 del, 21 L858R gene mutation) (mutation detection methods:ARMS-PCR, sequence method) 3. Never received anti-tumor therapies for the advanced stage; 4. Never used EGFR inhibitors; 5. Measurable disease by RECIST criteria; 6. --- L858R ---

Primary Outcomes

Measure: Progression free survival

Time: 2 years after the initial dose

Secondary Outcomes

Measure: The objective response rate

Time: Patients will be followed for an expected average of 6 months

Other Outcomes

Measure: Overall survival

Time: 3 year after the initial dose

Measure: Adverse events

Time: 1 year

73 A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety,Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm+ Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON).

The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer.

NCT02143466
Conditions
  1. Advanced Non Small Cell Lung Cancer
Interventions
  1. Drug: Part A - AZD9291 in combination with AZD6094
  2. Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)
  3. Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)
  4. Drug: Part A - AZD9291 in combination with intermittent selumetinib
  5. Drug: Part A - AZD9291 in combination with MEDI4736
  6. Drug: Part B - AZD9291 in combination with AZD6094
  7. Drug: Part B - AZD9291 in combination with selumetinib
  8. Drug: Part B - AZD9291 in combination with MEDI4736
  9. Drug: Part C - AZD6094 monotherapy (Japan only)
  10. Drug: Part C - AZD9291 in combination with AZD6094 (Japan only)
  11. Drug: Part D - AZD9291 in combination with AZD6094
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including exon 19 deletion and L858R). --- L858R ---

Primary Outcomes

Description: Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.

Measure: Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Description: Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent. Part C monotherapy cohort (Japan only): To investigate and confirm the safety and tolerability of AZD6094 when given orally to Japanese patients with advanced solid malignancies. Part C combination cohort (Japan only): To investigate the safety and tolerability of AZD9291 when given orally to Japanese patients with EGFRm+ NSCLC in combination with AZD6094 who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation. Part D: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 (300 mg OD) in patients with locally advanced or metastatic EGFRm+ NSCLC.

Measure: Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Secondary Outcomes

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-t after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-24 after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Terminal half life after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CL/f after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Volume of distribution after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmin after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times for the duration of treatment.

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUCss after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CLss/f after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Rac after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Time dependency of PK after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1.

Measure: Objective response rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Disease control rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Duration of response

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Percentage change in tumour size

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1 Expansion phase only

Measure: Progression free survival

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.

Measure: Overall survival

Time: Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first.

74 Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer

- Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, 20-30% of patients with EGFR-activating mutations show intrinsic resistance to EGFR-TKI. - EGFR-mutant non-small cell lung cancer (NSCLC) cells with BIM (BCL2L11) deletion polymorphism show the impaired generation of BIM with the proapoptotic BH3 domain, as well as resistance to EGFR-TKI-induced apoptosis. - Both BIM polymorphism (12.9%) and EGFR mutations (50% in lung adenocarcinoma) are more prevalent in the East Asian than in Caucasian populations. BIM is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGFR-TKI in EGFR-mutant NSCLC. - Vorinostat (suberoylanilide hydroxamic acid [SAHA]) is a small-molecule inhibitor of histone deacetylase (HDAC) and induces cell differentiation, cell cycle arrest, and apoptosis in several tumor cells. HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in patients with EGFR-mutant NSCLC in whom resistance to EGFR-TKI is associated with a common BIM polymorphism. EGFR-TKI resistance due to the BIM polymorphism may be able to be circumvented in combination with HDAC inhibition of vorinostat with gefitinib in NSCLC.

NCT02151721
Conditions
  1. Non-Small-Cell Lung Carcinoma
Interventions
  1. Drug: Vorinostat, gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.. Inclusion Criteria: - Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma) - NSCLC of clinicopathologic stage IIIB or IV for which radical radiation therapy is impracticable, or recurrence after surgery - EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance - Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment - Having a history of treatment with cytotoxic anticancer agents (not including pre- or postoperative chemotherapy that has passed 1 or more year from the day of final administration) - Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory - Having a lesion measureable according to the RECIST guidelines revised version 1.1 (20 mm or larger in 10-mm slice CT, 10 mm or larger in 5-mm slice CT, 15 mm or larger in the minor axis of a lymph node). --- L858R ---

- Verified HBs antigen positivity or HCV antibody positivity (excluding the case of confirmed HCV-RNA negativity) Inclusion Criteria: - Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma) - NSCLC of clinicopathologic stage IIIB or IV for which radical radiation therapy is impracticable, or recurrence after surgery - EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance - Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment - Having a history of treatment with cytotoxic anticancer agents (not including pre- or postoperative chemotherapy that has passed 1 or more year from the day of final administration) - Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory - Having a lesion measureable according to the RECIST guidelines revised version 1.1 (20 mm or larger in 10-mm slice CT, 10 mm or larger in 5-mm slice CT, 15 mm or larger in the minor axis of a lymph node). --- L858R ---

Primary Outcomes

Description: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Measure: MTD (Maximum Tolerated Dose)

Time: Second cycle (Day 28)

75 A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients With EGFR-mutant Lung Adenocarcinoma With Acquired Resistance to Erlotinib

This is a phase 2 study. The goal of this study is to find out what effects, good and/or bad, taking erlotinib and ruxolitinib has on the patients and on lung cancer. Erlotinib and ruxolitinib are FDA approved for other indications, but the use of erlotinib and ruxolitinib together has not been studied before and is not FDA-approved.

NCT02155465
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Ruxolitinib
  2. Drug: Erlotinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - Pathologic evidence of advanced (non-operable or metastatic) biopsy-proven stage IV or recurrent lung cancer reviewed at MSKCC. - a documented somatic activating mutation in EGFR (including but not limited to Exon 19 deletion or L858R) - Radiographic progression during treatment with erlotinib. --- L858R ---

Primary Outcomes

Measure: Maximally Tolerated Dose (MTD) (Phase I)

Time: 1 year

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD), at least a 20% increase in the sum of the diameter of the target lesions or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD

Measure: Assess Overall Response Rate

Time: 1 year

Secondary Outcomes

Description: Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0.

Measure: Number of Participants With NCI CTCAE Toxicity

Time: 2 years

Measure: Progression-free Survival

Time: 2 years

76 A Phase I, Open-label, Non-randomised Study to Assess the Effect of Itraconazole (a CYP3A4 Inhibitor) on the Pharmacokinetics of a Single Oral Dose of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2 part study in patients with EGFRm+ non small cell lung cancer (NSCLC), whose disease has progressed on an EGFRm TKI, who are refractory or resistant to standard therapy. Part A will assess the effect of multiple oral doses of itraconazole on the single dose pharmacokinetic (PK) parameters of AZD9291. On completion of Part A, patients may continue to take AZD9291 tablets (Part B) following the collection of the 216 hour sample on Day 19 if they and the Investigator deem it appropriate, until such time as their disease progresses, the Investigator believes they are no longer deriving clinical benefit, or they stop taking AZD9291 for any other reason.

NCT02157883
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Advanced (Inoperable) Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling
  2. Drug: AZD9291
  3. Drug: Itraconazole
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. ECOG performance status 0-1 with no deterioration over the previous 2 weeks. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Secondary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours

Measure: AUC(0-120) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration curve from time zero to last quantifiable dose

Measure: AUC(0-t) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax

Measure: Tmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life

Measure: t1/2 of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution

Measure: Vz/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of maximum plasma AZ5104 concentration

Measure: Cmax of AZ5104

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of maximum plasma AZ7550 concentration

Measure: Cmax of AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ7550 (metabolite to AZD9291) by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, and 216 hours post AZD9291 dose in Part A.

77 An Open-label, Randomised, Phase I, Study to Determine the Effect of Food on the Pharmacokinetics of Single Oral Doses of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2-part study in patients with epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung cancer (NSCLC) whose disease has progressed on treatment with an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI): Part A will determine the effect of food on the pharmacokinetics (PK) of AZD9291; Part B will allow patients further access to AZD9291 and will provide for additional safety data collection. Part A is a randomised, open-label, 2 treatment period crossover study in which patients will each receive a single oral dose of AZD9291 (1 x 80 mg tablet) at breakfast time (approximately 0800) in each of 2 treatment periods (once immediately following a high fat meal [fed], and once in the fasted state [fasted]), with a washout period of 9 days between doses. Approximately 38 patients are planned to be enrolled and dosed; at least 30 evaluable patients will be required to complete Part A (ie, the last PK sample in Treatment Period 2 [TP 2] has been collected). Additional patients may be enrolled to allow for at least 30 evaluable patients.

NCT02163733
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Advanced (Inoperable) Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291 tablets
  2. Procedure: Pharmacokinetic sampling - AZD9291
  3. Other: Dietary Fasted
  4. Other: Dietary High Fat
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 72 hours.

Measure: AUC(0-72) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of maximum plasma AZD9291 concentration.

Measure: Cmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Secondary Outcomes

Description: Area under the plasma concentration curve from zero extrapolated to infinity.

Measure: AUC of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Area under the plasma concentration curve from time zero to last quantifiable dose.

Measure: AUC(0-t) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of area under the plasma concentration time curve from zero to 120 hours.

Measure: AUC(0-120) of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of time to Cmax.

Measure: Tmax of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZD9291 by assessment of the terminal half-life.

Measure: t1/2 of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of apparent clearance following oral administration.

Measure: CL/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apprarent volume of distribution.

Measure: Vz/F of AZD9291

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 72 hours.

Measure: AUC(0-72) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of maximum plasma concentration.

Measure: Cmax of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Area under the plasma concentration curve from time zero to last quantifiable dose for AZ5104 and AZ7550 (metabolites to AZD9291).

Measure: AUC(0-t) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of area under the plasma concentration time curve from zero to 120 hours.

Measure: AUC(0-120) of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of time to Cmax.

Measure: Tmax of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

Description: Pharmacokinetics of AZ5104 and AZ7550 (metabolites to AZD9291) by assessment of the terminal half-life.

Measure: t1/2 of AZ5104 and AZ7550

Time: Blood samples collected on Day 1 and Day 10 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 120, 168, and 216 hours post AZD9291 dose in Part A.

78 A Multicenter Randomized Phase III Study Comparing Second-line Treatment With Chemotherapy Associated or Not to Erlotinib in NSCLC Patients With Secondary Resistance to TKI-EGFR

The current first line treatment of patients with EGFR activating mutation lung cancer is EGFR TKI. Compared to platinum-based chemotherapy, EGFR-TKIs are superior in terms of response rate and progression-free survival. However, an acquired resistance occurs almost constantly. The second-line treatment includes platinum-based chemotherapy in the absence of contraindication. This chemotherapy is then administered after discontinuing EGFR TKIs. However, a rebound phenomenon of the disease was described in patients who discontinued EGFR TKIs. Some clinical teams therefore recommend, as a precaution, in order to avoid any withdrawal phenomenon, to never discontinue EGFR TKIs in patients developing an EGFR TKI acquired resistance. It seems therefore useful to conduct a study to better define the therapeutic strategy to adopt in patients developing an acquired resistance after having received EGFR TKIs as first line treatment.

NCT02178397
Conditions
  1. NSCLC Patients With EGFR Activating Mutation
Interventions
  1. Drug: ERLOTINIB WITH CHEMOTHERAPY
  2. Drug: CHEMOTHERAPY ONLY
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Presence of one of the EGFR activating mutations in the tumor (exon 19 deletion or L858R, G719X or L861Q) - One additional line of previous chemotherapy is allowed if administered in adjuvant or neoadjuvant setting and received more than six months before. --- L858R ---

Primary Outcomes

Description: Efficacy will be assessed by the PFS, define as time between randomization of the patient in the study and disease progression (local, regional, distant and second cancer) or death (all causes). Alive patients free of progression will be censored at the last follow-up.

Measure: Efficacy by PFS

Time: From date of randomization until the date of first documented progression evaluated every 6-9 weeks

Secondary Outcomes

Description: difference between the scores of QoL at baseline and at 4 months after inclusion for the three targeted dimensions of EORTC QLQ-C30 (global quality of life, fatigue and physical functioning). A difference or 10 points or more at 4 months after inclusion for one score between the 2 arms will be considered as clinically relevant.

Measure: scores of QoL

Time: at 4 months after inclusion

Description: Overall survival defined as time interval between randomization and death (all causes). Alive patients will be censored at the last date of news or data cut off

Measure: Overall survival

Time: From date of randomization until the date of death from any cause, whichever came first, assessed up to 100 months

Description: Tumoral response (complete response, partial response, stable disease, progression) according to RECIST 1.1

Measure: Tumoral response

Time: every 6-9 weeks

Description: Toxicities according to NCI-CTC-AE v.4

Measure: Toxicities

Time: From date of randomization until study participation, assessed up to 100 months

Description: Rebound phenomenon (flare) defined by a hospitalization or a death within 3 weeks for disease progression after the end of TKI EGFR treatment (in the arm without EGFR TKI) and date of onset

Measure: Rebound phenomenon (flare)

Time: within 3 weeks after disease progression before inclusion

79 A Pilot Study Testing the Detection of Oncogenic Tumor Mutations in the Urine and Blood of Lung and Colorectal Cancer Patients

The purpose of this study is to see whether gene mutations can be found in the urine or blood of lung cancer patients and urine of colorectal cancer patients. Gene mutations are when DNA in a gene is damaged in a way that changes the genetic message carried by that gene. Gene mutations can sometimes cause lung cancers. These gene mutations are only found in lung and colorectal cancer cells, not the normal cells in your body. All lung cancer tumors and colorectal cancer tumors are now tested for different gene mutations as their presence affects lung cancer treatment. Tumor samples obtained from a biopsy or surgery are typically tested for these gene mutations.

NCT02186236
Conditions
  1. Lung Cancer
  2. Colorectal Cancer
MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine

- Patients must have had or intend to have EGFR mutation testing (specifically including exon 19 deletions and L858R) performed on their tumor with results available from a CLIA certified laboratory. --- L858R ---

- Patients must have a confirmed EGFR mutant lung cancer (exon 19 deletions and L858R) with molecular testing results available from a CLIA certified laboratory. --- L858R ---

Primary Outcomes

Description: The Trovagene urine-based assay will test to determine the presence of EGFR mutation in cfDNA or RAS/RAF mutation in colorectal cancer

Measure: EGFR detection in urinary cell free DNA [cfDNA]

Time: 2 years

Description: urine assay to identify EGFR mutations as compared to the gold standard of tumor tissue.

Measure: To validate the Trovagene urine assay

Time: 2 years

Secondary Outcomes

Description: The plasma-based assay will test to determine the presence of EGFR mutation in CTC and in cfDNA.

Measure: EGFR detection in plasma circulating tumor cells [CTC] and plasma cfDNA)

Time: 2 years

80 A Phase Ib Open-label Clinical Trial of Once Daily Oral Treatment of Afatinib Plus Weekly Intravenous Infusion of Xentuzumab (BI 836845) in Patients With EGFR Mutant Non-small Cell Lung Cancer With Progression Following Prior EGFR Tyrosine Kinase Inhibitors

Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy). Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs. Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

NCT02191891
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: BI 836845
  2. Drug: afatinib
MeSH:Carci Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R ---

AZD9291 or CO-1686) Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD) of BI 836845 in combination with afatinib - part A

Time: up to 12 months

Measure: Dose limiting toxicity (DLT) during the first treatment course - part A

Time: up to 28 days

Measure: Objective response (OR), defined as complete response (CR) or partial response (PR)

Time: up to 12 months

Secondary Outcomes

Measure: Disease control (DC), defined as complete response (CR), partial response (PR) or stable disease (SD)

Time: up to 12 months

Measure: Time to objective response, defined as the duration of time from the date of first treatment administration until objective response

Time: up to 12 months

Measure: Duration of objective response, defined as the duration of time from first objective response to the date of first objective tumour progression or death due to any cause

Time: up to 12 months

81 An Open-label Study of the Oral Administration of ASP8273 in Patients With Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

Purpose of the study is to determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. - the safety and tolerability of ASP8273. - the pharmacokinetics (PK) of ASP8273. - the antitumor activity of ASP8273.

NCT02192697
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: ASP8273
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the del ex19, L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using the Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE ver 4.0 - JCOG)

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by Dose Limiting Toxicities (DLTs)

Time: Up to Day 23

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR) at Week 24

Time: Week 24

Secondary Outcomes

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Measure: Phase I: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase I: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase I: Overall response rate (CR+PR)

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase I: Disease control rate (CR+PR+SD)

Time: Up to 18 months

Measure: Phase II: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase II: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase II: Disease control rate

Time: Up to 18 months

Measure: Phase II: Progression-free survival (PFS)

Time: Up to 18 months

Measure: Phase II: Overall survival (OS)

Time: Up to 18 months

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR)

Time: Up to 18 months

82 Randomized Study of Erlotinib vs Observation in Patients With Completely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase III ALCHEMIST trial studies how well erlotinib hydrochloride compared to observation works in treating patients with stage IB-IIIA non-small cell lung cancer that has been completely removed by surgery. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02193282
Conditions
  1. Lung Non-Squamous Non-Small Cell Carcinoma
  2. Stage IB Lung Non-Small Cell Carcinoma AJCC v7
  3. Stage II Lung Non-Small Cell Cancer AJCC v7
  4. Stage IIA Lung Non-Small Cell Carcinoma AJCC v7
  5. Stage IIB Lung Non-Small Cell Carcinoma AJCC v7
  6. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Other: Clinical Observation
  2. Drug: Erlotinib Hydrochloride
  3. Other: Laboratory Biomarker Analysis
  4. Other: Placebo Administration
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Lung Non-Squamous Non-Small Cell Carcinoma Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib hydrochloride (erlotinib) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R ---

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Lung Non-Squamous Non-Small Cell Carcinoma Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib hydrochloride (erlotinib) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Estimated using the method of Kaplan-Meier survival curves and a 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare OS between the two arms. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess whether the distribution of OS times differ with respect to treatment regimen after having adjusted for the stratification factors as well as other potential prognostic and treatment covariates.

Measure: Overall survival (OS)

Time: The time from randomization until death, assessed up to 10 years

Secondary Outcomes

Description: DFS will be defined as the proportion of patients alive and disease free at 2 years from the date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Disease free survival (DFS) rate

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed at 2 years

Description: Will be defined as the proportion of patients alive at 5 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 5 years

Time: At 5 years

Description: Will be defined as the proportion of patients alive at 10 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 10 years

Time: At 10 years

Description: Estimated using the method of Kaplan-Meier survival curves (21). A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall disease free survival (DFS) between the erlotinib hydrochloride and observation arms

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed up to 10 years

Description: The maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. All adverse events analysis will entail comparisons between the arms within Arms A and B, respectively. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.

Measure: Incidence of adverse events associated with each treatment arm

Time: Up to 10 years

83 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Simvastatin (a Sensitive CYP3A4 Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of simvastatin and simvastatin acid, following multiple oral dosing of AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197234
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling - AZD9291
  2. Drug: Simvastatin
  3. Drug: AZD9291 tablet dosing
  4. Procedure: Pharmacokinetic sampling - simvastatin
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of simvastatin by assessment of maximum plasma simvastatin concentration

Measure: Cmax of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Secondary Outcomes

Description: Pharmacokinetics of simvastatin and simvastatin acid by time to Cmax

Measure: Tmax of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Rate and extent of absorption of simvastatin by assessment of apparent clearance following oral administration

Measure: CL/F of Simvastatin

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of maximum plasma simvastatin acid concentration

Measure: Cmax of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin acid by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

Description: Pharmacokinetics of simvastatin and simvastatin acid by assessment of area under the plasma concentration time curve from time zero to last quantifiable dose

Measure: AUC(0-t) of Simvastatin and Simvastatin Acid

Time: Blood samples collected on Days 1 and 31 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 28, and 32 hours post simvastatin dose in Part A

84 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of Rifampicin (a CYP3A4 Inducer) on the Pharmacokinetics of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of rifampicin on the pharmacokinetic (PK) parameters of AZD9291 and metabolites AZ5104 and AZ7550 following multiple oral dosing of both rifampicin and AZD9291 in a fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients who complete Part A will be able to enter part B, and continue to receive AZD9291 80 mg once daily until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02197247
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling - AZD9291
  2. Drug: Rifampicin
  3. Drug: AZD9291 tablet dosing
  4. Procedure: Pharmacokinetic sampling - rifampicin
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of maximum plasma concentration at steady state (Css,max). AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Maximum Plasma Concentration for AZD9291 After Dosing Alone and in Combination With Rifampicin (Css,Max)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 doses were first without, then with rifampicin (Periods 1 and 2, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval for AZD9291 After Dosing Alone and in Combination With Rifampicin (AUCtau)

Time: Samples collected on Day 28 following AZD9291 alone and Day 49 following AZD9291 and rifampicin at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of AZD9291 by assessment of Css,max. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of Css,Max for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of Css,max. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Max for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of Css,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of AUCtau. AZD9291 alone before rifampicin (Period 1) and AZD9291 alone after rifampicin (Period 3).

Measure: Assessment of AUCtau for AZD9291 Before and After Rifampicin

Time: Samples collected on Day 28 and 77 following AZD9291 alone at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ5104 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ5104 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZ7550 (metabolite) by assessment of AUCtau. AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of AUCtau for AZ7550 (Metabolite)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of AUCtau. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of AUCtau for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of time to reach maximum plasma concentration at steady state (tss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Tss,Max for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of tss,max. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Tss,Max for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of Css,Min for AZD9291, and AZ5104 and AZ7550 (Metabolites)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of minimum plasma concentration at steady state (Css,min). AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of Css,Min for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of AZD9291 by assessment of the apparent plasma clearance following oral administration and multiple dosing (CLss/F). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of CLss/F for AZD9291

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Rate and extent of absorption of rifampicin by assessment of CLss/F. AZD9291 dosing in combination with rifampicin (Period 2).

Measure: Assessment of CLss/F for Rifampicin

Time: Samples collected on Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for Css,max (MRCss,max). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of Css,Max for AZ5104 and AZ7550 (MRCss,Max)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

Description: Assessment of the metabolite to parent ratio (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) for AUCtau (MRAUCtau). AZD9291 dosing alone and in combination with rifampicin (all periods).

Measure: Assessment of the Metabolic Ratios of AUCtau for AZ5104 and AZ7550 (MRAUCtau)

Time: Samples collected on Day 28 and 77 (following AZD9291 alone) and Day 49 (following AZD9291 and rifampicin) at pre-dose, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours post dose in Part A.

85 A Phase 1b Study of Erlotinib and Momelotinib for the Treatment of Epidermal Growth Factor Receptor (EGFR) Mutated EGFR Tyrosine Kinase Inhibitor (TKI) Naïve Metastatic Non-Small Cell Lung Cancer (NSCLC)

This study will evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) of momelotinib (MMB) and erlotinib, as well as define the maximum tolerated dose (MTD) of momelotinib (MMB) combined with erlotinib in adults with epidermal growth factor receptor (EGFR)-mutated, EGFR tyrosine kinase inhibitor (TKI) naive metastatic non-small cell lung cancer (NSCLC). Participants will be sequentially enrolled to receive progressively increasing doses of momelotinib (MMB) in combination with erlotinib. Escalation of momelotinib (MMB) doses will proceed to the MTD, defined as the highest tested dose associated with dose-limiting toxicities (DLT) during the first 28 days of combined erlotinib and momelotinib (MMB) treatment. There will be four dose levels and each treatment cycle will consist of 28 days.

NCT02206763
Conditions
  1. EGFR Mutated EGFR TKI Naive Metastatic NSCLC
Interventions
  1. Drug: Momelotinib (MMB)
  2. Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).. Key Inclusion Criteria: - Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation - Treatment naive OR one prior standard chemotherapy that is platinum-based - Adequate organ function defined as follows: - Hepatic: Total bilirubin < upper limit of the normal range (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN - Hematological: absolute neutrophil count (ANC) ≥1500 cells/mm^3, platelet ≥ 100,000 cells/mm^3, hemoglobin ≥ 9.0 g/dL - Renal: Serum creatinine < ULN OR calculated creatinine clearance (CLcr) of ≥ 60 ml/min - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Key Exclusion Criteria: - Known positive status for human immunodeficiency virus (HIV) - Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C) - Presence of > Grade 1 peripheral neuropathy - Symptomatic leptomeningeal, brain metastases, or spinal cord compression. --- L858R ---

Key Inclusion Criteria: - Metastatic NSCLC with documented EGFR exon 19 deletion or exon 21 (L858R) substitution mutation - Treatment naive OR one prior standard chemotherapy that is platinum-based - Adequate organ function defined as follows: - Hepatic: Total bilirubin < upper limit of the normal range (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN - Hematological: absolute neutrophil count (ANC) ≥1500 cells/mm^3, platelet ≥ 100,000 cells/mm^3, hemoglobin ≥ 9.0 g/dL - Renal: Serum creatinine < ULN OR calculated creatinine clearance (CLcr) of ≥ 60 ml/min - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 Key Exclusion Criteria: - Known positive status for human immunodeficiency virus (HIV) - Chronic active or acute viral hepatitis A, B, or C infection (testing required for hepatitis B and C) - Presence of > Grade 1 peripheral neuropathy - Symptomatic leptomeningeal, brain metastases, or spinal cord compression. --- L858R ---

Primary Outcomes

Description: Dose limiting toxicities refer to toxicities experienced during the first 28 days of combined erlotinib and momelotinib (MMB) treatment that have been judged to be clinically significant and related to study treatment.

Measure: Incidence of Dose Limiting Toxicities (DLTs)

Time: Up to 28 days

Measure: Safety as Assessed by the Incidence of Adverse Events (AEs)

Time: Up to 2 years plus 30 days

Measure: Safety as Assessed by the Percentage of Participants Experiencing Treatment-Emergent Graded Lab Abnormalities (including Chemistry, Coagulation, Hematology, and Urinalysis)

Time: Up to 2 years plus 30 days

Measure: Change from Baseline in Vital Signs

Time: Up to 2 years

Secondary Outcomes

Description: Progression-free survival is defined as the interval from first dose date of study drug (MMB/erlotinib) to the earlier of the first documentation of definitive disease progression or death from any cause; definitive disease progression is progression based on RECIST criteria v1.1.

Measure: Progression-Free Survival

Time: Until disease progression (up to 2 years)

Description: Overall survival is defined as the interval from first dose date of study drug (MMB/erlotinib) to death from any cause.

Measure: Overall Survival

Time: Until disease progression (up to 2 years)

Description: Overall response rate is defined as the proportion of participants who achieve a complete response or partial response.

Measure: Overall Response Rate

Time: Until disease progression (up to 2 years)

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: Pharmacokinetic (PK) Parameter: Cmax of momelotinib (MMB)

Time: Predose and up to 24 hours postdose

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of momelotinib (MMB)

Time: Predose and up to 24 hours postdose

Description: Cmax is defined as the maximum observed concentration of drug.

Measure: PK Parameter: Cmax of Erlotinib

Time: Predose and up to 24 hours postdose

Description: AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

Measure: PK Parameter: AUCtau of Erlotinib

Time: Predose and up to 24 hours postdose

86 An Open Label, Single-arm Phase IV Study to Assess the Efficacy and Safety of Afatinib as Second-line Therapy for Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harbouring an EGFR Mutation (Del19 or L858R) Who Have Failed First-line Treatment With Platinum-based Chemotherapy

The objectives of this single-arm, open-label trial are to assess the efficacy and safety of afatinib as second line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring a common EGFR mutation who have failed first-line platinum-based chemotherapy and to demonstrate that the efficacy and safety are comparable to the results seen in previous trials.

NCT02208843
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Afatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

An Open Label, Single-arm Phase IV Study to Assess the Efficacy and Safety of Afatinib as Second-line Therapy for Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Harbouring an EGFR Mutation (Del19 or L858R) Who Have Failed First-line Treatment With Platinum-based Chemotherapy. --- L858R ---

2. Documented EGFR mutation (L858R and/or Deletion 19) with no other known EGFR mutation. --- L858R ---

Primary Outcomes

Description: As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions

Measure: Objective Tumour Response (Complete Response [CR], Partial Response [PR]) as Assessed by the Investigator According to the RECIST Version 1.1

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

Secondary Outcomes

Description: Progression-free survival (PFS) is the time from treatment start to disease progression (or death if the patient died before progression). PFS as assessed based on investigator review according to the response evaluation criteria in solid tumours (RECIST) version 1.1.

Measure: Progression-free Survival (PFS) as Assessed by the Investigator According to RECIST 1.1.

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

Description: As Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), =30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

Measure: Disease Control (CR, PR, Stable Disease [SD]) as Assessed by the Investigator According to RECIST 1.1

Time: Post baseline tumour-imaging was performed at every 8 weeks until Week 56 and then every 12 weeks; up to 802 days

87 A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients With EGFR Mutation Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC)

This is the first time in patient study to assess the safety, tolerability and preliminary efficacy of AZD3759 in patients with advanced Non Small Cell Lung Cancer (NSCLC) In this study, patients with Leptomeningeal Metastasis and Brain Metastasis may also be enrolled to assess the anti-tumour efficacy, safety, pharmacokinetics and potential biological activity of AZD9291

NCT02228369
Conditions
  1. EGFR Mutation Positive Advanced Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD3759
  2. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del). --- L858R ---

Primary Outcomes

Description: Adverse events will be collected from Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.Physical exam (screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation). ECG and vital signs (screening, Day 1 and 2 of Cycle 0 for AZD3759 cohorts, Day 8 of Cycle 1 for AZD3759 cohorts, Day 1 of every 3-week cycle, treatment discontinuation, and if occurrence of any cardiac adverse event). Lab variables (screening, first dosing day, Day 1, 8 and 15 of multiple dosing, Day 1 of every 3-week cycle and treatment discontinuation). Eye exam (at screening and study drug discontinuation and upon occurrence of any visual AE). Echocardiogram or multigated radionuclide angiography (at screening,whenever necessary as clinically indicated throughout the study for AZD3759 cohorts.

Measure: Safety and Tolerability (The number of patients with each AE by system organ class, preferred term and CTCAE grade)

Time: From Informed consent until the end of the follow-up period which is defined as 28 days (+7 days) after study treatment is discontinued.

Secondary Outcomes

Description: The parent drug and N-demethylated metabolite in plasma samples will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, hour in Day 1; 24hour in Day 2 and 48hour in Day 3. AUC: Area Under Curve

Measure: Plasma concentration of AZD3759 and metabolite and pharmacokinetics parameters after single dose of AZD3759(Cmax, tmax, terminal rate constant, half life, AUC, clearance, volume of distribution, mean residence time)

Time: Cycle 0 Day 1 to 3 in Part A patients.

Description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1 . The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients. AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma,urine,cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).

Time: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A. CSF samples: pre-dose of Cycle 1 Day 8 in BM; Pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in LM

Description: The parent drug and N-demethylated metabolite in plasma samples from all patients will be analyzed: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12hour on Cycle 1 Day 8 and Cycle 3 Day 1. The parent drug and N-demethylated metabolite in urine samples from Part A patients will be analyzed: 0-12h at Cycle 1 Day 8. The parent drug and N-demethylated metabolite in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 1 Day 8 in brain metastasis patients; pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in leptomeningeal metastasis patients.

Measure: Plasma,urine, cerebrospinal fluid concentration of AZD3759 and metabolite and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)

Time: Blood samples: Cycle 1 Day 8 and Cycle 3 Day 1 in all patients. Urine samples: 0-12h at Cycle 1 Day 8 in Part A patients. CSF samples: pre-dose of Cycle 1 Day 8 and Cycle 3 Day 1 in Part B patients .

Description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolite and pharmacokinetics parameters after multiple dose of AZD9291(Cmax,ss, tmax,ss, Cmin,ss, AUCss, CLss/F).

Time: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.

Description: The parent drug and metabolites in plasma samples from all patients treated with AZD9291 will be analyzed: pre-dose of Cycle 1 Day 1, 8, 15; pre-dose, 1, 1.5, 2, 4, 6, 8, 10, 12, 24hour on Cycle 2 Day 1. The parent drug and metabolites in cerebrospinal fluid samples will be analyzed: pre-dose of Cycle 2 Day 1 in brain metastasis patients; pre-dose of Cycle 2 Day 1 and Cycle 3 Day 1 in leptomeningeal metastasis patients . AUCss: Area Under Curve Steady State CLss: Clearance Steady State

Measure: Plasma, cerebrospinal fluid concentration of AZD9291 and metabolites and pharmacokinetics parameters after multiple dosing (extent of accumulation, renal clearance, time dependency of pharmacokinetics and amount of drug excreted)

Time: Blood samples: Cycle 1 Day 1, 8, 15 and Cycle 2 Day 1. Cerebrospinal fluid samples: pre-dose of Cycle 2 Day 1 and pre-dose of Cycle 3 Day 1.

Description: After 28-day follow-up visit, patients will be followed for overall survival via telephone every 6 weeks until death, lost to follow-up or consent withdrawal

Measure: Overall survival follow up for all expansion patients

Time: Every 6 weeks after the 28- day safety follow-up visit

Description: Blood collection at pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15 to evaluate if AZD3759 affects 4b-hydroxy cholesterol which is an endogenous marker of CYP enzyme induction

Measure: 4b-hydroxy cholesterol in Part B patients with BM

Time: pre-dose of Cycle 0 Day 1 and Cycle 1 Day 15

Description: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 hour of Cycle 0 Day 1and Day 4; 24 hour of Cycle 0 Day 2 and Day 4.A Mixed Effects model with treatment (fed/fasted) and period as fixed effects and patient as a random effect will be used to compare AUC/Cmax in the fed state with AUC/Cmax in the fasted state.

Measure: The effect of food on the pharmacokinetics of a single dose of AZD3759 in plasma

Time: Cycle 0 Day 1 to Day 4 in Part B patients with BM

Description: Cerebrospinal fluid collection at screening and every 6 weeks until progression to evaluate the cerebrospinal fluid response rate which is defined as the percentage of leptomeningeal metastasis patients who have at least one cerebrospinal fluid response (100% clearance of tumour cells from cerebrospinal

Measure: Cerebrospinal fluid response rate for patients with LM and/or BM

Time: Screening and every 6 weeks (relative to first dose of multiple dosing) until progression, expected average 6 months

Description: Quality of life questionnaire-Brain Cancer 20 questionnaire completed by patients at screening, Day 1 of every 3-week cycle and treatment discontinuation. Use relevant symptom questions to evaluate improvement of central nervous system symptoms.

Measure: Changes from baseline in central nervous system symptoms (analyzed from QLQ-BN20) in patients with LM treated with AZD3759 /AZD9291

Time: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.

Description: Neurological exam will be performed: screening, single dosing day, Day 1 of every 3-week cycle of multiple dosing and treatment discontinuation

Measure: Changes from baseline in neurological exam in patients with LM treated with AZD3759 /AZD9291

Time: Screening, Day 1 of every 3-week cycle and treatment discontinuation, expected average 6 months.

Description: ORR assessed through the number of patients who achieve a disease response (i.e. complete response or partial response) assessed according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease and overall disease

Measure: Measurement of Objective Response Rate (ORR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: DCR assessed through the number of patients who achieve a best response of confirmed CR, confirmed PR or responding, or stable disease according to modified RECIST 1.1 criteria for central nervous system disease, extracranial disease, leptomeningeal disease and overall disease

Measure: Measurement of Disease Control Rate (DCR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: RR assessed through the number of patients who have at least one confirmed response of Complete Response or Responding prior to any evidence of progression according to modified RECIST 1.1 criteria for leptomeningeal disease

Measure: Measurement of Response Rate (RR)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: PFS assessed through change in tumour size (as well as assessment of non-target lesions and appearance of any new lesions) according to modified RECIST 1.1 criteria for Part B patients with brain metastasis and patients with leptomeningeal metastasis

Measure: Measurement of Progression Free Survival (PFS)

Time: Screening within 28days of treatments start and then every 6 weeks ± 1week(relative to first dose of multiple dosing) until objective disease progression or withdrawal from study,expected average 6 months.

Description: Best LM assessment via LANO criteria through the number of patients with LM present at baseline, without a requirement for confirmation. LANO assessments will be mapped to RECIST-like scores and performed via central imaging reading.

Measure: Best Leptomeningeal Metastasis (LM) assessment for AZD9291 LM patients

Time: Screening within 28days

88 A Phase 2, Open-Label, Multi-Center Study to Assess Safety and Efficacy of Second/Third-Line Treatment With NAB®-Paclitaxel (ABI-007) In Combination With Epigenetic Modifying Therapy Of CC-486, Or Immunotherapy of Durvalumab (MEDI4736), Or As Monotherapy In Subjects With Advanced Non-Small Cell Lung Cancer (NSCLC): Abound.2L+

This is a Phase 2, open-label, multicenter study to assess the efficacy and safety of second/third-line treatment with nab-paclitaxel in combination with the epigenetic modifying therapy of CC-486 or immunotherapy of durvalumab, and nab-paclitaxel monotherapy in subjects with advanced non-small cell lung cancer (NSCLC).

NCT02250326
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: nab-paclitaxel IV
  2. Drug: CC-486
  3. Drug: Duravalumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Known activating EGFR mutations (such as exon 19 deletions or L858R). 5. Known activating EML4-ALK mutations. --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time in months from the date of randomization/assignment to the date of disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria documented by computed tomography (CT) scan, not including symptomatic deterioration, or death (any cause) on or prior to the clinical cut-off date, which ever occurred earlier. Participants who did not have disease progression and had not died, regardless of whether they were discontinued from treatment, were censored at the date of last tumor assessment, on or prior to the clinical cut-off date that the participant was progression free. Progressive Disease was defined as at least a 20% increase in the sum of diameters of target lesions from nadir.

Measure: Kaplan Meier Estimate of Progression-Free Survival (PFS) as Assessed by the Investigator

Time: From date of first dose of IP to DP; up to data cut-off date of 30 August (Aug) 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 December (Dec) 2017 for Durva + nab-paclitaxel; participants were followed for PFS for up to 18 months

Secondary Outcomes

Description: Disease control rate was defined as the percentage of participants who had a CR, PR or SD during the course of the study, according to RECIST version 1.1 criteria, as evaluated by the investigator. RECIST Version 1.1 criteria is defined as follows: Complete Response is the disappearance of all target lesions; Partial Response is at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable Disease is neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. Responses were evaluated every 6 weeks.

Measure: Percentage of Participants Who Achieved a Complete Response (CR), Partial Response (PR) or Stable Disease (SD) According to RECIST V 1.1 Criteria

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Overall Response was defined as percentage of participants who achieved a radiologic confirmed complete response or partial response according to RECIST V 1.1 criteria and compared with baseline among all tumor assessments, where baseline was the last CT obtained prior to or on Day 1 of treatment. Per RECIST V 1.1 criteria, a CR is defined as a disappearance of all target lesions; a PR is defined as having at least a 30% decrease in the sum of diameters of target lesions from baseline. Responses were evaluated every 6 weeks.

Measure: Percentage of Participants Who Achieved a Best Overall Response of Complete Response or Partial Response According to RECIST V 1.1 Criteria

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Overall survival was defined as the time in months between randomization/treatment assignment and death from any cause. Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off, whichever was earlier. Participants who were lost to follow-up prior to the end of the study or who were withdrawn from the study were censored at the time of last contact.

Measure: Kaplan Meier Estimate of Overall Survival (OS)

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; participants were followed for overall survival up to 30 months

Description: TEAEs were defined as any adverse event or serious adverse event that occurred or worsened on or after the day of the first dose of the IP through 28 days after the last dose of IP for Arms A and C or up to 90 days after the last dose for Arm B, and those SAEs made known to the investigator at any time thereafter that are suspected of being related to IP. A serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild l intervention/therapy required Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death.

Measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Entire Treatment Period

Time: TEAEs were collected up to 4 weeks after receiving last dose of IP for nab-paclitaxel and CC-486 + nab-paclitaxel, and up to 90 days after the last IP dose for Durva + nab-paclitaxel; TEAEs were collected up to 86.1 weeks

Description: The discontinuation rate was defined as the percentage of participants who had study drug discontinued and was assessed throughout the conduct of the study.

Measure: Percentage of Participants Who Discontinued Study Treatment

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks.

Measure: Dose Intensity Per Week of Nab-Paclitaxel

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks.

Measure: Dose Intensity Per Week of CC-486

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: Dose intensity was the cumulative dose divided by the dosing period in weeks).

Measure: Dose Intensity Per Week of Durvalumab

Time: Up to 30 Aug 2017 for nab-paclitaxel and CC-486 + nab-paclitaxel and 23 Dec 2017 for Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

Description: A dose reduction occurred when the dose assigned at a visit was lower than the dose assigned at the previous visit. Dose reductions were typically caused by clinically significant laboratory abnormalities and/or TEAEs or toxicities.

Measure: Percentage of Participants With Study Drug Dose Reductions

Time: Up to 16 Jan 2017 for CC-486 + nab-paclitaxel and up to 23 Dec 2017 for nab-paclitaxel and Durva + nab-paclitaxel; maximum treatment duration = 82.1 weeks, 52.6 weeks and 66.1 weeks for nab-paclitaxel, CC-486 + nab-paclitaxel and Durva + nab-paclitaxel

89 A Randomized, Open-Label, Multicenter, Phase 3 Trial Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Subjects Receiving First Cytotoxic Chemotherapy for Metastatic or Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) and Who Are Current or Former Smokers

This is a 2-arm, Phase 3 study to evaluate the safety and efficacy of veliparib plus carboplatin and paclitaxel versus the Investigator's choice of standard chemotherapy in Lung Subtype Panel (LSP) positive subjects with metastatic or advanced non-squamous non-small cell lung cancer.

NCT02264990
Conditions
  1. Non-squamous Non-small Cell Lung Cancer
Interventions
  1. Drug: Paclitaxel
  2. Drug: Pemetrexed
  3. Drug: Carboplatin
  4. Drug: Cisplatin
  5. Drug: Veliparib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Subject has peripheral neuropathy ≥ grade 2. - Subject has squamous NSCLC, or an untreated known EGFR mutation of exon 19 deletion or L858R mutation in exon 21, or a known ALK gene rearrangement. --- L858R ---

Primary Outcomes

Description: Overall survival is defined as the number of days from the date that the participant was randomized to the date of the participant's death.

Measure: Overall Survival (OS) in the LSP (Lung Subtype Panel) positive subgroup

Time: Up to 3 years from first dose of study drug.

Secondary Outcomes

Description: Objective response rate is defined as the proportion of participants with complete or partial response as determined by the investigator per Response Evaluation Criteria In Solid Tumors (version 1.1).

Measure: Objective Response Rate (ORR) in the LSP (Lung Subtype Panel) positive subgroup and all participants

Time: Up to 3 years from first dose of study drug

Description: Progression-free survival is defined as the number of days from participant randomization to the date the participant experiences an event of disease progression (PD) or death (all causes of mortality), if PD is not reached.

Measure: Progression Free Survival (PFS) in the LSP (Lung Subtype Panel) positive subgroup and all participants

Time: Up to 5 years from first dose of study drug

Description: Overall survival is defined as the number of days from the date that the participant was randomized to the date of the participant's death.

Measure: Overall Survival (OS) in all participants

Time: Up to 5 years from first dose of study drug.

Other Outcomes

Description: Participants will answer the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L) and the Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 questionnaire.

Measure: Change in Quality of Life in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: From Screening (prior to dosing) up to 2 years

Description: The duration of overall response for a participant is defined as the number of days from when the criteria is met for a complete or partial response (whichever occurs first), to the date that progressive disease (PD) is objectively documented.

Measure: Duration of overall response (DOR) in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: Up to 3 years from randomization.

Measure: Change in Eastern Cooperative Oncology Group (ECOG) Performance Status in the LSP (Lung Subtype Panel) positive subgroup and in all participants

Time: From Screening (prior to dosing) up to 2 years

90 Phase II Trial of Afatinib in Combination With Weekly Paclitaxel in the Second Line Treatment of HER2 Amplified Advanced Gastric, Gastroesophageal Junction and Esophageal Cancer

The investigators are doing this research program to find out if the investigational drug, afatinib which is a medication known to block the function of the ErbB2 protein might help standard chemotherapy, in particular paclitaxel, work better. Afatinib (GILOTRIF) is a highly potent, irreversible inhibitor of the EGFR and HER2. On July 12, 2013 the United States Food and Drug Administration (US FDA) approved afatinib for the first-line treatment of patients with metastatic non-small cell lung cancer whose tumors had specific EGFR gene mutations (exon 19 deletions or exon 21 i.e. L858R substitution mutations) as detected by an FDA approved test. Paclitaxel is a standard, anti-cancer medicine that has been approved by the US Food and Drug Administration (FDA) for the treatment of lung cancer. The combination of Afatinib and Paclitaxel are considered investigational when used in this research program. An investigational drug is a drug that is not approved by the FDA for its indication.

NCT02274012
Conditions
  1. HER-2 Positive Gastric Cancer
  2. Gastrooesophageal Cancer
  3. Esophageal Cancer
Interventions
  1. Drug: Afatinib
  2. Drug: Paclitaxel
MeSH:Esophageal Neoplasms
HPO:Esophageal neoplasm

L858R substitution mutations) as detected by an FDA approved test. --- L858R ---

Primary Outcomes

Measure: Change of tumor burden (in centimeters) for participants during protocol therapy

Time: Change from Baseline Tumor burden, measured every 8 weeks, up to approximately 4 years

Secondary Outcomes

Description: Safety of BIBW 2992 will be evaluated as indicated by intensity and incidence of adverse events, graded according to US National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) Version 4.0. Safety endpoints include: events leading to dose reduction events leading to permanent treatment discontinuation the overall incidence and CTC criteria grade of adverse events, as well as relatedness of adverse events to treatment causes of death

Measure: Number of participants with adverse events.

Time: up to approximately 36 months

Description: CTC number changes from cycle 1, day 1 to cycle 2/3, day 1 will be correlated with response rate, progression-free survival as well as skin toxicity.

Measure: Total number of circulating tumor cell (CTC) numbers.

Time: up to approximately 36 months

Measure: Clinical benefit in progression free survival.

Time: every 3 months up to approximately 4 years

Measure: Clinical benefit in overall survival.

Time: every 3 months up to approximately 4 years

Description: Diagnostic tumor specimens will be retrieved for all subjects participating in the protocol. These specimens will be used for confirmation of ErbB2 status as well as correlative analyses of clinical response.

Measure: ErbB2 levels benefit during therapy.

Time: up to approximately 4 years

91 A Prospective Study of Plasma Genotyping as a Noninvasive Biomarker for Genotype-directed Cancer Care

Tumor genotyping has become an essential biomarker for the care of advanced lung cancer and melanoma, and is currently used to identify patients for treatment with targeted kinase inhibitors like erlotinib and vemurafenib. However, tumor genotyping can be slow and cumbersome, and is limited by availability of tumor biopsy tissue for testing. The aim of this study is to prospectively evaluate a blood-based genotyping tool that can quantify the presence of oncogenic mutations (EGFR, KRAS, BRAF) in patients with lung cancer and melanoma. This assay is being studied both as a diagnostic tool for classifying patient genotype, and a serial measurement tool for quantification of response and progression on therapy.

NCT02279004
Conditions
  1. NSCLC
  2. Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.. Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- L858R ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M --- --- L858R ---

Primary Outcomes

Description: We will determine the accuracy of a droplet digital PCR (ddPCR)-based plasma genotyping assay in performing noninvasive tumor genotyping.

Measure: Accuracy of Plasma Genotyping Assay

Time: 2 years

Secondary Outcomes

Description: The amount of time required to perform this noninvasive genotyping assay.

Measure: Turnaround Time of Plasma Genotyping Assay

Time: 2 years

Description: The ability of serial quantitative ddPCR-based plasma genotyping to predict early treatment failure in patients initiating a new line of therapy.

Measure: Early Treatment Failure

Time: 2 years

Description: We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.

Measure: Accuracy of Plasma NGS

Time: 2 years

92 Blood Detection of EGFR Mutation For Iressa Treatment

This study was proposed to validate the efficacy of gefitinib as first-line therapy in advanced lung adenocarcinoma with EGFR mutation determined by plasma cf-DNA.

NCT02282267
Conditions
  1. Lung Adenocarcinoma
Interventions
  1. Drug: Gefitinib
MeSH:Adenocarcinoma of Lung

- EGFR sensitive mutation (including exon 19 del and/or exon 21 L858R) in plasma cf-DNA by ddPCR. --- L858R ---

Primary Outcomes

Measure: objective response rate of gefitinib

Time: up to 6 months

93 Retrospective Multicenter Observational Study in NSCLC Patients With Epidermal Growth Factor Receptor (EGFR) Activating Mutation Treated First Line by Tyrosine Kinase Inhibitor (TKI)

The purpose of our retrospective study is to describe which circumstances EGFR TKI is continued despite progression according to the usual Response Evaluation CrIteria in Solid Tumours (RECIST) in patients with EGFR activating mutations and acquired resistance to EGFR TKI .We will collect their social and demographic data (age, sex), first Progression Free Survival ( PFS) - from start of EGFR TKI to 1st progression PFS 1- and - from first progression according to RECIST to second progression : PFS2- , Overall Survival (OS) - from diagnosis OS 1 and from first progression OS 2 -, mutational status. We will analyze more closely the mode of progression (site), the therapeutic approach at disease progression. We will define two subgroups: those for whom EGFR TKI was continued at least three months despite progression defined according to RECIST criteria, and those for whom a second-line treatment (chemotherapy without EGFR TKI) was chosen at disease progression. It will be individualized the subgroup of patients in whom it was continued TKI after progression.

NCT02293733
Conditions
  1. NSCLC Non Small Cells Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Variables as : age, gender, PS, histology, brain metastasis, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued or TKI stopped at progression, metastasis number and site, will be considered for adjustment.. Univariate and multivariate analysis of OS. • Univariate and multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. --- L858R ---

Following variables will be considered for adjustment: age, gender, PS, histology, brain metastases, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued to progression or TKI stopped at progression, metastasis number and site. --- L858R ---

Primary Outcomes

Description: • Primary outcome: the therapeutic management of secondary resistance to EGFR TKI (erlotinib or gefitinib) in patients with advanced NSCLC with EGFR activating mutation. Comparison of demographic, clinical, biological features and outcome of patients continuing EGFR TKI at progression versus interrupting TKI at progression. Composite measures will be performed : demographic and clinical data, Progression Free Survival (PFS), Overall Survival (OS), mutational status, mode of progression, therapeutic approach at progressive disease in patients with EGFR mutation treated in first line by EGFR TKI (all population and subgroups : patients receiving EGFR-TKI at progressive disease - Group 1 -, patients discontinuing EGFR TKI at progressive disease - Group 2- ).

Measure: Proportion of patients continuing TKI at 1st progression and proportion of patients discontinuing EGFR TKI at 1st progression. Analysis of the therapeutic management in the 2 groups. This outcome consists in multiple measures.

Time: Patients are followed up to 48 Months maximum

Secondary Outcomes

Description: A comparison of clinical data and outcome of patients receiving EGFR-TKI beyond progressive disease (group 1) versus discontinuing EGFR-TKI at progressive disease (group 2) will be made.

Measure: Comparison of clinical data and outcome of patients

Time: Patients are followed up to 48 Months maximum

Description: • Median Progression Free Survival (PFS) (months) in group 1 and 2 - from start of EGFR TKI to first progression : PFS 1- and - from first progression to second progression : PFS2 -.

Measure: Median Progression Free Survival (PFS)

Time: Patients are followed up to 48 Months maximum

Description: • Univariate an multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. Variables as : age, gender, PS, histology, brain metastasis, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued or TKI stopped at progression, metastasis number and site, will be considered for adjustment.

Measure: Univariate and multivariate analysis of Median over survival (OS)

Time: Patients are followed up to 48 Months maximum

Description: • Univariate and multivariate analysis of OS between the 2 groups will be adjusted using the Cox model. Following variables will be considered for adjustment: age, gender, PS, histology, brain metastases, EGFR mutations (deletions in exon 19, L858R mutations), TKI continued to progression or TKI stopped at progression, metastasis number and site

Measure: Univariate and multivariate analysis of OS

Time: Patients are followed up to 48 Months maximum

94 A Phase III, Double-blind, Randomised Study to Assess the Safety and Efficacy of AZD9291 Versus a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor as First Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non Small Cell Lung Cancer.

To assess the efficacy and safety of AZD9291 versus a standard of care epidermal growth factor receptor tyrosine kinase inhibitor in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

NCT02296125
Conditions
  1. Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291 80 mg/40 mg + placebo
  2. Drug: Placebo Erlotinib 150/100mg
  3. Drug: Placebo Gefitinib 250 mg
  4. Drug: Erlotinib 150/100 mg
  5. Drug: Gefitinib 250 mg
  6. Drug: Placebo AZD9291 80 mg/ 40 mg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The three domains of interest were separately analysed using an ANCOVA stratified by race (Asian versus Non-Asian) and mutation type (Ex19del versus L858R). --- L858R ---

4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). 5. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status. --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS. The primary endpoint of PFS was based on Investigator assessment.

Measure: Median Progression Free Survival (PFS) (Months)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent osimertinib compared with SoC EGFR-TKI therapy as measured by PFS.

Measure: Percentage of Participants in Progression Free Survival at 6, 12, and 18 Months

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression

Secondary Outcomes

Description: ORR was defined as the number (%) of participants with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy. ORR was based on Investigator assessment.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks relative to randomisation until progression

Description: Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy.

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression

Description: The DCR was defined as the percentage of participants who had a best overall response (BOR) of Complete response (CR), Partial response (PR) or Stable disease (SD) ≥6 weeks prior to any Progressive disease (PD) event and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy.

Measure: Disease Control Rate (DCR)

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression

Description: The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy

Measure: Depth of Response

Time: At baseline and every 6 weeks for the first 18 months and then every 12 weeks until objective disease progression

Description: Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of osimertinib compared with SoC EGFR-TKI therapy

Measure: Overall Survival (OS)- Number of Participants With an Event

Time: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)

Description: To characterise the pharmacokinetics (PK) of osimertinib

Measure: Plasma Concentrations of AZD9291

Time: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)

Description: To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ5104.

Measure: Plasma Concentrations of Metabolites AZ5104

Time: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)

Description: To characterise the pharmacokinetics (PK) of osimertinib metabolite AZ7550.

Measure: Plasma Concentrations of Metabolite AZ7550

Time: Blood samples collected from each participant at pre-dose, 0.5 to 2 hours, and 3 to 5 hours post-dose on Day 1 Cycle 1, and every other cycle thereafter up to and including Cycle 13 (approximately 9 months)

Description: The CTSQ-16 was a 16-item questionnaire measuring 3 domains related to participant's satisfaction with cancer therapy: Expectations of therapy, Feelings about side effects, and Satisfaction with therapy. Scores ranged from 0 to 100 for each domain, with a higher score associated with the best outcome on each domain. The three domains of interest were separately analysed using an ANCOVA stratified by race (Asian versus Non-Asian) and mutation type (Ex19del versus L858R). The results of the analyses were presented in terms of mean together with standard deviation.

Measure: Participants Reported Outcome by Cancer Therapy Satisfaction Questionnaire 16 Items (CTSQ-16 Questionnaire)

Time: Questionnaire completed in cycle 2 and 3, prior to Week 6 scan (approximately 2 months)

Description: The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)

Time: Questionnaires completed at baseline, first 9 months, and at week 1, 2, 3, 4, 5, 6, 12, 18, 24, 30 and 36

Description: The EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, combined to produce 5 functional scales, 3 symptom scales, 6 individual items, and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit up to 9 months (281 days), including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30)

Time: Questionnaires completed at baseline, first 9 months, and at week 6, 12, 18, 24, 30, and 36.

95 Phase 1/2 Open Label Study Of Pf 06459988 (Epidermal Growth Factor Receptor T790m Inhibitor) In Patients With Advanced Epidermal Growth Factor Receptor Mutant (Del 19 Or L858r + - T790m) Non Small Cell Lung Cancer

Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). The resulting PF-06459988 dose selected from the phase 1 portion will undergo a series of sub-studies to fully characterize the impact of food, antacid and CYP3A4 inhibitors/inducers. The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M.

NCT02297425
Conditions
  1. Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC
Interventions
  1. Drug: PF-06459988
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

A Study For Patients With EGFRm (Epidermal Growth Factor Receptor Mutant) Lung Cancer Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). --- L858R ---

The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M. --- L858R ---

Progression-Free Survival (PFS) - Phase 2. The period from study entry until disease progression, death or date of last contact.. Inclusion Criteria: - Evidence of histological or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del19 or L858R) NSCLC that is resistant to standard therapy. --- L858R ---

Inclusion Criteria: - Evidence of histological or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del19 or L858R) NSCLC that is resistant to standard therapy. --- L858R ---

Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC Lung Neoplasms null --- L858R ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Number of participants with Dose-limiting toxicities (DLT) (phase 1)

Time: up to 21 days

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response (phase 2)

Time: Time from first dose of study drug to objective response of CR or PR up to 24 months

Secondary Outcomes

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response for those patients with measurable disease (phase 1)

Time: time from first dose of study drug until objective response of CR or PR up to 24 months

Description: The period from study entry until disease progression, death or date of last contact.

Measure: Progression-Free Survival (PFS) - Phase 2

Time: time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

96 A Phase I, Open-Label, Non-Randomised, Multicentre Study to Assess the Effect of AZD9291 on the Pharmacokinetics of Rosuvastatin (a Sensitive BCRP Substrate) in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer (NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase inhibitor (TKI) agent. Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of rosuvastatin, following multiple oral dosing of AZD9291 in the fasted state. Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will provide for additional safety data collection. All patients from Part A who completed treatment may continue to receive AZD9291 80 mg once daily as a single agent until: disease progression; they are no longer deriving clinical benefit; or any other reason.

NCT02317016
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Procedure: Pharmacokinetic sampling - AZD9291
  2. Drug: AZD9291 tablet dosing
  3. Drug: Rosuvastatin
  4. Procedure: Pharmacokinetic sampling - rosuvastatin
  5. Procedure: Pharmacokinetic sampling - AZ5140 and AZ7550
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no deterioration over the previous 2 weeks (Appendix G). 6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. --- L858R ---

Primary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of Cmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1 [Period 1] and Day 32 [Period 3], respectively).

Measure: Assessment of Maximum Plasma Concentration (Cmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC from time zero extrapolated to infinity. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of AUC From Time Zero Extrapolated to Infinity for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Secondary Outcomes

Description: Rate and extent of absorption of rosuvastatin by assessment of tmax. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Maximum Plasma Concentration (Tmax) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of AUC0-t. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration at Time "t" (AUC0-t) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of CL/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance (CL/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of Vz/F. Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Volume of Distribution (Vz/F) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption of rosuvastatin by assessment of t1/2(lambda_z). Single rosuvastatin doses were first without, then with AZD9291 (Day 1; Period 1 and Day 32; Period 3, respectively).

Measure: Assessment of Terminal Elimination Half-life (t1/2[lambda_z]) for Rosuvastatin After a Single Dose Alone and in Combination With AZD9291

Time: Blood samples collected on Days 1 and 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post rosuvastatin dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of AUCtau. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Area Under the Plasma Concentration-time Curve During the Dosing Interval (AUCtau) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Maximum Plasma Concentration at Steady State (Css,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of tss,max after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Time to Reach Maximum Plasma Concentration at Steady State (Tss,Max) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291, and AZ5104 and AZ7550 (metabolites) by assessment of Css,min over the dosing interval. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Minimum Plasma Concentration at Steady State (Css,Min) for AZD9291, and AZ5104 and AZ7550 (Metabolites) Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Rate and extent of absorption for AZD9291 by assessment of CLss/F after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of Apparent Plasma Clearance at Steady State (CLss/F) for AZD9291 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRCss,max for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of Css,Max (MRCss,Max) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

Description: Assessment of MRAUCtau for AZ5104 and AZ7550 (calculated as AZ5104 to AZD9291 and AZ7550 to AZD9291) after multiple dosing. AZD9291 doses were first without, then with rosuvastatin (Days 4 to 31; Period 2 and Day 32; Period 3, respectively).

Measure: Assessment of the Metabolite to Parent Ratios of AUCtau (MRAUCtau) for AZ5104 and AZ7550 Following Administration of AZD9291 and Rosuvastatin Together

Time: Blood samples collected pre-dose on Days 11, 18, and 25 and on Day 32 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, and 24 hours post AZD9291 dose in Part A.

97 A Phase 2, Multicenter, Randomized, Double-blind Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib in Subjects Who Have Previously Untreated Metastatic, EGFR-mutated Non-small Cell Lung Cancer (NSCLC) and BDX004 Positive Label

Phase 2 multicenter, controlled, randomized, double-blind study to evaluate the efficacy and safety of ficlatuzumab versus placebo when administered with erlotinib in subjects with previously untreated metastatic EGFR-mutated NSCLC and BDX004 Positive Label.

NCT02318368
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Ficlatuzumab
  2. Drug: Erlotinib
  3. Drug: placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- An EGFR exon 19 deletion and/or an exon 21 (L858R) substitution mutation. --- L858R ---

Primary Outcomes

Description: Progression Free Survival is defined as the time from the date of randomization to the date of the first objective documentation of radiographic disease progression or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS)

Time: Approximately 24 months

Secondary Outcomes

Description: To evaluate Safety and tolerability of ficlatuzumab plus erlotinib versus placebo plus erlotinib in subjects who have previously untreated metastatic EGFR-mutated NSCLC and a BDX004 Positive Label.

Measure: Number of Participants With Adverse Events

Time: Approximately 24 months

98 An epidemiOlogy Study to deteRmine the Prevalence of EGFR muTations in RUSsian Patients With Advanced NSCLC (ORTUS)

This is a multicentre, non-interventional, prospective study to be carried out in representative oncology departments / institutions in order to determine the prevalence of EGFR mutations in treatment-naive Russian patients with cytologically verified advanced NSCLC in Russia.

NCT02321046
Conditions
  1. Non-Small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment. --- L858R ---

Primary Outcomes

Measure: EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment

Time: up to 18 months

Secondary Outcomes

Measure: Patient characteristics: Gender. Age. Race, ethnicity. Smoking habits. Family history of NSCLC.

Time: up to 18 months

Description: Date of the cytological verification of the NSCLC diagnosis. Disease stage and TNM classification. Morphological classification. Extent of the disease. Performance Status ECOG, including at diagnosis

Measure: Disease information/diagnostic procedures

Time: up to 18 months

Measure: EGFR mutations profile in cytology and/or histology (depending on the availablility of samples) and plasma samples at the time of every progression or in 1.5 year follow up in case of no progression

Time: up to 18 months

Description: 1st line and subsequent lines of therapy treatment, therapy regimen, medicines used for therapy (drugs by INN), for EGFRm+ patients - number of cycles of antitumor therapy, onset date, end date of each line

Measure: Characteristics of the 1st line and subsequent lines of antitumor therapy

Time: up to 18 months

Description: Treatment response/ progression of disease on every line of antitumor therapy: progressive disease, partial response, stable disease and complete response according to RECIST 1.1 evaluation and/or any other clinical assessment. Death: Disease-related or for other reasons

Measure: Clinical outcome/Patient response (for EGFRm+ patients who entered observation phase)

Time: up to 18 months

99 A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.

The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

NCT02335944
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: INC280
  2. Drug: EGF816
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion criteria: - Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC - Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. --- L858R ---

Primary Outcomes

Measure: Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D)

Time: First 28 days of treatment

Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1

Time: At least 24 weeks

Description: Frequency of treatment-emergent adverse events

Measure: Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity

Time: At least 24 weeks

Secondary Outcomes

Description: Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II)

Time: At least 24 weeks

Description: Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II)

Time: At least 24 weeks

Description: ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Overall Response Rate (Phase Ib and Phase II Group 4)

Time: At least 24 weeks

Description: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Disease Control Rate (Phase I/II)

Time: At least 24 weeks

Description: Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Progression Free Survival (Phase I/II)

Time: At least 24 weeks

Description: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Duration of Response (Phase I/II)

Time: At least 24 weeks

Description: OS is defined as the time from first dose of the study treatment to the date of death due to any cause.

Measure: Overall Survival (Phase I/II)

Time: At least 24 weeks

Measure: Plasma concentration versus time profiles

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Description: TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Time to Response (Phase I/II)

Time: At least 24 weeks

100 Gefitinib Alone or With Concomitant Whole Brain Radiotherapy for Patients Harboring an EGFR Mutation With Multiple Brain Metastases From Non-Small-cell Lung Cancer: a Phase II/III Randomized Controlled Trial

1. Compare the effect and safety of gefitinib alone with gefitinib plus concomitant WBRT(whole-brain radiotherapy ) in treatment of NSCLC patients harboring an EGFR mutation with multiple BM. 2. Verify the failure pattern of NSCLC patients harboring an EGFR mutation with multiple BM. 3. Explore the rescuable therapy after progression of disease.

NCT02338011
Conditions
  1. Non-Small Cell Lung Cancer
  2. Brain Metastases
  3. EGFR Gene Mutation
Interventions
  1. Drug: Gefitinib
  2. Radiation: WBRT
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Brain Neoplasms
HPO:Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - years of age or older - ECOG score ≤ 2 - Recursive Partitioning Analysis(RPA) Class I-II; - The pathological diagnosis of primary non-small cell lung cancer and detection of pulmonary primary ARMs; - Sequencing EGFR mutation(primary lesion or metastases,exon 19 deletions or exon 21 L858R (EGFR mutation in exon 21, L858R point mutation) mutations; - Enhanced MRI showed brain metastases ≥ 4; - 1 or 2 line treatment revealed failure; - No use of EGFR-TKIs(Tyrosine kinase inhibitors) previously; - No treatment for BM previously,including WBRT, SRS, surgery or experimental therapy; - Expected survival period over 3 months; - Two weeks before randomization, organs function in patients with meet the following criteria: - bone marrow:HB(hemoglobin) ≥ 90g/L, neutrophil≥ 1.5 × 109/L and platelet ≥ 100 × 109/L; - liver function:total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal; - renal function:more than 1.5 times the upper limit of normal serum creatinine or creatinine clearance rate ≥ 60 ml/min; - Urine dipstick testing the proteinuria < 1+; if the urine dipstick test value, 1+, is 24 hours total urine protein must < 500mg; - blood glucose:normal range,DM(diabetes mellitus) patients are under treatment and have a stable state; - Can understand and consent Exclusion Criteria: - Patients have been treated with brain radiation or surgery of BM; - Prior of EGFR-TKIs; - Mixed with small cell lung cancer patients with components; - Wild-type of EGFR; - Unable to tolerate MRI scanning; - Post 2 line treated patients; - Brain meninges metastases or incorporate with brain meninges metastases; - 5 years before other cancers except NSCLC treatment in patients with the start of the study (except for simple operation resection and there are at least 5 consecutive years disease free survival, has been cured of cervical carcinoma in situ, has cured the base cell cancer and bladder epithelial tumor); - Before entering the group 4 weeks received any other investigational drugs; - Incorporate with local symptoms(hemiplegic paralysis, anepia, nystagmus, ataxia.et); --- L858R ---

Inclusion Criteria: - years of age or older - ECOG score ≤ 2 - Recursive Partitioning Analysis(RPA) Class I-II; - The pathological diagnosis of primary non-small cell lung cancer and detection of pulmonary primary ARMs; - Sequencing EGFR mutation(primary lesion or metastases,exon 19 deletions or exon 21 L858R (EGFR mutation in exon 21, L858R point mutation) mutations; - Enhanced MRI showed brain metastases ≥ 4; - 1 or 2 line treatment revealed failure; - No use of EGFR-TKIs(Tyrosine kinase inhibitors) previously; - No treatment for BM previously,including WBRT, SRS, surgery or experimental therapy; - Expected survival period over 3 months; - Two weeks before randomization, organs function in patients with meet the following criteria: - bone marrow:HB(hemoglobin) ≥ 90g/L, neutrophil≥ 1.5 × 109/L and platelet ≥ 100 × 109/L; - liver function:total bilirubin ≤ 1.5 times the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal; - renal function:more than 1.5 times the upper limit of normal serum creatinine or creatinine clearance rate ≥ 60 ml/min; - Urine dipstick testing the proteinuria < 1+; if the urine dipstick test value, 1+, is 24 hours total urine protein must < 500mg; - blood glucose:normal range,DM(diabetes mellitus) patients are under treatment and have a stable state; - Can understand and consent Exclusion Criteria: - Patients have been treated with brain radiation or surgery of BM; - Prior of EGFR-TKIs; - Mixed with small cell lung cancer patients with components; - Wild-type of EGFR; - Unable to tolerate MRI scanning; - Post 2 line treated patients; - Brain meninges metastases or incorporate with brain meninges metastases; - 5 years before other cancers except NSCLC treatment in patients with the start of the study (except for simple operation resection and there are at least 5 consecutive years disease free survival, has been cured of cervical carcinoma in situ, has cured the base cell cancer and bladder epithelial tumor); - Before entering the group 4 weeks received any other investigational drugs; - Incorporate with local symptoms(hemiplegic paralysis, anepia, nystagmus, ataxia.et); --- L858R --- --- L858R ---

Primary Outcomes

Description: Compare the progression free survival(PFS) and safety in two arms,including intracranial PFS、extracranial PFS and overall PFS.

Measure: Time to progression

Time: 12-14 months

Secondary Outcomes

Measure: Overall survival

Time: 3 years

Description: intracranial or extracranial site

Measure: Disease Progression Classification

Time: 3 years

Description: measured by ECGO(Eastern Cooperative Oncology Group) PS (Performance Status)

Measure: Health-related quality of life

Time: 3 years

Description: measured by scale of MMSE( Mini Mental Status Examination)

Measure: Mental Status

Time: 3 years

101 PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER

This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

NCT02349633
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: PF-06747775
  2. Drug: Palbociclib
  3. Drug: Avelumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER. --- T790M --- --- L858R ---

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. --- L858R ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M --- --- T790M --- --- L858R ---

Partial Inclusion criteria: Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC: 1. --- L858R ---

In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm (del 19 or L858R) with any T790M status are eligible to enroll. --- L858R ---

Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. --- T790M --- --- L858R ---

Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. --- T790M --- --- L858R ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Partial Inclusion criteria: Evidence of histologically or cytologically confirmed diagnosis of locally advanced or metastatic EGFRm (del 19 or L858R) NSCLC: 1. --- L858R ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. --- L858R ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Phase 1 Primary Endpoint - Number of patients with dose limiting toxicities during Phase 1

Time: 21 days

Description: Cohort 1 is an evaluation of PF 06747775 single agent at RP2D Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either palbociclib or avelumab, respectively, based on safety and tolerability. Determination of the RP2D will be performed using the mTPI design. For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib combination, a randomized evaluation of the combination vs PF-06747775 single agent (2:1 ratio) will be initiated (Cohort 2B). For Cohort 3, after determination of the RP2D for the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an overall total of approximately 20 patients to further explore the safety, PK, and antitumor activity of the combination.

Measure: Phase 1b/2 - Cohort 1 = confirmed OR per RECIST; Cohort 2A = Cycle 2 DLT; Cohort 2B = PFS and Cohort 3 = Cycle 1 DLT

Time: Cohorts 1, 2A and 2B = 21 day cycles and Cohort 3 = 28 day cycles

Secondary Outcomes

Description: Number of patients with OR based assessment of confirmed CR or PR according to RECIST. CR are those that persist on repeat imaging at least 4 weeks after the initial documentation of response. PR are those that are greater or equal to a 30% decrease ( per RECIST) under the baseline of the sum of diameters of all target measurable disease

Measure: Phase 1: Secondary Endpoint - Number of patients with Objective Response (OR)

Time: Time from first dose of study drug until OR of CR or PR up to 24 months

Description: PFS (cohort 1, 2A and 3) ORR (cohort 2A, 2B and 3) DOR (All cohorts)

Measure: Phase 1b/2

Time: Time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

102 A Randomized, Double-blind Phase 2 Study of Itacitinib in Combination With Erlotinib Versus Erlotinib Alone in Subjects With Stage IIIB/ IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Activating Mutations

The purpose of this study is to determine if Itacitinib in combination with erlotinib is safe and effective in the treatment of nonsquamous non-small cell lung cancer (NSCLC) that is Stage IIIB/Stage IV or recurrent whose tumors have EGFR activating mutations.

NCT02355431
Conditions
  1. Solid Tumors and Hematologic Malignancy
  2. NSCLC (Non-small Cell Lung Carcinoma)
Interventions
  1. Drug: Itacitinib
  2. Drug: erlotinib
  3. Drug: placebo
MeSH:Carcinoma, Non-Small-Cell Lung Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of nonsquamous NSCLC that is Stage IIIB, Stage IV, or recurrent (including Stage II). - Documented evidence of an activating mutation in EGFR in tumor samples (exon 19 deletions or point mutation L858R in exon 21 or point mutations at codon 719). --- L858R ---

Primary Outcomes

Description: Subjects will take erlotinib daily and begin dosing with itacitinib once daily (QD) on Cycle 1, Day 1. The safety and tolerability of the regimen will be assessed during the first 21 days of therapy

Measure: Part 1: Determination of the dose of itacitinib that is safe and tolerable in combination with erlotinib as measured by the number of dose-limiting toxicities (DLTs) observed in the evaluation cohort.

Time: Baseline through Day 21

Measure: Part 2: Overall Survival (OS)

Time: Randomization until death. Approximately 31 months.

Description: PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner.

Measure: Part 2: Progression-free survival (PFS)

Time: Randomization to disease progression, or death due to any cause if sooner. Approximately 23 months.

Secondary Outcomes

Description: Objective response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment

Measure: Part 2: Objective Response

Time: Baseline through end of study. Approximately 31 months.

Description: Duration of response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Measure: Part 2: Duration of Response

Time: Baseline through end of study. Approximately 31 months.

Measure: Part 2: Safety and tolerability of the treatment regimens assessed by a summary of adverse events and clinical laboratory assessments.

Time: Baseline through approximately 30 days post treatment discontinuation. Assessed after approximately 31 months.

103 A Phase I/Ib Trial of MK-3475 (Pembrolizumab) and Afatinib in EGFR-Mutant Non-small Cell Lung Cancer With Resistance to Erlotinib

This phase I/Ib trial studies the side effects and best dose of pembrolizumab when given together with afatinib dimaleate in treating patients with non-small cell lung cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment, or has come back and does not respond to erlotinib hydrochloride. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and afatinib dimaleate together may be an effective treatment for non-small cell lung cancer.

NCT02364609
Conditions
  1. Recurrent Non-Small Cell Lung Carcinoma
  2. Stage IIIA Non-Small Cell Lung Cancer
  3. Stage IIIB Non-Small Cell Lung Cancer
  4. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib Dimaleate
  2. Biological: Pembrolizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.. Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R ---

Crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) - Subjects that require treatment with a strong inhibitor of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) will be excluded; they may be included if there is an alternate treatment available (not a strong CYP3A4 inhibitor) and they are willing to switch prior to enrollment; if a subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug administration - Receiving drugs known to be strong inducers or inhibitors of permeability (P)-glycoprotein that are known to interact with afatinib including, but not limited to: ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; the subject must stop the strong inducer or inhibitor of P-glycoprotein 7 days before or 5 half lives before study drug administration (whichever timepoint is longer) - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study - Hormonal treatment within 2 weeks prior to start of study treatment - Radiotherapy within 4 weeks prior to enrollment, except as follows: - Palliative radiation to target organs other than chest may be allowed up to 2 weeks prior to enrollment, and - Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with sponsor-investigator prior to enrolling - Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of study Inclusion Criteria: - Incurable, advanced or metastatic/recurrent non-small cell lung cancer with EGFR activating mutations (exon 19 del, exon 21 L858R, L861Q, G718X); who have radiologic and/or clinically progressive disease on erlotinib at any point during the patient's cancer treatment as determined by the Investigator - Be willing and able to provide written informed consent for the trial - Have a life expectancy of at least 3 months - Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Adequate archival tissue for determination of EGFR-mutation status and PD-L1 status with a leftover cell block (or equivalent) for additional immune correlates from a tumor lesion biopsied in the last 60 days that has not been previously irradiated occurring: 1) after progression on erlotinib and no intervening systemic treatment between biopsy and initiation of MK-3475 and afatinib or amenable to repeat biopsy - Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance scale - Be willing to consent for biopsy at baseline (if inadequate archival tissue per inclusion criteria above) and an on treatment biopsy; have a tumor in a location that in the opinion of the investigator that is amenable to biopsy or have provided tissue for PD-L1 and other biomarker analysis from a newly obtained (within 60 days) formalin fixed tumor tissue from a recent biopsy of a tumor lesion not previously irradiated; no systemic antineoplastic therapy may be administered between the PD- L1 biopsy and initiating study medication; fine needle aspirates are not acceptable; needle or excisional biopsies, or resected tissue is required; the tissue sample must be received by the central vendor (Labcorp) and evaluated for adequacy prior to starting therapy - There is no limit to the number of prior treatments for this phase I trial - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9 g/dL or >= 5.6 mmol/L - Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN - Creatinine clearance should be calculated per institutional standard - Serum total bilirubin =< 1.5 x ULN - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR < 5 x ULN for subjects with liver metastases - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants; activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants - Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required - Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year - Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy Exclusion Criteria: - Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment - Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment - Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier; denosumab is allowed as long as not < 1 week prior to study day 1 and not administered on day of MK-3475 infusion - Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent - Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study - Note: if subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy - Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment - Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study - Has evidence of interstitial lung disease or active, non-infectious pneumonitis that required oral or intravenous glucocorticoids to assist with management; lymphangitic spread of the non-small cell lung cancer (NSCLC) is not exclusionary - Has an active infection requiring intravenous systemic therapy - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial - History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia as determined by the investigator; myocardial infarction within 6 months prior to enrollment - Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment - Has received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-cluster of differentiation (CD)137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) - Known hypersensitivity to afatinib or the excipients of any of the trial drugs - Prior participation in an afatinib clinical study, even if not assigned to afatinib treatment - Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) - Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) - Has received a live vaccine within 30 days prior to the first dose of trial treatment - The presence of poorly controlled gastrointestinal disorders that could affect the absorption of the afatinib (e.g. --- L858R ---

Primary Outcomes

Description: Descriptive summaries will be provided for number and proportion with specific type and grade of toxicities.

Measure: Maximum tolerated dose (MTD) recommended dose of pembrolizumab in combination with lead in pembrolizumab and afatinib dimaleate

Time: Day 21

Description: Will be determined by the overall assessment of the MTD and toxicities observed in the dose de-escalation portion of this study.

Measure: Recommended phase II dose

Time: Day 21

Secondary Outcomes

Description: Descriptive summaries will be provided for numbers and proportion of patients responding.

Measure: Overall response rate per RECIST 1.1

Time: Up to 3 years

Description: Kaplan-Meier plot and life-table summary will be used.

Measure: Progression free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 3 years

Other Outcomes

Description: Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in plasma EGFR-mutant DNA levels

Time: Baseline to up to 3 years

Description: Descriptive associations with response rate and PFS will be performed. Standard descriptive methods will be used to summarize the baseline levels and changes in baseline levels will allow to examine whether observed patterns are consistent with hypothesized patterns.

Measure: Changes in PDL1 expression by immunohistochemistry

Time: Baseline to up to 3 years

104 A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY OF PF- 06439535 PLUS PACLITAXEL-CARBOPLATIN AND BEVACIZUMAB PLUS PACLITAXEL -CARBOPLATIN FOR THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER.

This is a multinational, double-blind, randomized, parallel-group Phase 3 clinical trial evaluating the efficacy and safety of bevacizumab-Pfizer plus paclitaxel and carboplatin versus bevacizumab-EU plus paclitaxel and carboplatin in first-line treatment for patients with advanced (unresectable, locally advanced, recurrent or metastatic) non-squamous NSCLC.

NCT02364999
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Bevacizumab-Pfizer
  2. Drug: Bevacizumab-EU
  3. Drug: Paclitaxel
  4. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Known sensitizing EGFR mutations (for example, deletion 19 or L858R) or EML4-ALK translocation positive mutations. --- L858R ---

Primary Outcomes

Description: ORR refers to percentage of participants who achieved complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions except nodal disease (target nodes must decrease to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits.

Measure: Objective Response Rate (ORR) by Week 19

Time: 25 weeks

Secondary Outcomes

Description: AE was defined as any untoward medical occurrence in a clinical investigation participant administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were defined as AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were defined as any untoward medical occurrence at any dose that resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduction normal life functions). AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Measure: Number of Participants With Treatment-Emergent Adverse Events

Time: 55 weeks

Description: Laboratory evaluation included hematology (hemoglobin, white blood cells, platelets and absolute neutrophil count), blood chemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, serum or plasma creatinine, sodium, potassium, total calcium, magnesium, blood urea nitrogen or urea, and albumin ), coagulation (international normalized ratio for prothrombin time and activated partial thromboplastin time) and urinalysis (dipstick followed by a quantitative urine protein analysis for results of 2+ or greater).

Measure: Number of Participants With Laboratory Abnormalities (Without Regard to Baseline Abnormality)

Time: 55 weeks

Description: DOR was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of PD or to death due to any cause in the absence of documented PD. DOR was based on the Brookmeyer and Crowley method.

Measure: Duration of Response (DOR)

Time: 55 weeks

Description: This outcome measure refers to the possibility of being progression free at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Measure: Progression Free Survival Rate at 55 Weeks

Time: 55 weeks

Description: This outcome measure refers to the possibility of being alive at 55 weeks since start of study treatment, estimated from the Kaplan-Meier curve using the product-limit method.

Measure: Survival Rate at 55 Weeks

Time: 55 weeks

Measure: Serum Concentration of Bevacizumab up to 1 Year

Time: Pre-dose from Cycle 1 to Cycle 17, 2.5 hours post-dose in Cycle 1, and 1.5 hours post-dose in Cycle 5

Description: ADA assay was performed using a sensitive, specific, and semi-quantitative electrochemiluminescent (ECL) method, which used biotinylated- and ruthenium-labeled PF-06439535 as reagents. Samples with ADA titer greater than or equal to (>=) 2.29 were considered positive.

Measure: Number of Participants With Anti-Drug Antibody (ADA)

Time: 55 weeks

Description: Only samples that were confirmed positive for ADA were further tested for NAb. The NAb analysis was conducted using a single validated quasi-quantitative enzyme-linked immunosorbent assay (ELISA) that utilized PF-06439535 as a reagent. Samples with NAb titer >=1.70 were considered positive.

Measure: Number of Participants With Neutralizing Antibody (NAb)

Time: 55 weeks

105 T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry

The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin).

NCT02368990
Conditions
  1. Non Small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation prior to enrolment into the study that the tumour harbours the following EGFR mutations known to be associated with EGFR-targeted TKI sensitivity: Ex19Del, L858R, L861Q, and G719X. --- L858R ---

There are Epidermal Growth Factor Receptor (EGFR) mutations known to be associated with EGFR-targeted TKI sensitivity ( Ex19Del, L858R, L861Q, and G719X). --- L858R ---

Primary Outcomes

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause or censoring (at end of 24 months).To assess efficacy of permetrexed + cisplatinum/carboplatin as the 2nd line of treatment of NSCLC.

Measure: Overall Survival

Time: 24 months from last subject in

Secondary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visits

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the date of complete or partial response until the first date of recurrence or progression. To assess the efficacy of 2nd line treatment and beyond.

Measure: Duration of Response as defined by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause. This will be done to assess efficacy of pemetrexed + cisplatin/carboplatin as the 2nd line treatment of NSCLC.

Measure: Progression Free Survival

Time: 24 months from last subject in

106 A Phase Ib, Open-label, Multi-centre Study to Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Anti-tumour Activity of Volitinib in Combination With Gefitinib in Patients With Epidermal Growth Factor Receptor-mutated Non-small Cell Lung Cancer Who Have Progressed on Epidermal Growth Factor Receptor Inhibitor Treatment

This is a Phase 1b, open-label, multicentre study of AZD6094 in combination with gefitinib in patients with epidermal growth factor receptor (EGFR) mutation positive (m+) and progressed on EGFR Tyrosine kinase inhibitor (TKI) treatment.

NCT02374645
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Volitinib
  2. Drug: gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed locally advanced or metastatic NSCLC patients who are harbouring an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X). --- L858R ---

Primary Outcomes

Description: the grade of AE event according to CTC AE 4.0

Measure: Number of adverse events and serious adverse events

Time: From ICF signed to within 28 days after the last dose

Secondary Outcomes

Description: Peak Plasma Concentration (Cmax)

Measure: The Pharmacokinetics (PK) profiles of AZD6094

Time: Cycle 1 Day1 and Day 15

Description: Area under the plasma concentration versus time curve (AUC)

Measure: The Pharmacokinetics (PK) profiles of AZD6094

Time: Cycle 1 Day1 and Day 15

Description: 6-months PFS, 12 months PFS and 24 month PFS

Measure: Progression-free survival (PFS)

Time: from enrolled until progression or death due to any cause, assessed up to 2 year

Description: CR+PR+SD

Measure: Disease control rate(DCR)

Time: 12 weeks and 24 weeks

107 A Study to Evaluate the Efficacy of Rh-Endostatin (Endostar®) in Combination With Icotinib for Advanced Non-Small Cell Lung Cancer With EGFR Mutations

This single-arm pilot study tries to invesitgate how well giving icotinib with rh-endostatin (Endostar®) works in treating patients with advanced stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. Icotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Anti-angiogeneiss drug, such as rh-endostatin, can block tumor growth by inhibiting the ability of tumors to grow new blood vessels and spread. It is not yet known whether icotinib is more effective when given with rh-endostatin in NSCLC patients with EGFR activating mutations.

NCT02375022
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Endostar and icotinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - Histologic documentation of non small cell lung cancer, with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

- Other active malignancy Inclusion Criteria: - Histologic documentation of non small cell lung cancer, with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

EGFR mutation status: activating mutation (defined as deletion 19 or exon 21 L858R mutation). --- L858R ---

Primary Outcomes

Measure: Objective response rate

Time: 6 months

Secondary Outcomes

Measure: Progression free survival

Time: 12 months

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety: Number of Participants with Adverse Events

Time: 12 months

108 SHERLOC: A Phase 2 Study of MM-121 in Combination With Docetaxel Versus Docetaxel Alone in Patients With Heregulin Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer (Merrimack Pharmaceuticals Inc.)

The purpose of this study is to determine whether the combination of MM-121 plus docetaxel is more effective than docetaxel alone in regards to PFS in patients with heregulin-positive NSCLC.

NCT02387216
Conditions
  1. Non-Small Cell Lung Cancer
  2. NSCLC
  3. Adenocarcinoma
  4. Heregulin
Interventions
  1. Drug: MM-121
  2. Drug: Docetaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Serum levels of MM-121 will be measured at a central lab using an enzyme-linked immunosorbent assay.. Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Non-Small Cell Lung Cancer NSCLC Adenocarcinoma Heregulin Lung Neoplasms Carcinoma, Non-Small-Cell Lung This study is a randomized, open-label, international, multi-center, phase 2 study in patients with Heregulin-positive NSCLC histologically classified as adenocarcinoma that have progressed following no more than two systemic therapies for locally advanced or metastatic disease, one of which must have been a platinum containing regimen. --- L858R ---

Serum levels of MM-121 will be measured at a central lab using an enzyme-linked immunosorbent assay.. Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Inclusion Criteria: - Patients with a diagnosis of cytologically or histologically documented adenocarcinoma of the lung with either metastatic disease (stage IV), Stage IIIB or Stage IIIC disease not amenable to surgery with curative intent - Not received more than 2 prior systemic therapies- one of which must have been a platinum based regimen- for primary or recurrent disease - Tissue submitted for HRG-biomarker testing - ECOG performance status (PS) of 0 or 1 Exclusion Criteria: - Known ALK mutation - Presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene - Received >2 prior systemic anti-cancer drug regimen for locally advanced disease - Prior treatment with an anti-ErbB3 antibody - CTCAE grade 3 or higher peripheral neuropathy - Symptomatic CNS metastases or CNS metastases requiring steroids - Any other active malignancy requiring systemic therapy - Clinically significant cardiac disease Non-Small Cell Lung Cancer NSCLC Adenocarcinoma Heregulin Lung Neoplasms Carcinoma, Non-Small-Cell Lung This study is a randomized, open-label, international, multi-center, phase 2 study in patients with Heregulin-positive NSCLC histologically classified as adenocarcinoma that have progressed following no more than two systemic therapies for locally advanced or metastatic disease, one of which must have been a platinum containing regimen. --- L858R --- --- L858R ---

Primary Outcomes

Description: Disease status will be assessed according to RECIST v 1.1

Measure: Progression Free Survival

Time: Time from randomization to progression

Secondary Outcomes

Description: Time from randomization to death

Measure: Overall survival

Time: Approximately 3 years

Description: Based on RECIST v1.1

Measure: Objective Response Rate

Time: approximately 3 years

Description: Time from randomization to progression

Measure: Time to Progression

Time: approximately 3 years

Description: Adverse events analysis

Measure: Rate of adverse events reported with the combination of MM-121 with docetaxel

Time: approximately 3 years

Description: Pharmacokinetic (PK) profile of MM-121 when given in combination with docetaxel, and of docetaxel when given in combination with MM-121. PK evaluation will be performed on samples obtained at Week 1 pre-dose and post-dose and at pre-dose at Cycle 2 and beyond to assess pre-treatment trough concentrations of MM-121. The maximum observed concentration (Cmax) will be presented and calculated using non-compartmental analysis. Serum levels of MM-121 will be measured at a central lab using an enzyme-linked immunosorbent assay.

Measure: Pharmacokinetic (PK) parameters of MM-121 in combination with docetaxel and docetaxel when given in combination with MM-121.

Time: approximately 3 years

109 Phase I/Ib Trial of Single Agent PBF-509 and in Combination With PDR001 for Patients With Advanced NSCLC

The purpose of this study is to determine the safety, tolerability, feasibility and preliminary efficacy of the administration of PBF-509 (Adenosine A2a receptor antagonist) as single agent or in combination with PDR001 (programmed cell death 1 receptor antibody (PD-1 Ab)) to NSCLC patients.

NCT02403193
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: PBF-509_80 mg
  2. Drug: PBF-509_160 mg
  3. Drug: PBF-509_320 mg
  4. Drug: PBF-509_640 mg
  5. Drug: Combo PBF-509 (160 mg) + PDR001
  6. Drug: Combo PBF-509 (320 mg) + PDR001
  7. Drug: Combo PBF-509 (640 mg) + PDR001
  8. Drug: RP2D (PBF-509+PDR001)_immuno naïve
  9. Drug: Experimental: RP2D (PBF-509+PDR001)_immuno treated
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Patients must previously have received at least one prior line of therapy for their disease 3. EGFR mutation with exon 19 deletion or L858R mutation (Exon 21) or ALK rearrangement positive must have failed prior TKI therapy 4. Able, willing to give written consent for available archival tumor samples (not mandatory) and tumor biopsies before and during protocol therapy (mandatory). --- L858R ---

Primary Outcomes

Description: The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.

Measure: Maximum Tolerated Dose (MTD) of PBF-509 as single agent

Time: 28 days

Description: The MTD evaluation will be based on the DLT Evaluable Population which includes all patients enrolled in the dose-escalation portion of the trial, who receive the protocol-assigned treatment with PDR001 and PBF-509 and complete the safety follow-up through the DLT evaluation period, or experience a DLT during the DLT evaluation period.

Measure: Maximum Tolerated Dose (MTD) of the combination (PBF-509+PDR001) treatment

Time: 56 days

Secondary Outcomes

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients after oral administration of PBF-509.

Measure: Time to PBF-509 peak concentration in plasma "Tmax"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the time (in minutes) to reach the maximum "PBF-509" concentration in plasma samples of patients during a dosing interval at steady state.

Measure: Time to PBF-509 peak concentration in plasma at steady state "Tmax,ss"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed after administration.

Measure: PBF-509 peak concentration in plasma "Cmax"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-509 observed during a dosing interval at steady state.

Measure: PBF-509 peak concentration in plasma at steady state"Cmax,ss"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase. "AUC(0-inf)" will be given in Amount·time/ volume units

Measure: The area under PBF-509 plasma concentration-time curve to infinite time "AUC(0-inf)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve from zero up to a definite time t. "AUC(0-t)" will be given in Amount·time/ volume units.

Measure: The area under PBF-509 plasma concentration-time curve up to time 't' "AUC(0-t)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the area under the concentration-time curve over the dosing interval. "AUC(0-τ)" will be given in Amount·time/ volume units.

Measure: The area under PBF-509 plasma concentration-time curve over the dosing interval "AUC(0-τ)"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the terminal half-life of PBF-509 in plasma. "t½" will be given in hours (h)

Measure: PBF-509 half-life in plasma " t½"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent volume of distribution during terminal phase after oral / extravascular administration. "Vd/F" will be given in Volume or volume/kg units.

Measure: PBF-509 apparent volume of distribution following extravascular administration"Vd/F"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the apparent total plasma or serum clearance of drug after oral administration. "Cl/F" will be given in the Volume/ time or volume/ time/ kg units.

Measure: PBF-509 total body clearance following extravascular administration "Cl/F"

Time: 8 days

Description: The parameter will be calculated from plasma samples collected at days 1 and 8 after drug administration. It will consist in the accumulation ratio calculated from Cmax,ss at steady state and Cmax after single dosing.

Measure: The PBF 509 accumulation index "Rac"

Time: 8 days

Description: ORR: Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). ORR is defined as confirmed complete response (CR) or partial response (PR) based on modified RECIST v1.1.

Measure: Efficacy as measured by Objective response rate (ORR)

Time: 3 years

Description: The disease control rate (DCR) will be estimated considering the following variables: Complete response (CR), Partial response (PR) and stable disease (SD) as described by Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). These variables will be assessed based on Imaging-based evaluation methods as chest x-ray, conventional computed tomography (CT) and magnetic resonance imaging (MRI) that will be performed every 2 cycles of 28 days administration

Measure: Efficacy as measured by Disease control rate (DCR)

Time: 3 years

Description: Duration of response (DoR) is defined as the duration from the first documentation of OR to the first documented disease progression or death due to any cause, whichever occurs first.

Measure: Efficacy as measured by duration of response (DoR)

Time: 3 years

Description: Progression-free survival (PFS) will be measured from the start of treatment until the documentation of disease progression or death due to any cause, whichever occurs first. For subjects who are alive and progression-free at the time of data cut-off for analysis, PFS will be censored at the last tumor assessment date.

Measure: Efficacy as measured by progression-free survival (PFS)

Time: 3 years

Description: Overall survival (OS) will be determined as the time from the start of treatment until death due to any cause.

Measure: Efficacy as measured by overall survival (OS)

Time: 3 years

110 Open Label Multicenter Phase I/II Study of the Safety and Efficacy of PDR001 Administered to Patients With Advanced Malignancies

The purpose of this "first-in-human" study of PDR001 is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of PDR001 administered i.v. as a single agent to adult patients with solid tumors. By blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, PDR001 inhibits the PD-1 immune checkpoint, resulting in activation of an antitumor immune response by activating effector T-cells and inhibiting regulatory T-cells. This study has been designed as a phase I/II, multi-center, open-label study starting with a phase I dose escalation part followed by a phase II part. PDR001 will be administered every 2 weeks until patient experiences unacceptable toxicity, progressive disease per immune related Response Criteria (irRC) and/or treatment is discontinued at the discretion of the investigator or the patient.

NCT02404441
Conditions
  1. Melanoma
  2. NSCLC
  3. Triple Negative Breast Cancer
  4. Anaplastic Thyroid Cancer
  5. Other Solid Tumors
Interventions
  1. Biological: PDR001
MeSH:Thyroid Neoplasms Triple Negative Breast Neoplasms Thyroid Carcinoma, Anaplastic
HPO:Anaplastic thyroid carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Only patients with EGFR mutation-negative tumor are eligible (defined as negative for exon 19 deletions and for the L858R mutation in EGFR at a minimum; however, if more extensive EGFR mutation testing has been performed, the tumor must not harbor any known activating EGFR mutations in Exons 18-21 in order to be considered EGFR mutation-negative). --- L858R ---

Primary Outcomes

Description: To estimate the recommended phase 2 dose (RP2D) and/or the maximum tolerated dose (MTD) for PDR001

Measure: Part l: The exposure (AUC(0-336h)) after first dose of treatment

Time: 8 months

Description: To estimate the RP2D and/or the MTD for PDR001

Measure: Part l: Incidence of dose limiting toxicities (DLTs)

Time: 8 months

Description: As per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 - to estimte the anti-tumor activity of PDR001. Each cycle = 28 days

Measure: Part ll: Overall response Rate (ORR)

Time: 61 months

Secondary Outcomes

Description: To assess emergence of anti-PDR001 antibodies following one or more intravenous (i.v.) infusions of PDR001. Each cycle = 28 days; End of treatment = expected to be in average 1 year after the start of study treatment

Measure: Presence and/or concentration of anti-PDR001

Time: 42 months

Description: Preliminary antitumor activity of PDR001

Measure: Overall Response Rate (ORR) - Phase l only

Time: 27 months

Description: Preliminary antitumor activity of PDR001

Measure: Progression Free Survival (PFS) - Phase l/ll

Time: 61 months

Description: Preliminary antitumor activity of PDR001

Measure: Duration of Response (DOR) - Phase l/ll

Time: 61 months

Description: Preliminary antitumor activity of PDR001

Measure: Disease Control Rate (DCR) - Phase l/ll

Time: 61 months

Description: Preliminary antitumor activity of PDR001

Measure: Overall Response Rate (ORR) per immune related Response Criteria - Phase ll only

Time: 61 months

Description: Characterize the pharmacokinetic (PK) profile of PDR001

Measure: Serum pharmacokinetic (PK) parameter AUCs

Time: 37 months

Description: Characterize the pharmacokinetic (PK) profile of PDR001

Measure: Serum Pharmacokinetic (PK) parameter Cmax

Time: 37 months

Description: Characterize the pharmacokinetic (PK) profile of PDR001

Measure: Serum Pharmacokinetic (PK) parameter Tmax

Time: 37 months

111 A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer

The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC.

NCT02411448
Conditions
  1. Metastatic Non-Small Cell Lung Cancer
Interventions
  1. Drug: Ramucirumab
  2. Drug: Placebo
  3. Drug: Erlotinib
  4. Drug: Gefitinib
  5. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Study of Ramucirumab (LY3009806) in Combination With Erlotinib in Previously Untreated Participants With EGFR Mutation-Positive Metastatic NSCLC (RELAY) The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). --- L858R ---

- Eligible for first-line treatment with erlotinib based on documented evidence of tumor harboring an activating EGFR mutation [exon 19 deletion or exon 21 (L858R) substitution mutation]. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the date of radiographically documented progressive disease (PD) based on investigator assessment, or the date of death due to any cause, whichever is first assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Progression Free Survival (PFS)

Time: Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months)

Description: A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section.

Measure: Number of Participants With Treatment-Emergent Adverse Events

Time: Cycle 1 Day 1 through End of Study (Up To 3 Years)

Secondary Outcomes

Description: OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who was not known to have died as of the data-inclusion cutoff date for a particular analysis,OS was censored for that analysis at the date of last contact prior to the data-inclusion cutoff date (contacts considered in the determination of last contact date include adverse event (AE) date, lesion assessment date, visit date, and last known alive date).

Measure: Part B: Overall Survival (OS)

Time: Randomization to Date of Death from Any Cause (Up To 37 Months)

Description: ORR was defined as the percentage of randomized participants achieving a best overall response of partial response (PR) or complete response (CR) assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DCR was defined as the percentage of randomized participants achieving a best overall response of CR,PR, or stable disease(SD) assessed via Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1. CR was defined as the disappearance of all lesions,pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions.PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease(PD) was at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DoR was defined as the date of first documented CR or PR (responder) to the date of progressive disease or the date of death due to any cause, whichever was earlier. If a responder was not known to have died or have progressive disease, then the participant was censored at the date of last evaluable tumor assessment.CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 37 Months)

Description: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Measure: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Time: Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1

Description: Part B: Number of Participants With Anti-Ramucirumab Antibodies.

Measure: Part B: Number of Participants With Anti-Ramucirumab Antibodies

Time: Cycle 1 Predose through Follow-up (Up To 37 Months)

Description: The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-millimeter (mm) lines. A higher score for any item represented a higher level of symptoms/problems. The LCSS total score was defined as the mean of all 9 items. Average symptom burden index (ASBI) was calculated as the mean of the six symptom-specific questions from the LCSS. Potential scores range from 0 (for best outcome) to 100 (for worst outcome).

Measure: Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS)

Time: Baseline, End of Study (Up To 37 Months)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 10 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 28 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 40 (each cycle is 2 weeks)

112 Randomized Double-blinded Comparative Trial to Study the Add-on Activity of Combination Treatment of Nicotinamide on Progression Free Survival for EGFR Mutated Lung Cancer Terminal Stage Patients Being Treated With Gefitinib or Erlotinib

Nicotinamide is an inhibitor of human sirtuins (HDAC III), and is found to re-activate epigenetically silenced tumor suppressors, RUNX3 (runt-related gene 3) and others, in cancer cells. Nicotinamide was found to be effective in several animal cancer models including lung, bladder, liver, etc. The purpose of this study is to determine whether nicotinamide is also effective in the treatment of human lung cancer.

NCT02416739
Conditions
  1. Non-Small-Cell Lung Carcinoma
Interventions
  1. Drug: Nicotinamide
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Non-Small-Cell Lung Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung The standard therapy to the EGFR (epidermal growth factor receptor) mutation positive non-small-cell lung cancer patients who are not eligible to operation is to administer EGFR-TKIs (tyrosine kinase inhibitors, gefitinib or erlotinib). --- L858R ---

Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Inclusion Criteria: - Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy - EGFR mutated (exon 19 deletion or L858R mutation) - Life expectation more than 3 months - More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously - ECOG (Eastern Cooperative Oncology Group ) performance status grade 0~2 - Who signed the informed consent form Exclusion Criteria: - Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy - Who has metastasized brain lesion that needs operation or radiation therapy - Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney - Who does Not agree to contraception - Who has allergy to nicotinamide Non-Small-Cell Lung Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung The standard therapy to the EGFR (epidermal growth factor receptor) mutation positive non-small-cell lung cancer patients who are not eligible to operation is to administer EGFR-TKIs (tyrosine kinase inhibitors, gefitinib or erlotinib). --- L858R --- --- L858R ---

Primary Outcomes

Description: Cox regression analysis

Measure: Hazard ratio (PFS) of the nicotinamide arm to the placebo arm

Time: two year

Secondary Outcomes

Description: chi-square test of complete response and partial response (RECIST 1.1)

Measure: Response rate

Time: two year

Description: measured by the cancer-related QOL questionaire response (questioned at each visit)

Measure: Difference in quality of life between the nicotinamide arm and the placebo arm

Time: two year

Description: Cox regression analysis

Measure: Overall survival

Time: two year

113 Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study

The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure.

NCT02418234
Conditions
  1. Non-small Cell Lung Cancer Stage III
  2. Non-Small-Cell Lung Cancer Metastatic
Interventions
  1. Other: mutation detection
  2. Other: ARMS and ddPCR
  3. Genetic: ctDNA analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Investigator confirmed progression according RECIST 1.1 during EGFR-TKI treatment within 28 days of the enrollment - Activating mutation (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) in the EGFR gene or have had at least partial response with EGFR TKI lasting ≥ 6 months - Patient must be able to comply with the protocol Exclusion Criteria: - Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 defined disease progression for more than 28 days while on previous EGFR-TKI treatment. --- G719A --- --- L858R ---

Primary Outcomes

Description: The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).

Measure: Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay

Time: up to 2 years

Description: The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.

Measure: Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient

Time: up to 2 years

Secondary Outcomes

Description: The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure

Time: up to 2 years

Description: The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure

Time: up to 2 years

114 Correlation Between Epithelial Growth Factor Receptor(EGFR) Mutation Using cfDNA and CTCs in Patients With Non-Small Cell Lung Cancer

Correlation of epithelial growth factor receptor mutation in blood of lung cancer patient and clinical outcome.

NCT02422628
Conditions
  1. Lung Cancer
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

3. Tumor harboring EGFR mutation including activating mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861 4. Treatment naive 5. Patients will receive EGFR-TKI as first line treatment. --- L858R ---

3. Tumor with no EGFR mutation detected (mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861) 4. EGFR TKI treatment naïve and without any EGFR TKI treatment in the following process ------- Exclusion criteria For exclusion in the study of NSCLC patients and control subjects should fulfill the following criteria: 1. Subjects should not enter the study if any of the following exclusion criteria are fulfilled: Involvement in the planning and/or conduct of the study (applies to staff at the study site) 2. Previous enrolment in the present study 3. --- L858R ---

Primary Outcomes

Measure: Progressive disease measured by RECIST criteria after receiving 1st line EGFR-TKI

Time: 3 years

115 A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

NCT02438722
Conditions
  1. Recurrent Non-Small Cell Lung Carcinoma
  2. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib Dimaleate
  2. Biological: Cetuximab
  3. Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R ---

Crohn's disease, malabsorption, etc) - Patients must be able to swallow medication by oral route - Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50% - Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed - Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive - Patients must not have any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug - Patients must not be planning to receive any other investigational agents during the course of protocol treatment - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab - Prestudy history and physical must be obtained with 28 days prior to registration - Patients must have Zubrod performance status of 0 - 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R ---

Primary Outcomes

Measure: OS (phase III)

Time: From date of registration to date of death due to any cause, assessed up to 3 years

Measure: PFS (phase II)

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Secondary Outcomes

Measure: PFS

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Description: Compared between arms using a chi-squared test of independence at the 1-sided 5% level.

Measure: Response rates

Time: Up to 3 years

Measure: Time to treatment discontinuation

Time: From date of registration to date of discontinuation of treatment or death due to any cause, assessed up to 3 years

Measure: Time to treatment failure

Time: From date of registration to date of first documentation of progression or symptomatic deterioration, early discontinuation of treatment, or death due to any cause, assessed up to 3 years

Description: Assessed using a chi-squared or Fisher's exact test (as appropriate) at the 1-sided 5% level.

Measure: Toxicity rates assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 3 years

Other Outcomes

Description: For each of these markers, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the absolute difference between the copy number after progression and the copy number in the pre-treatment specimen (or an appropriate transformation of the difference, determined after exploratory data analysis) is not equal to zero.

Measure: Change in copy number alterations in MET, EGFR, and HER2, analyzed using fluorescence in situ hybridization

Time: Baseline up to 3 years (after disease progression)

Description: To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.

Measure: Change in the ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Baseline up to 3 years (at progression)

Description: To evaluate the hypothesis that H-score positive status at baseline is associated with absolute difference in PFS (and OS) among patients randomized to receive afatinib dimaleate monotherapy a test of interaction will be performed at the 1-sided 20% level.

Measure: EGFR immunohistochemistry H-score

Time: Baseline

Description: Tumor marker levels over time will be evaluated using a linear mixed model for continuous markers and using generalized estimating equations for binary markers. A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.

Measure: Levels of circulating tumor markers

Time: Up to 3 years

Description: To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test..

Measure: Presence of de novo EGFR T790M mutation or other molecular alterations

Time: Baseline

Description: To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). Cox regression will be used to assess the predictive association of the ratio in the afatinib dimaleate monotherapy arm with both OS and PFS

Measure: Ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Up to 3 years

116 A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02442349
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, N Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, N Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in Asia Pacific patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) sensitising mutation positive (ie, G719X, exon 19 deletion, L858R, L861Q) and T790M mutation positive (hereafter referred to as EGFRm+ and T790M+) un-resectable, locally advanced or metastatic NSCLC (Stage IIIB-IV), who have progressed on an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(EGFR-TKI), either as first line treatment or following one line of EGFR-TKI and one line of platinum containing doublet chemotherapy. --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time of first dose until objective disease progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time first dose until date of progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

117 Pilot Study of Local Therapies for Oligometastatic Non-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations

This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.

NCT02450591
Conditions
  1. Oligometastatic Lung Adenocarcinoma
Interventions
  1. Drug: Erlotinib
  2. Other: Local Therapies
MeSH:Adenocarcinoma of Lung

At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.. Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

Primary Outcomes

Description: At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.

Measure: Feasibility as Measured by at Least Five Patients Will Need to Complete Local Therapy.

Time: 2 years

118 A Phase Ib/II, Open-label, Multicenter Trial With Oral cMET Inhibitor INC280 Alone and in Combination With Erlotinib Versus Platinum With Pemetrexed in Adult Patients With EGFR Mutated, cMET-amplified, Locally Advanced/Metastatic Non-small Cell Lung Cancer (NSCLC) With Acquired Resistance to Prior EGFR Tyrosine Kinase Inhibitor (EGFR TKI)

The purpose of this study was to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of INC280 in combination with erlotinib in the Phase Ib of this study, and to assess the anti-tumor activity and safety of INC280 alone, and in combination with erlotinib, versus platinum with pemetrexed in the Phase II of this study, in adult patients with EGFR mutated, cMET amplified, advanced/metastatic non-small cell lung cancer with acquired resistance to prior EGFR TKI.

NCT02468661
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: INC280 single agent
  2. Drug: erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Composite pharmacokinetics of erlotinib in the presence of INC280.. Inclusion Criteria: - Locally advanced or metastatic NSCLC - EGFR mutation (L858R and /or ex19del) - cMET amplification by FISH (GCN ≥ 6), - Acquired resistance to EGFR TKI (1st or 2nd generation) - ECOG performance status (PS) ≤ 1. Exclusion Criteria: - Prior treatment with 3rd generation TKI - PhaseII : Prior treatment with any of the following agents: - Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor. --- L858R ---

- Platinum-based chemotherapy as first line treatment Inclusion Criteria: - Locally advanced or metastatic NSCLC - EGFR mutation (L858R and /or ex19del) - cMET amplification by FISH (GCN ≥ 6), - Acquired resistance to EGFR TKI (1st or 2nd generation) - ECOG performance status (PS) ≤ 1. Exclusion Criteria: - Prior treatment with 3rd generation TKI - PhaseII : Prior treatment with any of the following agents: - Crizotinib, or any other cMET inhibitor or HGF-targeting inhibitor. --- L858R ---

Primary Outcomes

Description: To determine MTD and/or RP2D of INC280 in combination with erlotinib

Measure: Phase Ib: Frequency and characteristics of Dose Limiting Toxicity (DLTs) to the INC280 and erlotinib combination

Time: First 28 days of dosing

Secondary Outcomes

Description: ORR, proportion of patients with a best overall response of complete response or partial Response (CR+PR)

Measure: Phase Ib: Overall response rate (ORR)

Time: Every 3 weeks, up to 5 years

Description: DCR, proportion of patients with best overall response of CR, PR or SD

Measure: Phase Ib: Disease Control Rate (DCR)

Time: Every 6 weeks, up to 2 years

Description: DOR, defined as time from the first documented CR or PR to first documented progression or death due to any cause

Measure: Phase Ib: Duration of Response (DOR)

Time: Every 6 weeks, up to 2 years

Description: PFS, defined as time from the first dose of study treatment to disease progression or death due to any cause

Measure: Phase Ib: Progression-free Survival (PFS)

Time: Every 6 weeks, up to 2 years

Description: Safety and tolerability of INC280 in combination with erlotinib assessed by change in vital signs, laboratory results and electrocardiogram (ECG).

Measure: Phase Ib: Number of patients with adverse events (AEs) as a measure of safety and tolerability

Time: Every 3 weeks, up to 2 years

Description: Composite pharmacokinetics of INC280 in the presence of erlotinib.

Measure: Phase Ib: Plasma concentration-time profiles of INC280 and pharmacokinetic parameters

Time: 6 weeks

Description: Composite pharmacokinetics of erlotinib in the presence of INC280.

Measure: Phase Ib: Plasma concentration-time profiles of erlotinib in the presence of INC280

Time: 6 weeks

119 A Single Arm, Open-label, Phase 2 Study Evaluating the Efficacy, Safety and PK of HM61713 in Patients With T790M-positive NSCLC After Treatment With an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor

The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT02485652
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: HM61713
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R ---

Primary Outcomes

Description: To assess the anti-tumor efficacy of HM61713 as measured by objective response rate (ORR).

Measure: Objective response rate (ORR)

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Secondary Outcomes

Description: To assess clinical efficacy of HM61713 regarding disease control rate (DCR).

Measure: Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Duration of overall tumor response (DR).

Measure: Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Progression-free survival (PFS).

Measure: Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Overall survival (OS).

Measure: Overall survival (OS), defined as the time from first administration of study drug until death from any cause

Time: From first dose to end of study or date of death from any cause whichever came first, assessed up to 48 months

Description: To assess clinical efficacy of HM61713 regarding Time to progression (TTP).

Measure: Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding tumor shrinkage.

Measure: Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST tumor response

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Peak concentration (Cmax) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Trough plasma concentration (Ctrough) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Area under the plasma concentration time curve over the 24-hour dosing interval (AUC) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status.

Measure: Patient reported outcomes (PROs)

Time: At baseline and every 6 weeks from time of discontinuation, assessed up to 24 months

Description: To evaluate the effect of HM61713 on the QT interval.

Measure: ECG/QTc (absolute values and change from baseline)

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: Incidence of reported AEs and abnormal laboratory tests (AEs will be assessed using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4).

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: QTc interval as assessed by digital ECG with central reading. The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.

Time: Adverse events will be collected from baseline until 28 days after the last dose

120 Genomic Landscape of EGFR Mutant NSCLC Prior to Afatinib and at the Time of Disease Progression Following Afatinib

The investigators propose to conduct a pilot feasibility study of single agent afatinib in patients with previously untreated metastatic EGFR (epidermal growth factor receptor) mutant adenocarcinoma of the lung (NSCLC = non-small cell lung cancer) with the sole purpose of characterizing the genomic landscape before afatinib and at the time of disease progression.

NCT02491775
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Non-Small Cell Lung Cancer
  3. Non-small Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R ---

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Description: The investigators will compare tumor sequencing prior to afatinib treatment to the time of disease progression to see if the genetic sequencing changed between pre-treatment and progression. The investigators plan to conduct exome and transcriptome sequencing of tumor before therapy with afatinib and at the time of relapse. In addition, exome sequencing of peripheral blood DNA will be done (for germline). Given the complexities of genomic analyses of paired samples in the face of limited data, the investigators will not be able to do any formal power calculations in this feasibility study. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Measure: Genetic changes associated with disease progression following treatment with afatinib

Time: Estimated to be 1 year

Secondary Outcomes

Description: Investigators will look at tumor tissue associated with a therapeutic response and compare with tumor tissue associated with disease progression and see if there are any mutation differences. Therapeutic Response Complete response is disappearance of all target lesions and non-target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Types of mutations in signaling kinases associated with therapeutic response

Time: Estimated to be 1 year

Description: A variant is considered to have mutant biased expression if the variant is expressed and the variant allele frequency is greater than 20% higher in the RNA-seq data compared to the exome sequencing data. A variant is considered to have wild type biased expression if the gene is expressed, the region of the variant is covered at 5X or greater depth, and the VAF is at least 20% lower in the RNA-seq data compared to the exome sequencing data. Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

Measure: Allelic ratio of wild type to mutant EGFR (roughly corrected for intrinsic differences in tumor cellularity) with duration of response

Time: Estimated to be 1 year

121 A Phase 1b/2 Study of ASP2215 in Combination With Erlotinib in Subjects With EGFR Activating Mutation-Positive (EGFRm+) Advanced NSCLC Who Have Acquired Resistance to an EGFR Tyrosine Kinase Inhibitor (TKI)

The purpose of the Phase 1b part of the study was to evaluate the safety and tolerability of ASP2215 in combination with erlotinib and determine the recommended phase 2 dose (RP2D) of ASP2215. The purpose of the Phase 2 part of the study was to evaluate the objective response rate (ORR) of the RP2D of ASP2215 in combination with erlotinib.

NCT02495233
Conditions
  1. Non-Small-Cell Lung Cancer
Interventions
  1. Drug: Gilteritinib
  2. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Participant had a documented exon 19 deletion or exon 21 L858R EGFR activating mutation. --- L858R ---

Primary Outcomes

Measure: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: Cycle 1 and Cycle ≥2 (up to 141 days)

Description: Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) that started after administration of the study drugs and occurred within 30 days of the last dose of the study drugs. If a participant experienced an event both during the preinvestigational period and during the investigational period, the event was considered a TEAE only if it worsened in severity.

Measure: Number of Participants With Adverse Events

Time: From first dose of study drug up to 30 days after the last dose of study (maximum study drug exposure 114 days)

Secondary Outcomes

Measure: Area Under the Concentration-time Curve at 24 Hours (AUC24) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Maximum Concentration (Cmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Time After Dosing When Cmax Occurs (Tmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Description: All participants in Gilteritinib 120 mg + Erlotinib 150 mg group discontinued before cycle 3.

Measure: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) of Gilteritinib

Time: Predose on Day 1, 3, 8, 15, 22, 28 of cycle 1, Day 1 of cycle 3 and Day 1 of cycle 4

Measure: AUC24 of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Cmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Tmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Ctrough of Erlotinib

Time: Day 8, 15, 22, 28 of cycle 1

Description: ORR was defined as Objective Response Rate (ORR) was the proportion of patients whose best overall response was complete response (CR) or partial response (PR) per RECIST version 1.1. Only patients with measurable disease at baseline were to be included in the analysis of ORR.

Measure: Objective Response Rate (ORR) in Phase 1b

Time: End of treatment (approximately 4 months)

122 A Phase I Trial of AZD9291 and Necitumumab in EGFR-Mutant Non-Small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be a better treatment for EGFR-mutant non-small cell lung cancer.

NCT02496663
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Necitumumab
  2. Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 5.0. The recommended phase II dose (RP2D) will be the MTD, pending review of other safety/tolerability considerations. The RP2D will be determined based upon the MTD in the dose escalation portion as well as other considerations such as toxicities at additional courses. After completing the 4 expansion cohorts, the dose level will be re-reviewed to confirm that the RP2D is in fact well tolerated.

Measure: Maximum tolerated dose (MTD) of necitumumab combined with osimertinib

Time: 21 days

Description: Will be graded according to NCI CTCAE version 5.0. Grade and attribution will be summarized by dose level, cycle, organ system and type.

Measure: Incidence of toxicity

Time: Up to 1 year

Secondary Outcomes

Description: Will be graded according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR). Point estimates and associated 90% confidence intervals will be calculated.

Measure: Objective response rate (ORR) in patients treated at the recommended phase II dose

Time: Up to 1 year

Description: Kaplan-Meier plots will be used to summarize the progression-free survival. Medians and associated 95% confidence intervals will be calculated.

Measure: Progression-free survival (PFS)

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

Description: DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease. Point estimates and associated 90% confidence intervals will be calculated.

Measure: Disease control rate (DCR) with combination osimertinib and necitumumab

Time: Up to 1 year

Other Outcomes

Description: The PK analyses will be descriptive and will permit comparison of the plasma levels of osimertinib and its metabolites in the presence of necitumumab (in this trial) with levels in other studies where osimertinib is given alone or combined with other drugs. We will estimate mean PK parameters as well as the between-patient variability. Results will be listed and plotted, by dose as well as by objective response, qualitative patterns will be described, and means and standard deviations will be calculated for use in planning follow-up studies.

Measure: Pharmacokinetic (PK) parameters of osimertinib in combination with necitumumab

Time: Prior to dosing on day 1 of course 2, 1, 2, 4, 6, 8, and 24 hours after dosing in course 2 (dose escalation and cohort A); prior to treatment on day 1 of course 2 for up to 4 courses (cohorts B, C, and D)

Description: Will study biopsied tumor tissue as well as serial plasma deoxyribonucleic acid specimens. For each cohort alone, Fisher's exact test, and in a stratified analysis including all cohorts, an exact logistic regression model, will be used to examine the association with objective response and a Cox proportional hazards model will be used to examine the association with PFS. Odds ratio's and hazard ratio's will be estimated and associated 90% two-sided confidence intervals will be constructed. Testing will be one-sided, at the 0.05-level.

Measure: Presence of biomarkers of response and resistance to previous EGFR-tyrosine kinase inhibitors

Time: Up to 1 year

123 Phase II Study of ASP8273 - An Open-Label, Study of the Oral Administration of ASP8273 in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor-NaïvePatients With Non-Small Cell Lung Cancer Harboring EGFR Mutations

The purpose of this study is to determine the safety, the antitumor activity and the pharmacokinetics of ASP8273 in EGFR tyrosine kinase inhibitor (EGFR-TKI)-naïve patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations.

NCT02500927
Conditions
  1. EGFR-TKI-naïve Patients With NSCLC Harboring EGFR Activating Mutations
Interventions
  1. Drug: ASP8273 Capsules
  2. Drug: ASP8273 Capsules A
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients confirmed to have the deletion of exon 19 (del ex19), L858R, G719X, or L861Q mutation among the EGFR activating mutations (patients at the study site who are documented to have any of the above-stated EGFR activating mutations can be enrolled in the study). --- L858R ---

Primary Outcomes

Measure: Safety assessed by AEs

Time: Up to 18 months

Measure: Safety assessed by Laboratory tests

Time: Up to 18 months

Measure: Safety assessed by Vital signs

Time: Up to 18 months

Measure: Safety assessed by Percutaneous oxygen saturation (SpO2)

Time: Up to 18 months

Measure: Safety assessed by Body weight

Time: Up to 18 months

Description: ECG: Electrocardiogram

Measure: Safety assessed by 12-lead ECG

Time: Up to 18 months

Measure: Safety assessed by Ophthalmologic examination

Time: Up to 18 months

Measure: Safety assessed by Chest X-ray examination

Time: Up to 18 months

Measure: Safety assessed by Chest computed tomography (CT) examination

Time: Up to 18 months

Measure: Safety assessed by ECOG Performance Status

Time: Up to 18 months

Secondary Outcomes

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR) or Partial Response (PR)among all analyzed subjects

Measure: Overall response rate

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as Complete response (CR), Partial Response (PR), or Stable disease (SD) among all analyzed subjects

Measure: Disease control rate

Time: Up to 18 months

Measure: Plasma concentrations of unchanged ASP8273

Time: Up to Day1 of Cycle 3

124 A Phase 1 Trial of MLN0128 (TAK-228) in Combination With Osimertinib (AZD9291) in Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02503722
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage III Lung Non-Small Cell Cancer AJCC v7
  4. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  5. Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  6. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Other: Laboratory Biomarker Analysis
  2. Drug: Osimertinib
  3. Other: Pharmacological Study
  4. Drug: Sapanisertib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Descriptive statistics and plotting of data will also be used to better understand potential relationships.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion) - Progressive disease on osimertinib (AZD9291) given first line - For the dose expansion portion ONLY, patient must: 1) have progression of disease with first line osimertinib administered for advanced or metastatic disease as the last previous systemic treatment, 2) be treatment naïve for other 3rd generation EGFR-TKI (CO-1686) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - For the dose expansion, no other systemic therapies for advanced/metastatic disease is permissible after first line osimertinib - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated; patients with small brain metastases for which radiation or surgery is not indicated, may be eligible on discussion with the study chair. --- L858R ---

medically significant (symptomatic) bradycardia, complete left bundle branch block, third degree heart block and second-degree heart block or history of arrhythmia requiring an implantable cardiac defibrillator; or within the last 6 months before administration of the first dose of drug: - Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) - Placement of a pacemaker for control of rhythm - Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures - Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures - New York Heart Association (NYHA) class III or IV heart failure - Symptomatic pulmonary embolism or asymptomatic pulmonary emboli within the last 3 months - Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTcF >= 470 msec (mean value) obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value, or history of congenital long QT syndrome, or torsades de pointes); any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Left ventricular ejection fraction (LVEF) by either multigated acquisition (MUGA) or echocardiography (ECHO) less than lower limit of normal - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Concurrent anti-cancer therapy - History of hypersensitivity attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) or osimertinib (AZD9291) - Pregnant women or women who are breast feeding are not eligible for the study; the effects of MLN0128 (TAK-228) and osimertinib (AZD9291) on the developing human fetus are unknown - Women of non-child bearing potential must be: - Women more than 50 years must be post-menopausal for at least 12 months following the end of all exogenous hormonal treatments OR - Women under 50 years must be postmenopausal for at least 12 months following the end of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution OR - Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation - Women of child bearing potential must have a negative serum or urine pregnancy test within 7 days of registration and must agree to: - Practice 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 120 days (or longer, as mandated by local labeling [e.g., United Surgical Partners International (USPI), Summary of Product Characteristics (SmPC), etc.;]) after the last dose of study drug, OR - Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to: - Practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR - Practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together - Not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug - Inability to discontinue drugs that are strong cytochrome P450 3A4 (CYP3A4) or P450 3A5 (CYP3A5), cytochrome P450 2C19 (CYP2C19), and cytochrome P450 2C9 (CYP 2C9) inhibitors and/or inducers; and substrates of CYP 3A4/5 or CYP1A2 that are sensitive or have a narrow therapeutic window at least three weeks prior to study registration - Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug - Consumption of grapefruit or grapefruit juice is not permitted during the study; patients should not consume food or beverages containing the fruit or juice of grapefruits or Seville oranges within 7 days before the first dose of study drug and throughout the study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with MLN0128 (TAK-228) and osimertinib (AZD9291) - No concomitant use of proton pump inhibitors (PPI) is allowed; any prior PPI must be discontinued at least one week before receiving MLN0128 (TAK-228) Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically or cytologically confirmed non-squamous NSCLC - NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion) - Progressive disease on osimertinib (AZD9291) given first line - For the dose expansion portion ONLY, patient must: 1) have progression of disease with first line osimertinib administered for advanced or metastatic disease as the last previous systemic treatment, 2) be treatment naïve for other 3rd generation EGFR-TKI (CO-1686) and mTOR inhibitors - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from a combined positron emission tomography (PET)/CT may be used if it is of diagnostic quality; laboratory parameters are not acceptable as the only evidence of disease - For the dose expansion, no other systemic therapies for advanced/metastatic disease is permissible after first line osimertinib - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated; patients with small brain metastases for which radiation or surgery is not indicated, may be eligible on discussion with the study chair. --- L858R ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC)

Time: 28 days

Description: Toxicities will be graded according to the NCI CTCAE v4. CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Dose-limiting toxicity (DLT) of sapanisertib in combination with osimertinib in patients with EGFRm NSCLC

Time: 28 days

Secondary Outcomes

Description: Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Non-DLTs associated with the administration of sapanisertib and osimertinib

Time: Up to 30 days after completion of study treatment

Description: PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.

Measure: Pharmacokinetic (PK) profiles of sapanisertib in combination with osimertinib

Time: Baseline, and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib administration, before administration and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib on day 26 of course 1; and day 1 of course 2

Description: Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

Description: Will be assessed using RECIST 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival of patients with T790M- NSCLC in an expansion cohort

Time: At 6 months

Description: Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates analyzed in tumor and blood. Descriptive statistics and plotting of data will also be used to better understand potential relationships.

Measure: Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid specimens

Time: Up to 2 years

125 Randomized Blinded Phase III Assessment of Second or Third-Line Chemotherapy With Docetaxel + Plinabulin Compared to Docetaxel + Placebo in Patients With Advanced Non-Small Cell Lung Cancer and With at Least One Measurable Lung Lesion

To compare the overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy with docetaxel + plinabulin (DP Arm) to patients treated with docetaxel + placebo (D5W) (D Arm) for advanced or metastatic disease. Secondary purposes of the study are: - To compare the neutropenia (incidence of Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 × 10^9/L]) on Day 8 (+/- 1 day) of Cycle 1), DoR, neutrophil count on Day 8 (+/- 1 day) of Cycle 1, incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1, QoL (EORTC QLQ-C30 [item 30, average overall quality of life over all observable weeks]), ORR, and PFS in patients with NSCLC treated in the DP Arm to patients treated in the D Arm as 2nd- or 3rd-line therapy for advanced or metastatic disease. - To compare the safety and adverse events profile of the DP Arm to D Arm. - To compare dose intensity of docetaxel (percent dose administered compared to dose assigned) between the 2 treatment arms. - To evaluate population pharmacokinetics in patients enrolled in China and rest of world (RoW).

NCT02504489
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Docetaxel + Plinabulin (DP)
  2. Drug: Docetaxel (D)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Radiographic tumor assessment is to be performed within 28 days prior to randomization. 5. patients with nonsquamous NSCLC must have been tested for EGFR exon 19 deletion and Exon 21 L858R substitution mutation. --- L858R ---

Primary Outcomes

Description: Overall survival of NSCLC patients receiving 2nd- or 3rd-line systemic therapy

Measure: Overall Survival

Time: Approximately 2 years after study initiation

Secondary Outcomes

Description: Incidence of Grade 4 neutropenia on Day 8 of Cycle 1

Measure: Grade 4 neutropenia

Time: During 1st 21-day cycle

Description: Neutrophil count on Day 8 of Cycle 1

Measure: Neutrophil count

Time: During 1st 21-day cycle

Description: incidence of docetaxel dose reduction and/or docetaxel dose withheld in Cycle 2 due to neutropenia in Cycle 1

Measure: docetaxel dose reduction and/or docetaxel dose withheld

Time: During 2nd 21-day cycle

Description: Average Quality of Life score over all observed weeks (scale 0 - 30, higher value represents better outcome)

Measure: Quality of Life (EORTC QLQ-C30)

Time: Approximately 2 years after study initiation.

Description: Overall response rate

Measure: ORR

Time: Approximately 2 years after study initiation.

Description: Progress-free survival

Measure: PFS

Time: Approximately 2 years after study initiation.

Description: Duration of response

Measure: DoR

Time: Approximately 2 years after study initiation.

126 A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacy and Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA).

To assess the efficacy and safety of AZD9291 versus Placebo, in patients with Epidermal Growth Factor Receptor Mutation Positive stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy

NCT02511106
Conditions
  1. Stage IB-IIIA Non-small Cell Lung Carcinoma
Interventions
  1. Drug: AZD9291 80 mg/40 mg
  2. Drug: Placebo AZD9291 80 mg/40 mg
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M. --- L858R ---

Stage IB-IIIA Non-small Cell Lung Carcinoma Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung cancer (NSCLC) with centrally confirmed, most common sensitising EGFR mutations (Ex19Del and L858R) either alone or in combination with other EGFR mutations as confirmed by a central test, who have had complete tumour resection, with or without postoperative adjuvant chemotherapy. --- L858R ---

Primary Outcomes

Description: Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence)

Measure: Disease free survival (DFS)

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Secondary Outcomes

Description: Defined as the proportion of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis

Measure: Disease free survival (DFS) rate at 2, 3 and 5 years

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Description: Defined as the time from the date of randomization until date of death due to any cause

Measure: Overall Survival (OS)

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Defined as the proportion of patients alive at 5 years, estimated from a Kaplan Meier plot of OS at the time of the primary analysis

Measure: Overall Survival rate at 5 years

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Measured by SF-36 Questionnaire consisting in 36 items that is an instrument for assessing a person's general health status over the past 28 days. The scores for each of the 8 health domain scores and for each of the physical and mental component summary measures from the SF-36 v2 will be summarized in terms of mean changes from baseline at each post-baseline assessment.

Measure: Patient health-related quality of life and symptoms (HRQoL) by SF-36v2 Health Survey

Time: From date of randomization until treatment completion or discontinuation (max. 36 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291

Measure: Plasma concentrations of AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZ5104 and AZ7550 metabolites

Measure: Plasma concentrations of AZ5104 and AZ7550 metabolites and ratio of metabolite to AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Other Outcomes

Description: AEs graded by CTCAE version 4.0

Measure: Incidence of Adverse Events (AEs)

Time: From date of randomization until 28 days after treatment completion (max. 37 months)

127 A Single Arm Phase IV Study of Afatinib in Elderly Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Exon 19 Deletions or Exon 21(L858R) Substitution Mutations

Continuous treatment until progression or occurence of intolerable Adverse Event (AE) or end of trial. The end of trial is one year after the last patient has entered the study.

NCT02514174
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. ErbB Receptors
Interventions
  1. Drug: Afatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Single Arm Phase IV Study of Afatinib in Elderly Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Exon 19 Deletions or Exon 21(L858R) Substitution Mutations. --- L858R ---

Staging is based on American Joint Committee on Cancer (AJCC) Staging for NSCLC 7th edition (R12-4710) - Evidence of common EGFR mutation (Del 19 and/or L858R) - Age >= 70 years - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (R01-0787) - Further inclusion criteria apply. --- L858R ---

Primary Outcomes

Description: On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants Reporting an Adverse Event (AE) Leading to Dose Reduction of Afatinib

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Secondary Outcomes

Description: Percentage of participants with adverse event being diarrhoea of CTCAE grade 3 or higher. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Diarrhoea of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Percentage of participants with adverse event = rash/acne (grouped term) of CTCAE grade 3 or higher. MedDRA preferred terms that described AEs of similar nature were grouped together as "grouped term" to ensure that important events would not be underestimated. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Rash/Acne (Grouped Term) of CTCAE Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Percentage of participants with adverse event = stomatitis (grouped term) of CTCAE grade 3 or higher. MedDRA preferred terms that described AEs of similar nature were grouped together as "grouped term" to ensure that important events would not be underestimated. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Stomatitis (Grouped Term) of CTCAE Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Percentage of participants with adverse event = paronychia (grouped term) of CTCAE grade 3 or higher. MedDRA preferred terms that described AEs of similar nature were grouped together as "grouped term" to ensure that important events would not be underestimated. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent for study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria).

Measure: Percentage of Participants With Adverse Event = Paronychia (Grouped Term) of CTCAE Grade 3 or Higher

Time: On-treatment period + 28 days (residual effect period), up to 1057 + 28 days

Description: Time to first dose reduction of afatinib caused by adverse events is defined as time from the date of the first administration of afatinib to the date of first dose reduction of afatinib caused by adverse events. Participants without AEs leading to dose reduction were censored at date of last intake of afatinib. On-treatment period = First administration of afatinib until progression or intolerable adverse events or other reasons necessitating withdrawal (participant's withdrawal of consent from study treatment, participant diagnosed with interstitial lung disease, participant no longer able to receive study treatments, participant had a significant deviation from the protocol or eligibility criteria). The cumulative probability of no dose reduction at the respective time point is given by the Kaplan-Meier estimate at the respective time point based on time to first dose reduction of afatinib caused by adverse events.

Measure: Time to First Dose Reduction of Afatinib Caused by Adverse Events

Time: On-treatment period, up to 1057 days

128 Pemetrexed Disodium and Cisplatin Chemotherapy Combined With Synchronous Gefitinib vs Chemotherapy Alone as Adjuvent Therapy in Patient With Stage II-IIIA, Epidermal Growth Factor Receptor Mutant Expressing Lung Adenocarcinoma

This randomized phase III trial is studying gefitinib and synchronous pemetrexed/cisplatin chenmotherapy to see how well it works compared to pemetrexed/cisplatin chenmotherapy alone in treating patients who have undergone surgery for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR activating mutation in Asian population.

NCT02518802
Conditions
  1. Lung Neoplasms
Interventions
  1. Drug: Gefitinib
  2. Drug: Pemetrexed
MeSH:Adenocarcinoma Lung Neoplasms Adenocarcinoma of Lung
HPO:Neoplasm of the lung

- Target population is completely resected pathological stage II-IIIA(N1-N2) NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation. --- L858R ---

Primary Outcomes

Description: To evaluate the disease free survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for pathological stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: From date of randomization to the first documented disease progression or death, whichever occurs first, assessed up to 3 and 5 years.

Secondary Outcomes

Description: To evaluate the overall survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.

Measure: Overall survival

Time: From date of randomization to the first documented death, assessed up to 5 years.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

129 A Phase 1B Study of AZD9291 in Combination With Navitoclax in EGFR-Mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor

This phase Ib trial studies the side effects and best dose of osimertinib and navitoclax when given together and to see how well they work in treating patients with previously treated epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer that has spread to other places in the body (metastatic) or has not responded to previous treatment with initial EGFR kinase inhibitor. Osimertinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02520778
Conditions
  1. Advanced Lung Non-Squamous Non-Small Cell Carcinoma
  2. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  3. Stage III Lung Non-Small Cell Cancer AJCC v7
  4. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  5. Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  6. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Navitoclax
  2. Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R ---

Primary Outcomes

Description: Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Incidence of toxicity (dose escalation)

Time: Up to 2 years

Description: Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with > 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).

Measure: Feasibility of the combination therapy in T790M+ lung cancer (dose expansion)

Time: Up to 12 weeks (3 cycles of treatment)

Secondary Outcomes

Description: Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.

Measure: Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax

Time: Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2)

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.

Measure: Objective response rate

Time: Baseline up to 30 days after completion of study drug

Description: Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.

Measure: Change in plasma concentration of EGFR T790M and other EGFR mutations

Time: Baseline to up to 2 years

Description: Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.

Measure: Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue

Time: Baseline

130 The Postoperative Adjuvant Therapy of Gefitinib for High Risk Stage Ib NSCLC Patients With EGFR Sensitive Mutation, an Open, Paired, Non-interventional, Multi-center Clinical Study

Currently, whether adjuvant therapy should be applied to Stage Ib non-small cell lung cancer (NSCLC) patients who received radical resection remains controversial. There is still no clear evidence that the postoperative adjuvant chemotherapy or other treatments can improve the survival rate for patients with stage Ib NSCLC. Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib and Erlotinib are widely accepted as the first-line therapy for Epidermal growth factor receptor (EGFR) gene mutation late stage NSCLC patients. However the effect is largely uncertain for early stage patients who received surgery. The investigators aim to evaluate the effect of postoperative adjuvant use of Gefitinib for high risk stage Ib EGFR sensitive mutation NSCLC patients.

NCT02526537
Conditions
  1. NSCLC
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

2. Patients with pathology confirmed Ib stage NSCLC 3. Patients with deletion of exon 19 or mutation of L858R at exon 21 in EGFR gene 4. ECOG score of 0-1 5. Life expectancy over 12 weeks 6. --- L858R ---

Primary Outcomes

Measure: Relapse Free Survival in 2 years

Time: Treatment period: 2 years (24 months)

Secondary Outcomes

Measure: Relapse Free Survival in 3 years

Time: Follow-up: 3 years

Measure: 5 year Overall Survival

Time: Follow-up: 5 years

Measure: Relapse Free Survival in 5 years

Time: Follow-up: 5 years

131 Phase I, Open-Label, Two Parts Study in Chinese Patients With Advanced NSCLC Who Have Progressed Following Prior Therapy With an EGFR Tyrosine Kinase Inhibitor Agent

A Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291 administered orally once daily in Chinese patients with locally advanced or metastatic non small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent. 2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

NCT02529995
Conditions
  1. Carcinoma, Non-Small-Cell Lung With EGFR Mutation Positive
Interventions
  1. Drug: AZD9291 40 mg
  2. Drug: AZD9291 80 mg
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

In addition other lines of therapy may have been given - Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 6. World Health Organisation (WHO) performance status 0-1 7. --- L858R ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Rate and extent of absorption of single dose AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of apparent plasma clearance at steady state

Measure: CL(ss)/F of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: Treatment discontinuation plus 28 days or 12 months after last subject first dose (LSFD). Results are based on data cut off of 2 Nov 2016.

132 A Phase 1/2 Trial of Erlotinib and Onalespib Lactate in EGFR-Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02535338
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Erlotinib Hydrochloride
  2. Other: Laboratory Biomarker Analysis
  3. Drug: Onalespib Lactate
  4. Other: Pharmacological Study
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R ---

Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.. Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R ---

m^2 for patients with creatinine levels above institutional normal - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.3 upper limit of normal (ULN) - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib and/or onalespib administration - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Patients who are receiving any other investigational agents - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib and/or onalespib - History of pneumonitis attributed to an EGFR inhibitor; history of radiation pneumonitis is allowed provided steroid administration for pneumonitis was not required - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Left ventricular ejection fraction =< 50% as demonstrated by echocardiogram or multigated acquisition scan (MUGA) - Drugs that are known to increase torsades de pointes should be avoided; patients must discontinue these medications prior to enrollment on study; selection of alternate concomitant medications with no or minimal torsades de pointes potential is recommended - Strong CYP3A4 inducers and inhibitors should be avoided; selection of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is recommended; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with erlotinib and onalespib - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - Prior treatment with a Hsp90 inhibitor - Treatment with proton pump inhibitors within 3 days prior to study entry; if treatment with an histamine (H2)-receptor antagonist such as ranitidine is required, erlotinib must be taken 10 hours after the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor antagonist; although the effect of antacids on erlotinib pharmacokinetics has not been evaluated, the antacid dose and the erlotinib dose should be separated by several hours, if an antacid is necessary - Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) Inclusion Criteria: - PHASE I: Patients must have metastatic/recurrent, histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with progressive disease by RECIST 1.1 on a previous EGFR-tyrosine kinase inhibitor (TKI); OR patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on platinum containing chemotherapy - PHASE II COHORT A: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR activating mutation (exon 21 L858R, exon 19 deletion, exon 18 G719X, exon 21 L861Q) with stable disease by RECIST 1.1 as best response on erlotinib compared to pre-treatment erlotinib imaging by RECIST 1.1 or progressive disease compared to pre-treatment imaging by RECIST 1.1 after a minimum duration of treatment on erlotinib of 12-weeks; patients must be enrolled within 6 months of initiation of erlotinib - PHASE II COHORT B: Patients must have metastatic/recurrent histologically confirmed NSCLC that harbors an EGFR exon 20 insertion with progressive disease on or after platinum doublet chemotherapy - FOR PHASE I: If patient is on erlotinib at the time of signed consent, the patient does NOT need to be discontinued prior to initiation of erlotinib and onalespib; other EGFR-TKIs must be discontinued at least 7 days prior to initiation of erlotinib and onalespib - FOR PHASE II COHORT A: If patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to receiving treatment erlotinib and onalespib; last dose of erlotinib must be less than 28 days from when patient signs consent - FOR PHASE II COHORT B: (EGFR exon 20 insertions): Prior EGFR-TKIs including erlotinib is allowed; if patient is on erlotinib at the time of signed consent, erlotinib does NOT need to be discontinued prior to initiation of erlotinib and onalespib - Local testing for EGFR-mutations for this study is acceptable provided it was performed in a Clinical Laboratory Improvement Act (CLIA) certified lab - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin within normal institutional limits - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal - Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 --- L858R --- --- L861Q --- --- L858R ---

Primary Outcomes

Description: Will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Measure: Incidence of dose-limiting toxicities from onalespib lactate in combination with erlotinib hydrochloride (Phase I)

Time: Up to 28 days

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase II)

Time: Up to at least 1 year

Secondary Outcomes

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase I)

Time: Up to at least 1 year

Description: Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to at least 1 year

133 An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in First-line Treatment of Patients With Stage IIIB/IV Non-small Cell Lung Cancer Tumors With EGFR Activating Mutations

The purpose of the study was to evaluate the progression free survival (PFS), based on independent radiologic review (IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. This study also assessed Overall survival (OS); Overall response rate (ORR) as assessed by IRR; PFS as assessed by the investigator; Disease control rate (DCR) as assessed by IRR; Duration of Response (DOR) by IRR; Safety of ASP8273; and Quality of Life (QOL) and patient-reported outcome (PRO) parameters.

NCT02588261
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: naquotinib mesilate
  2. Drug: Erlotinib
  3. Drug: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Neutrophil count > 1,000/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin > 8.0 g/dL - Serum creatinine ˂ 2.0 x upper limit of normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 mL/min as calculated by the Cockcroft Gault Method - Total bilirubin ˂1.5 x ULN (except for subjects with documented Gilbert's syndrome) - AST and ALT ˂ 3.0 x ULN or ≤ 5 x ULN if subject has documented liver metastases - Serum sodium level is ≥ 130 mmol/L - Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without T790M mutation, by local or central testing on examination of a NSCLC FFPE specimen (archival or fresh biopsy). --- L858R ---

Subjects harboring both exon 19 deletion and exon 21 L858R mutations are not eligible. --- L858R ---

Primary Outcomes

Description: PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by IRR. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.

Measure: Progression Free Survival (PFS) as Assessed by Independent Radiologic Review (IRR)

Time: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)

Secondary Outcomes

Description: All events of death after the first study drug administration were included.

Measure: Percentage of Deaths

Time: From date of randomization up to data cut-off date 21 Dec 2017 (approximately 22 months)

Description: Percentage of participants with OR was defined as the proportion of participants with best overall response as complete response (CR) or partial response (PR) without confirmation based on the RECIST v1.1 as assessed by the blinded IRR. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response (OR)

Time: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)

Description: PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on RECIST V1.1, as assessed by local investigator. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.

Measure: PFS as Assessed by the Investigator

Time: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)

Description: Percentage of participants with disease control was defined as the proportion of participants whose best overall response was rated as CR, PR or stable disease (SD) among all analyzed participants based on RECIST V1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug.

Measure: Percentage of Participants With Disease Control

Time: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)

Description: DOR was defined as the time from the date of the first response CR/PR (whichever was first recorded) as assessed by IRR to the date of radiographical progression or date of censoring. If a participant had not progressed, the participant was censored at the date of last radiological assessment or at the date of first CR/PR if no post-baseline radiological assessment was available. Results are based Kaplan-Meier estimate.

Measure: Duration of Response (DOR)

Time: From date of first response up to data cut-off date 09 May 2017 (approximately 15 months)

Description: Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization.

Measure: Number of Participants With Adverse Events (AEs)

Time: From first dose of study drug up to 30 days after last dose of study drug taken up to data cut-off 09 May 2017

Description: ACT-EGFRI-18 is an 18-item Likert-scaled questionnaire, used to assess the effect of EGFR inhibitors on quality of life (QoL). The questionnaire is arranged in three HRQL dimensions: physical (seven items), social/emotional (six items), and functional well-being (five items). The response scores ranged from 0 to 4, and the response categories include "not at all", "a little bit", "somewhat", "quite a bit", and "very much." Negatively worded items (e.g., "My skin bleeds easily "or "My skin condition affects my mood") are reverse-scored, so that participants who experience a higher impact of symptom burden on HRQL receive a lower score (range 0-72).

Measure: Functional Assessment of Cancer Therapy - EGFR Inhibitors Subscale (FACT-EGFRI-18) Questionnaire

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: The EORTC-QLQ-LC13 is a validated module of the EORTC-QLQ-Core 30, which includes module items that evaluate symptoms such as cough, hemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling hands or feet, hair loss and pain. The total score for the questionnaire ranges from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems.

Measure: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC-QLQ-LC13)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: EORTC-QLQ-LC30 is a 30-item cancer-specific questionnaire with multitrait scaling was used to create five functional domain scales: Physical, Role, Emotional, Social and Cognitive; two items evaluate global QoL; in addition, three symptom scales assess Fatigue, Pain and Emesis; and six single items assess other symptoms. The total score ranges from 0 to 100, with a high score for a functional scale representing a high/healthy level of functioning and a high score for a symptom scale or item representing a high level of symptomatology or problems.

Measure: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: The EQ-5D is a generic preference-based measure that indirectly measures the utility for health that generates an index-based summary score based upon societal preference weights. The EQ-5D-5L consists of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale (VAS) for health status. Each item has 5 response levels ranging from level 1 (no problem or none) to level 5 (unable to perform activity). The VAS ranges from 0 (worst health status) and 100 (best health status).

Measure: EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

134 An Open-label, Multi-Centered, Dose Escalation Phase Ib Study (Expansion Stage) of Epitinib (HMPL-813) in Patients With Advanced Solid Tumors

Epitinib (HMPL-813) is a selective EGFR tyrosine kinase inhibitor. Epitinib has demonstrated strong inhibitory effects on multiple tumors with overexpressed EGFR or sensitive EGFR mutations in pre-clinical setting. This first-in-human study is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity(DLT), safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of Epitinib.

NCT02590952
Conditions
  1. Solid Tumor
Interventions
  1. Drug: Epitinib
MeSH:Neoplasms
HPO:Neoplasm

On day 2/15/29/56, PK samples are collected predose in the morning.. Inclusion Criteria: - Histopathology confirmed solid tumors - Failed to standard treatment or no standard treatments for uncontrolled, recurrent and/or metastatic advance tumor (whatever previous surgery conditions) - Age 18-70 - ECOG 0-2, and no worse within 7days - Life expected > 12 weeks - written informed consent form voluntarily - For dose expansion cohort, subjects must be eligible for the following inclusion criteria: - EGFR sensitizing mutation in exon 19 deletion or exon 21(L858R). --- L858R ---

- Unrecovered from any previous therapy related toxicity to CTCAE 0 or 1or unrecovered from any previous surgery - Known dysphagia or drug malabsorption - Active infections such as acute pneumonia, hepatitis B immune-active periodphase - ocular surface diseases or dry eye syndrome - skin disease with obvious symptoms and signs - significant cardiovascular disease, including II-IV atrioventricular block, and acute myocardial infarction within 6 months, significant angina or Coronary artery bypass graft within 6 months - Female patients who are pregnant or feeding, or childbearing potential patient with pregnant testing positive - Any abnormal of clinical and laboratory so that patients unsuitable to attend the trial sine in the opinion of the investigator - Patients unable to comply with the protocol since significant psychological or psychogenic abnormal Inclusion Criteria: - Histopathology confirmed solid tumors - Failed to standard treatment or no standard treatments for uncontrolled, recurrent and/or metastatic advance tumor (whatever previous surgery conditions) - Age 18-70 - ECOG 0-2, and no worse within 7days - Life expected > 12 weeks - written informed consent form voluntarily - For dose expansion cohort, subjects must be eligible for the following inclusion criteria: - EGFR sensitizing mutation in exon 19 deletion or exon 21(L858R). --- L858R ---

Primary Outcomes

Description: for each patient, adverse events are collected from the date of consent until 30 days after trial discontinuation

Measure: incidence of all types/grades of adverse events

Time: from first patient in till 30 days after the last patient last visit. It is estimated that last patient last visit happens in Oct 2016.

Secondary Outcomes

Measure: Objective Response Rate

Time: An average of one year

Description: Based on single-dose PK result, multi-dose stage subjects take epitinib either once a day or twice a day. For twice a day epitinib uptake, on day 1/14/28, PK samples are collected predose, 1, 4, 8, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 2/3/7, PK samples are collected predose, 4, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 15/29/56, PK samples are collected predose in the morning. For once a day epitinib uptake, on day 1/14/28 PK samples are collected predose, 0.5, 1, 2, 4, 6, 8, 12 hours post-dose. On day 7, PK samples are collected predose and 4 hours post-dose. On day 2/15/29/56, PK samples are collected predose in the morning.

Measure: Area under the plasma concentration versus time curve (AUC)

Time: At single-dose stage (day 1-day 7): predose, 0.5,1, 2, 3, 4, 5, 6, 8,12,24, 36, 48, 72, 144 hours post-dose.

Description: Based on single-dose PK result, multi-dose stage subjects take epitinib either once a day or twice a day. For twice a day epitinib uptake, on day 1/14/28, PK samples are collected predose, 1, 4, 8, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 2/3/7, PK samples are collected predose, 4, 12 hours post-dose in the morning and 4 hours post-dose in the evening. On day 15/29/56, PK samples are collected predose in the morning. For once a day epitinib uptake, on day 1/14/28 PK samples are collected predose, 0.5, 1, 2, 4, 6, 8, 12 hours post-dose. On day 7, PK samples are collected predose and 4 hours post-dose. On day 2/15/29/56, PK samples are collected predose in the morning.

Measure: Peak Plasma Concentration (Cmax)

Time: At single-dose stage (day 1-day 7): predose, 0.5,1, 2, 3, 4, 5, 6, 8,12,24, 36, 48, 72, 144 hours post-dose.

135 Adjuvant Nivolumab in Resected Lung Cancers (ANVIL) - A Randomized Phase III Study of Nivolumab After Surgical Resection and Adjuvant Chemotherapy in Non-Small Cell Lung Cancers

This phase III ALCHEMIST treatment trial studies how well nivolumab after surgery and chemotherapy work in treating patients with stage IB-IIIA non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

NCT02595944
Conditions
  1. Stage IB Lung Non-Small Cell Carcinoma AJCC v7
  2. Stage II Lung Non-Small Cell Cancer AJCC v7
  3. Stage IIA Lung Non-Small Cell Carcinoma AJCC v7
  4. Stage IIB Lung Non-Small Cell Carcinoma AJCC v7
  5. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Nivolumab
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.. Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To evaluate whether adjuvant therapy with nivolumab will result in improved overall survival (OS) and/or disease-free survival (DFS) over standard observation in patients with stage IB >= 4 cm, II and IIIA, non-small cell lung cancer (NSCLC) following surgical resection and standard adjuvant therapy. --- L858R ---

Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.. Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Inclusion Criteria: - Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins - Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization - Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation (centrally as part of the ALCHEMIST-SCREEN protocol) and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (centrally as part of ALCHEMIST-SCREEN and/or locally) - NOTE: if the results of the central EGFR testing are negative, but the ALK testing was not able to be completed by the ALCHEMIST central lab, the ALK status will be considered negative (unless locally positive for ALK rearrangement) and the patient may be considered for enrollment onto EA5142, once PD-L1 results are received and all other eligibility requirements are met - Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol - Women must not be pregnant or breast-feeding due to unknown and potentially harmful effects of nivolumab on the developing fetus or child - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion - Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements - No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody) - Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required) - Minimum time between date of surgery and randomization is 4 weeks (28 days) - Maximum time allowed between surgery and randomization: - 3 months (90 days) if no chemotherapy is administered - 8 months (240 days) if adjuvant chemotherapy was administered - 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered - Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required) - Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal (within 2 weeks prior to randomization) - Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN) (within 2 weeks prior to randomization) - White blood cell (WBC) >= 2000/uL (within 2 weeks prior to randomization) - Neutrophils >= 1000/uL (within 2 weeks prior to randomization) - Platelets >= 100 x 10^3/uL (within 2 weeks prior to randomization) - Hemoglobin >= 8 g/dL (within 2 weeks prior to randomization) - Serum creatinine =< 2 x ULN (within 2 weeks prior to randomization) - Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy - Patients must not be receiving any other investigational anti-cancer agents while on study - Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll - Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible - Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To evaluate whether adjuvant therapy with nivolumab will result in improved overall survival (OS) and/or disease-free survival (DFS) over standard observation in patients with stage IB >= 4 cm, II and IIIA, non-small cell lung cancer (NSCLC) following surgical resection and standard adjuvant therapy. --- L858R --- --- L858R ---

Primary Outcomes

Description: DFS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparisons of DFS will use a logrank tests stratified on the randomization stratification factors with a one-sided type I error rate corresponding to the significance level associated with population being analyzed; that is, 1.5% for the overall population and 1% for the >= 50% population. The latter test will only be performed in the event that the primary test in all-comers is not statistically significant. Other comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Measure: Disease-free survival (DFS)

Time: Time from randomization to the earliest event defined as disease recurrence, any new lung cancer (even in the opposite lung), or death from any cause at any known point in time, assessed up to 10 years

Description: OS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparisons of OS will use a logrank tests stratified on the randomization stratification factors with a one-sided type I error rate corresponding to the significance level associated with population being analyzed; that is, 1.5% for the overall population and 1% for the >= 50% population. The latter test will only be performed in the event that the primary test in all-comers is not statistically significant. Other comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Measure: Overall survival (OS)

Time: Time from randomization to death from any cause, assessed up to 10 years

Secondary Outcomes

Description: Toxicity rates will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Measure: Incidence of toxicity graded according to Common Terminology Criteria for Adverse Events version 5.0

Time: Up to 10 years

136 A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of JNJ-61186372, a Human Bispecific EGFR and cMet Antibody, in Subjects With Advanced Non-Small Cell Lung Cancer

The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of JNJ-61186372 as a monotherapy and in combination with lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination chemotherapy (JNJ-61186372 in combination with standard of care carboplatin and pemetrexed) in 21 day treatment cycle for participants with advanced non-small cell lung cancer (NSCLC).

NCT02609776
Conditions
  1. Non-Small-Cell Lung Cancer
Interventions
  1. Drug: JNJ-61186372
  2. Drug: JNJ-61186372
  3. Drug: Lazertinib
  4. Drug: Carboplatin
  5. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

For Part 1 Chemotherapy Combination Cohort only: Participants must have histologically or cytologically confirmed NSCLC that is metastatic or unresectable and be eligible for treatment with combination carboplatin and pemetrexed, in accordance with standard of care, and be willing to receive additional investigational therapy with JNJ-61186372 - For Part 1 Combination Dose Escalation with lazertinib only: Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation and (a) be treatment naïve for metastatic disease, without access to third generation TKI in the front-line setting, or (b) have progressed after front-line treatment with first (erlotinib or gefitinib) or second generation (afatinib) TKI and are ineligible for Cohort MET-1, or (c) have been treated with a third generation TKI (eg, osimertinib) in either the front line or second-line setting, and are not eligible for enrollment in either Cohort C or MET-1. --- L858R ---

For Part 2 only: Participants must also have disease with a previously diagnosed activating epidermal growth factor receptor (EGFR) mutation (includes both inhibitor sensitive primary mutations such as Exon 19 deletion and L858R (Cohort C, E, and MET-1), as well as marketed TKI-resistant mutations such as Exon 20 insertion (Cohort C, D and MET-1) or activating cMet Exon 14 skipping mutation (Cohort MET-2). --- L858R ---

Cohort E (combination JNJ-61186372 and lazertinib): Participants must have been diagnosed with EGFR Exon 19del or L858R activating mutation, and have progressed after first or second-line treatment with a third generation TKI (eg, osimertinib) - Participant must have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Exclusion Criteria: - Participant has uncontrolled inter-current illness, including but not limited to poorly controlled hypertension, or diabetes, ongoing or active infection, (that is, has discontinued all antibiotics for at least one week prior to first dose of study drug), or psychiatric illness/social situation that would limit compliance with study requirements. --- L858R ---

Primary Outcomes

Description: The Dose Limiting Toxicity (DLT) is based on drug related adverse events and includes unacceptable hematologic toxicity, non-hematologic toxicity of Grade 3 or higher, or elevations in hepatic enzymes suggestive of drug-induced liver injury.

Measure: Part 1: Number of Participants With Dose Limiting Toxicity (DLT)

Time: Up to Day 28

Description: An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

Measure: Part 2: Number of Participants With Adverse Events (AEs) and Serious AEs

Time: Screening up to follow-up (30 [+7] days after the last dose)

Description: Overall response rate (ORR) is defined as the percentage of participants who achieve either a CR or PR as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). CR: disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (< 10 mm short axis) and normalisation of tumour marker levels; PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and Persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.

Measure: Part 2: Overall Response Rate (ORR)

Time: Up to End of Treatment Follow (EOT) Up Period (30 [+7] days after the last dose)

Description: DOR will be calculated as time from initial response of CR (disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size ([<] 10 [mm] short axis) and normalisation of tumour marker levels) or PR (at least a 30 [%] decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits) to progressive disease (PD) or death due to underlying disease, whichever comes first, only for participants who achieve CR or PR.

Measure: Part 2: Duration of Response (DOR)

Time: Up to EOT Follow Up Period (30 [+7] days after the last dose)

Description: Clinical benefit rate is defined as the percentage of participants achieving complete response (CR): disappearance of all target lesions and non-target lesions. All lymph nodes must be non-pathological in size (less than [<] 10 millimeter [mm] short axis) and normalisation of tumour marker levels or partial response (PR): at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits or durable stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study and persistence of one or more non-target lesion(s) and/or maintenance of tumour marker level above the normal limits.

Measure: Part 2: Percentage of Participants With Clinical Benefit

Time: Up to EOT Follow Up Period (30 [+7] days after the last dose)

Description: Ctrough is the observed serum concentration immediately prior to the next administration.

Measure: Trough Serum Concentration (Ctrough) of JNJ-61186372

Time: Up to EOT (30 days after last dose)

Description: The AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau)

Measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of JNJ-61186372

Time: Up to EOT (30 days after last dose)

Secondary Outcomes

Description: The Cmax is the maximum observed serum concentration of JNJ-61186372.

Measure: Maximum Serum Concentration (Cmax) of JNJ-61186372

Time: Cycle 1 Day 1: predose through end of infusion (EOT) or Follow Up (approximately 16 months) (each cycle is of 28 days)

Description: The Tmax is defined as time to reach maximum observed serum concentration of JNJ-61186372.

Measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of JNJ-61186372

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: The AUC(t1-t2) is the area under the serum JNJ-61186372 concentration-time curve from time t1 to t2.

Measure: Area Under the Serum Concentration-Time Curve From t1 to t2 Time (AUC[t1-t2]) of JNJ-61186372

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: The AUCtau is the area under the serum concentration-time curve during a dose interval time period (tau)

Measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of JNJ-61186372

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: The Ctrough is the observed serum concentration immediately prior to the next administration.

Measure: Trough Serum Concentration (Ctrough) of JNJ-61186372

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: Cmax is the maximum observed serum concentration of lazertinib.

Measure: Maximum Serum Concentration (Cmax) of Lzertinib

Time: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)

Description: Tmax is defined as time to reach maximum observed serum concentration of lazertinib.

Measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of Lazertinib

Time: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)

Description: Ctrough is the observed serum concentration immediately prior to the next administration.

Measure: Trough Serum Concentration (Ctrough) of Lazertinib

Time: Cycle 1 Day 1: predose through EOT (30 [+7] days after last dose [Cycle 4 Day 15]) (each cycle is of 28 days)

Description: The R is the accumulation ratio calculated as Cmax or AUC after multiple doses divided by Cmax or AUC after the first dose, respectively.

Measure: Accumulation ratio (R) of JNJ-61186372

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: Serum levels of antibodies to JNJ-61186372 for evaluation of potential immunogenicity.

Measure: Number of Participants With Anti-Drug Antibodies (ADA)

Time: Cycle 1 Day 1: predose through EOT or Follow Up (approximately 16 months)

Description: PFS is defined as the time from first infusion of study drug to PD or death due to any cause.

Measure: Progression-Free Survival (PFS)

Time: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)

Description: TTF is defined as the time from the first infusion of the study drug to discontinuation of treatment for any reason, including disease progression, treatment toxicity, death, and will be utilized to capture clinical benefit for patients continuing treatment beyond RECIST v1.1 defined disease progression.

Measure: Time to Treatment Failure (TTF)

Time: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)

Description: OS is defined as the time from first infusion of study drug to death due to any cause.

Measure: Overall Survival (OS)

Time: Up to End of Treatment Follow Up Period (30 [+7] days after the last dose)

137 A Phase 2, Multicenter Study of Tesevatinib in Subjects With Non-Small Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment With a Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal Metastases

A study to assess the activity of tesevatinib in subjects with NSCLC and activating EGFR mutations who have disease progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who heave either BM or LM at initial presentation.

NCT02616393
Conditions
  1. Non-Small Cell Lung Cancer
  2. Leptomeningeal Metastases
  3. Brain Metastases
Interventions
  1. Drug: Tesevatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Brain Neoplasms Meningeal Carcinomatosis
HPO:Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

Subjects with a history of atrial arrhythmias should be discussed with the medical monitor - Has an active infectious process - Female subject who is pregnant or lactating - Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign body - Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470 msec) using the Fridericia method of correction for heart rate - Gastrointestinal (GI) condition that interferes with drug absorption - Non-malignant neurological disease that would interfere with evaluation of symptoms or signs of brain metastases Cohort B Inclusion Criteria: - History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation) or, if previously treated, history of an activating EGFR mutation that has had a clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled). --- L858R ---

Primary Outcomes

Description: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC), activating EGFR mutations, and BM as measured by RECIST 1.1 evaluated changes in BM size (Cohort A)

Measure: Clinical Activity of tesevatinib against BM using RECIST 1.1

Time: 12 months

Description: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating EGFR mutations and/or LM as measured by improvement in CTCAE v4.03 symptoms and signs (Cohort B)

Measure: Clinical Activity of tesevatinib against LM using Symptom Resolution

Time: 12 months

Description: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC), activating EGFR mutations, and BM at initial presentation as measured by RECIST 1.1 evaluated changes in BM size (Cohort C)

Measure: Clinical Activity of tesevatinib against BM at initial presentation using RECIST 1.1

Time: 12 months

Secondary Outcomes

Description: To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib for BM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

Measure: Quality of Life in Subjects Receiving tesevatinib for BM

Time: 12 months

Description: To evaluate changes in QOL in subjects receiving tesevatinib for LM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

Measure: Quality of Life in Subjects Receiving tesevatinib for LM

Time: 12 months

Description: To evaluate changes in QOL in subjects receiving tesevatinib for BM at initial presentation using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

Measure: Quality of Life in Subjects Receiving tesevatinib for BM at initial presentation

Time: 12 months

Description: To determine the median progression-free survival (PFS) in Cohort A by assessing the median number of days from Cycle 1, Day 1 until disease progression or death

Measure: Median Progression-Free Survival in Cohort A

Time: 12 months

Description: To determine the rate of CNS non-progression at 3 and 6 months Cohort A by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1

Measure: Rate of CNS Non-Progression in Cohort A

Time: 12 months

Description: To determine the rate of Non-CNS time to progression in Cohort A by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression

Measure: Non-CNS Time to Progression in Cohort A

Time: 12 months

Description: To determine the rate of CNS TTPin Cohort A by assessing the median number of days in Cycle 1, Day 1 to disease progression

Measure: CNS TTP in Cohort A

Time: 12 months

Description: To determine the median progression-free survival (PFS) in Cohort B by assessing the median number of days from Cycle 1, Day 1 until disease progression or death

Measure: Median Progression-Free Survival in Cohort B

Time: 12 months

Description: To determine the rate of CNS non-progression at 3 and 6 months Cohort B by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1

Measure: Rate of CNS Non-Progression in Cohort B

Time: 12 months

Description: To determine the rate of Non-CNS time to progression in Cohort B by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression

Measure: Non-CNS Time to Progression in Cohort B

Time: 12 months

Description: To determine the rate of CNS TTP in Cohort B by assessing the median number of days in Cycle 1, Day 1 to disease progression

Measure: CNS TTP in Cohort B

Time: 12 months

Description: To determine the median overall survival (OS) in Cohort A by measuring the median number of days from Cycle 1, Day 1 until death

Measure: Median Overall Survival in Cohort A

Time: 12 months

Description: To determine the median OS in Cohort B by measuring the median number of days from Cycle 1, Day 1 until death

Measure: Median Overall Survival in Cohort B

Time: 12 months

Description: Evaluate the activity of tesevatinib in subjects with NSCLC as measured by decreases in NSCLC cells in the CSF using standard cytology as assessed by the percent change in the number of NSCLC cells in the CSF for each patient in cohort B from screening to Cycle 1, Day 14, from Day 14 to Cycle 3, Day 1, and from screening to Cycle 3, Day 1 (Cohort B)

Measure: Clinical Activity of tesevatinib against LM using Standard Cytology

Time: 12 months

Description: Evaluate the activity of tesevatinib in subjects with NSCLC as measured by changes in MRI findings consistent with leptomeningeal metastases (absent or present) for each patient in Cohort B from Cycle 1, Day 1 to Cycle 3, Day 1 and from Cycle 1, Day 1 to Cycle 5 Day 1 (Cohort B)

Measure: Clinical Activity of tesevatinib against LM using Improvement in MRI Findings

Time: 12 months

Description: To determine the median progression-free survival (PFS) in Cohort C by assessing the median number of days from Cycle 1, Day 1 until disease progression or death

Measure: Median Progression-Free Survival in Cohort C

Time: 12 months

Description: To determine the rate of CNS non-progression at 3 and 6 months Cohort C by assessing the percentage of subjects in Cohort C without CNS disease progression 3 and 6 months after Cycle 1, Day 1

Measure: Rate of CNS Non-Progression in Cohort C

Time: 12 months

Description: To determine the rate of Non-CNS time to progression in Cohort C by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression

Measure: Non-CNS Time to Progression in Cohort C

Time: 12 months

Description: To determine the rate of CNS TTPin Cohort C by assessing the median number of days in Cycle 1, Day 1 to disease progression

Measure: CNS TTP in Cohort C

Time: 12 months

Description: To determine the median overall survival (OS) in Cohort C by measuring the median number of days from Cycle 1, Day 1 until death

Measure: Median Overall Survival in Cohort C

Time: 12 months

Description: To evaluate the concentration of tesevatinib in CSF versus plasma in Cohort B by obtaining PK analysis of plasma pre-dose on both Cycle 1 Day 14 and Cycle 3 Day 1, as well as obtaining PK samples of both plasma and CSF 4-8 hours after tesevatinib administration on Cycle 1 Day 14 and on Cycle 3 Day 1.

Measure: Pharmacokinetics in Cohort B: Concentration of tesevatinib in CSF versus plasma

Time: 12 Months

138 A Phase II, Open-Label, Multicentre Study to Assess the Anti-tumour Activity of Afatinib in Patients With Activating Epidermal Growth Factor Receptor Mutation in Circulating Tumor DNA

Treatment efficacy of afatinib will be assessed in patients with lung cancer harboring EGFR mutations which were detected from circulating tumor DNA.

NCT02629523
Conditions
  1. Lung Neoplasms
  2. EGFR Gene Mutation
Interventions
  1. Drug: Afatinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: 1. Stage IIIB or IV lung cancer diagnosed radiologically with or without pathologic diagnosis 2. Age> 18 year-old 3. ECOG performance status 0~2. 4. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from circulating DNA 5. --- L858R ---

Primary Outcomes

Description: Efficacy evaluation RECIST v1.1

Measure: Efficacy evaluation RECIST v1.1

Time: 2 months

Secondary Outcomes

Measure: Progression Free Survival

Time: 2 years

139 A Phase 1b/2 Study of the Safety and Efficacy of Rociletinib (CO-1686) Administered in Combination With MPDL3280A in Patients With Activating EGFR Mutation-positive (EGFRm) Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

This clinical research study is being carried out in two parts, Phase 1 and Phase 2. The primary purpose of the Phase 1 portion of the study is to observe the safety of the combination of rociletinib and MPDL3280A in EGFR-mutant NSCLC patients. The primary purpose of the Phase 2 portion of the study is to evaluate the safety and anti-tumor effects of the combination of rociletinib and MPDL3280A, at the best doses for the combination determined in Phase 1, in patients with EGFR-mutant NSCLC.

NCT02630186
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
  2. Drug: MPDL3280A
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Given the limited sample size, no formal statistical analysis is planned.. Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R ---

- For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve Exclusion Criteria: - Unresolved toxicities from prior therapy - Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases - Previous treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1) - Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4 therapeutic antibodies - Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures - Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (bisphosphonate use for prevention of skeletal events allowed) - Known hypersensitivity to any component of the MPDL3280A or rociletinib formulations or history or hypersensitivity to chimeric humanized antibodies or fusion proteins - History of autoimmune disease - History of prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation - Treatment with systemic immunosuppressive medications within 2 weeks prior to first day of study treatment (inhaled corticosteroids and mineralocorticoids allowed) - Live attenuated vaccine within 4 weeks prior to first day of study treatment - Active tuberculosis, active hepatitis, or positive HIV status - Class II to IV heart failure as defined by the New York Heart Association functional classification system - Untreated or uncontrolled cardiovascular disease or other symptomatic cardiac dysfunction - QTCF > 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan (history of radiation pneumonitis in radiation field may be allowed) - Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R ---

Primary Outcomes

Description: The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A.

Measure: Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03

Time: Continuously, up to approximately 18.5 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of Rociletinib and Its Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of Rociletinib and Metabolites

Time: Approximately every 6 weeks up to 24 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 8

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of MPDL3280A

Time: Cycle 1 Day 1

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of MPDL3280A

Time: Approximately every 6 weeks up to 24 months

Description: To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI.

Measure: Objective Response Rate Per RECIST v1.1 in Phase 2

Time: Approximately every 6-9 weeks

Secondary Outcomes

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study.

Measure: Number of Patients Alive at Study Termination

Time: Up to approximately 18.5 months

Description: Tumor tissue, plasma, and blood specimens will be used for pharmacodynamic assessment of rociletinib and/or MPDL3280A activity, to evaluate the concordance of mutant EGFR detection between tissue and plasma, and to explore biomarkers that may be predictive of response or resistance to rociletinib and/or MPDL3280A. Biomarkers and changes in biomarker status will be investigated for associations with rociletinib and/or MPDL3280A exposure, safety, and clinical activity. Given the limited sample size, no formal statistical analysis is planned.

Measure: Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA

Time: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months

140 A Randomized Open-label Phase 3 Trial Comparing Bevacizumab + Erlotinib vs Erlotinib Alone as First Line Treatment of Patients With EGFR Mutated Advanced Non Squamous Non Small Cell Lung Cancer

The purpose of this study is to test whether the combination of bevacizumab and erlotinib can prolong progression free survival as compared with erlotinib alone as first-line treatment in patients with non small cell lung cancer (NSCLC) with activating mutation of EGFR.

NCT02633189
Conditions
  1. Non-squamous Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Age ≥18 years 2. Histological documentation of primary non squamous lung carcinoma 3. Stage IV or IIIB disease with supraclavicular metastatic nodes (according to TNM 7th edition) 4. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21 L858R mutation or other activating/sensitizing mutations, such as exon 21 L861Q, exon 18 G719S, G719A and G719C, exon 20 S768I and V769L). --- L858R ---

Primary Outcomes

Description: as determined by investigator

Measure: progression free survival

Time: up to 2 years

Description: as determined by an independent central review board blinded to study treatment

Measure: progression free survival

Time: up to 2 years

Secondary Outcomes

Measure: overall survival

Time: 1 year

Measure: changes in quality of life scores from baseline

Time: up to 2 years

Measure: number of patients with complete and partial responses , investigator assessed

Time: 6 months

Measure: number of patients with complete and partial responses , centrally reviewed

Time: 6 months

Measure: worst grade toxicity per patient

Time: up to one year

Measure: progression free survival according to type of EGFR mutation (exon 19del, exon 21L858R, other)

Time: 2 years

Other Outcomes

Description: samples taken at baseline, 6 weeks, 6 months, and at progression

Measure: number and type of EGFR mutations in plasma samples

Time: up to 2 years

141 A Phase II, Open Label, Multicenter Study of Bevacizumab in Combination With Erlotinib Versus Erlotinib Alone in Patients With EGFR Mutant Non-small Cell Lung Cancer Who Have Brain Metastases

This is an open-label, randomized, multicenter phase II study conducting in 3 medical centers in Asia. Patients will receive erlotinib in combination with bevacizumab or erlotinib alone. This study will enroll EGFR-mutant NSCLC patients who have asymptomatic brain metastases. The primary objective is to compare the systemic progression-free survival (PFS) to bevacizumab plus erlotinib versus erlotinib alone in patients with EGFR mutant NSCLC who have asymptomatic brain metastases.

NCT02655536
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Brain Neoplasms
Interventions
  1. Drug: Bevacizumab plus erlotinib
  2. Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung Brain Neoplasms
HPO:Brain neoplasm Non-small cell lung carcinoma

- A tumor harboring an EGFR mutation known to be associated with erlotinib sensitivity (exon 19 deletion and L858R) - Documented brain metastases. --- L858R ---

Patients will be stratified according to the EGFR L858R mutation and the EGFR exon 19 deletion mutation. --- L858R ---

Primary Outcomes

Description: The PFS will be evaluated from date of randomization until the date of documented progression or the date of death from any cause, whichever came first.

Measure: Progression-free survival

Time: The PFS will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.

Secondary Outcomes

Measure: overall survival

Time: The survival will be assessed from date of randomization until the date of death from any cause. The survival will be assessed every 3 weeks up to 36 months.

Description: The response rate will be evaluated from date of randomization until the date of documented progression or the date of death from any cause, whichever came first.

Measure: overall response rate

Time: The response rate will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.

Description: The Time-to- CNS progression will be evaluated from date of randomization until the date of documented CNS progression.

Measure: Time-to-central nervous system (CNS) progression

Time: Time-to-central nervous system(CNS) progression will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.

Description: The Time-to-extra-CNS progression will be evaluated from date of randomization until the date of documented extra-CNS progression.

Measure: Time to extra-CNS progression

Time: Time to extra-CNS progression will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.

Description: The PFS-2 will be evaluated from date of randomization until the date of second documented progression or the date of death from any cause, whichever came first.

Measure: The PFS-2 in patients in patients with CNS progression only

Time: The PFS-2 will be evaluated per RECIST 1.1 criteria every 6 weeks for the first 12 months and then every 12 weeks up to 36 months.

Description: Time to neurological symptom will be assessed from date of randomization until the dated of documented progression of neurological symptom.

Measure: Time to neurological symptom progression

Time: Time to neurological symptom progression will be evaluated every 3 weeks up to 36 months.

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE version 4.03

Time: Treatment-related adverse events will be evaluated from date of randomization until 30 days after discontinuation of the trial. It will be evaluated every 3 weeks up to 36 months.

142 An Open-label, Single-arm Phase IV Study of Afatinib in Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Who Have Poor Performance Status and Whose Tumors Have the Common Epidermal Growth Factor Receptor (EGFR) Mutations, Exon 19 Deletions or Exon 21(L858R) Substitution Mutations

There is a medical need for improving treatment of poor performance status patients with EGFR driver mutations and documenting safety and tolerability of existing agents.

NCT02695290
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. ErbB Receptors
Interventions
  1. Drug: Afatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

An Open-label, Single-arm Phase IV Study of Afatinib in Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer Who Have Poor Performance Status and Whose Tumors Have the Common Epidermal Growth Factor Receptor (EGFR) Mutations, Exon 19 Deletions or Exon 21(L858R) Substitution Mutations. --- L858R ---

The staging is based on American Joint Committee on Cancer (AJCC) Tumor Node Metastatic (TNM) classification of malignant tumors, 7th edition - Evidence of common EGFR activating mutations (Del 19 and/or L858R) - Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 or 3 - Adequate organ function, defined as all of the following: - Absolute neutrophil count (ANC) > 1500 / mm3 - Platelet count >75,000 / mm3. --- L858R ---

Primary Outcomes

Description: Percentage of patients with occurrence of Adverse Events (AEs) leading to dose reduction of afatinib.

Measure: Percentage of Patients With Occurrence of Adverse Events (AEs) Leading to Dose Reduction of Afatinib

Time: Up to 98 days

Secondary Outcomes

Description: Percentage of patients with occurrence of Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher diarrhoea, rash/acne+, stomatitis+ and paronychia+ (+ represents grouped term).

Measure: Percentage of Patients With Occurrence of CTCAE Grade 3 or Higher Diarrhoea, Rash/Acne+, Stomatitis+ and Paronychia+ (+ Represents Grouped Term)

Time: Up to 98 days

Description: Time to first dose reduction of afatinib caused by Adverse Events (AEs) defined as time from the date of the first administration of afatinib to the first dose reduction of afatinib caused by AEs.

Measure: Time to First Dose Reduction of Afatinib Caused by Adverse Events (AEs)

Time: Up to 98 days

143 Genomic Landscape of EGFR Mutant NSCLC Prior to Rociletinib and at the Time of Disease Progression Following Rociletinib

Though patients whose tumors harbor EGFR T790M mutation appear to benefit from rociletinib, there is a need to understand the molecular mechanisms that lead to primary and acquired resistance to rociletinib. The investigators propose to conduct a clinical trial of rociletinib of patients with EGFR-mutant NSCLC with activating EGFR mutations (including exon 19 deletion or L858R mutation), with or without EGFR T790M mutation. In these patients, pre-treatment and post-progression biopsy specimens will be subjected to genomic analysis to fully understand the clonal evolution and the molecular mechanisms underpinning treatment resistance.

NCT02705339
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Non-Small Cell Lung Cancer
  3. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
  2. Procedure: Biopsy
  3. Procedure: Blood draw
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The investigators propose to conduct a clinical trial of rociletinib of patients with EGFR-mutant NSCLC with activating EGFR mutations (including exon 19 deletion or L858R mutation), with or without EGFR T790M mutation. --- L858R ---

Inclusion Criteria: - Histologically or cytologically confirmed metastatic stage IIIB/IV lung adenocarcinoma with known activating mutations in the EGFR TK domain (including exon 19 deletion and L858R) - Prior EGFR TKI therapy with progression, and documented EGFR T790M mutation on tumor biopsy; however, this need not be only second line - Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. --- L858R ---

Primary Outcomes

Description: -The investigators plan to conduct exome and transcriptome sequencing of tumor before therapy with rociletinib and at the time of relapse. In addition, exome sequencing of peripheral blood DNA will be done (for germ line).

Measure: Somatic genetic changes in the tumor associated with disease progression

Time: Until the time of disease progression (estimated median of 3 months)

Secondary Outcomes

Description: ORR: Percentage of patients experiencing complete response or partial response Complete Response (CR): Disappearance of all target lesions and non-target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Overall response rate (ORR)

Time: Until the time of disease progression (estimated median of 3 months)

Measure: Overall survival (OS)

Time: Until death (estimated median of 8 months)

Description: -PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

Measure: Progression-free survival (PFS)

Time: Until the time of progression (estimated median of 3 months)

Measure: Duration of treatment

Time: Until the time of removal from study (estimated median of 3 months)

144 A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 (AP32788) in Non-Small Cell Lung Cancer

The purpose of this phase 1/2 study is to evaluate the safety, recommended phase 2 dose (RP2D), dose limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics of oral TAK-788, anti-tumor activity of TAK-788 in participants with NSCLC with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) and anti-tumor activity of TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations, and to explore relationship between tumor and/or plasma biomarkers, and TAK-788 efficacy, safety, and/or cytochrome P450 3A (CYP3A) induction. The study will also determine the efficacy of TAK-788 in participants with locally advanced or metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations who have received at least 1 prior line of therapy for locally advanced or metastatic NSCLC.

NCT02716116
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: TAK-788
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Part 2: Expansion Cohort 4 Specific Inclusion Criteria: 1. Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R. --- L858R ---

Primary Outcomes

Measure: Dose Escalation Cohort: RP2D of Orally Administered TAK-788

Time: Day 1 to 28 (Cycle 1)

Measure: Expansion Cohorts 1, 2, 4, 5 and 7: Confirmed Objective Response Rate (ORR) Assessed by the Investigator

Time: up to 36 months after first dose

Measure: Expansion Cohort 3: Intracranial ORR (iORR) Assessed by Independent Review Committee (IRC)

Time: up to 36 months after first dose

Measure: Extension Cohort: Confirmed ORR Assessed by IRC

Time: up to 36 months after first dose

Measure: Expansion Cohort 6: Confirmed ORR Assessed by IRC

Time: up to 36 months after first dose

Secondary Outcomes

Measure: Dose Escalation and Expansion Cohorts: Safety Analysis of TAK-788 Assessed by Adverse Events, Toxicity Grades, and Laboratory Test Results

Time: up to 36 months after first dose

Measure: Dose Escalation Cohort: Identify DLTs and MTD of TAK-788

Time: Day 1 to 28 in Cycle 1 (Cycle length is equal to [=] 28 days)

Measure: Dose Escalation and Expansion Cohorts: Tmax: Time of First Occurrence of Maximum Plasma Concentration (Cmax)

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: AUC 24: Area Under the Concentration-time Curve from Time Zero to 24 hours for TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: AUCt: Area Under the Concentration-time Curve from Time Zero to Time t for TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: RAC (Cmax): Accumulation Ratio Based on Cmax of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: Ctrough: Observed Concentration at the end of a Dosing Interval of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: RAC (AUC): Accumulation Ratio Based on AUC of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: Cmax: Maximum Observed Concentration of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Expansion Cohorts 1, 2, 3, 4, 5, and 7: Confirmed ORR as Assessed by IRC

Time: up to 36 months after first dose

Measure: Expansion Cohorts: Best Overall Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion Cohorts: Best Target Lesion Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Duration of Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Time to Response as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion Cohort 3: Duration of Intracranial Response (iDOR)

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Disease Control Rate (DCR) as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Progression Free Survival (PFS) as Assessed by the Investigator and IRC

Time: up to 36 months after first dose

Measure: Expansion Cohort 3: Intracranial PFS (iPFS)

Time: up to 36 months after first dose

Measure: Expansion and Extension Cohorts: Overall Survival (OS)

Time: up to 36 months after first dose

Measure: Extension Cohort: Confirmed ORR as Assessed by the Investigator

Time: up to 36 months after first dose

Measure: Dose Escalation and Expansion Cohorts: Cmax: Dose Linearity for TAK-788 Exposure

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Dose Escalation and Expansion Cohorts: AUC: Dose Linearity for TAK-788 Exposure

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)

Measure: Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and Health-related Quality of Life (HRQoL) Based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30)

Time: up to 30 days after last dose of drug (approximately up to 37 months)

Measure: Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and health-related Global Quality of Life (HRQoL) Based on Quality of Life Questionnaire Lung Cancer Module-13 (QLQ-LC13)

Time: up to 30 days after last dose of drug (approximately up to 37 months)

Measure: Expansion Cohorts 6: Confirmed ORR as Assessed by the Investigator

Time: up to 36 months after first dose

145 Phase II Study Evaluating the Combination of Cetuximab With Afatinib as First-line Treatment for Patients With EGFR Mutated Non Small Cell Lung Cancer

Until recently, the first line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) was a platine-based chemotherapy. It has been changed by the discovery of EGFR (Epidermal Growth Factor Receptor) mutations and associated treatment with Tyrosine Kinase Inhibitor (TKI) of EGFR. The superiority of EGFR TKI over chemotherapy for EGFR mutated patients has been proved in several phase III trials with gefitinib, erlotinib or afatinib. Nevertheless, all patients will progress after 9 to 12 months of treatment due to the appearance of a treatment resistance. Afatinib is an irreversible EGFR TKI. It binds to its receptor permanently.Contrary to erlotinib and gefitinb which inhibits only EGFR, afatinib inhibits the kinase activity of all HER family (Human Epidermal growth factor Receptor). Nevertheless, there is no proof that afatinib delay the appearance of resistance. Cetuximab is a monoclonal antibody which binds specifically with EGFR. The double inhibition of EGFR by afatinib and cetuximab has demonstrated its efficacy in pre-clinical models. The hypothesis of this study is that the combination between cetuximab and afatinib will permit to delay or decrease the appearance of resistances.

NCT02716311
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib
  2. Drug: Cetuximab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- S768I --- --- T790M --- --- L858R ---

Primary Outcomes

Measure: Time to Treatment Failure

Time: 9 months

Secondary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 1 month

Measure: Response Rate

Time: 9 months

Measure: Overall survival

Time: 6 months

Measure: Overall survival

Time: 9 months

Measure: Overall survival

Time: 12 months

Measure: Progression-Free Survival

Time: 6 months

Measure: Progression-Free Survival

Time: 9 months

Measure: Progression-Free Survival

Time: 12 months

Measure: Progression-Free Survival

Time: 18 months

146 Pilot, Phase 2 Study Assessing Intracranial Activity of AZD9291 (TAGRISSO) in Advanced EGFRm(EGFR Mutation) NSCLC Patients With Asymptomatic Brain Metastases

Patients will receive AZD9291 at a dose of 80 mg once daily. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT (Positron Emission Tomography-Computed Tomography) scan. In case of isolated CNS progression which may or may not be accompanied by asymptomatic systemic progression, AZD9291 dose will be escalated to 160 mg once daily. For patients whose intracranial disease will progress further, brain radiotherapy (in the form of SRS or WBRT) will be administered; treatment with AZD9291 will be interrupted and re-initiated at a standard dose after the end of radiotherapy course in the absence of symptomatic systemic progression. The treatment will be continued until symptomatic systemic progression, unacceptable toxicity or further intracranial progression following brain radiotherapy administration (whichever occurs first). All patients will be followed until death or 5 years.

NCT02736513
Conditions
  1. Lung Cancer
Interventions
  1. Drug: AZD9291

- Exon 19 deletion, L858R, T790M and uncommon sensitizing EGFR mutations in treatment-naïve patients are allowed. --- L858R ---

Primary Outcomes

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: Intracranial overall response rate as defined by modified RECIST

Time: 5 years

Secondary Outcomes

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: Intracranial disease control rate (IDCR) as defined by mRECIST

Time: 5 years

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: median time to intracranial response (mTTIR) as defined by mRECIST

Time: 5 years

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: median intracranial progression free survival (mIPFS) as defined by mRECIST

Time: 5 years

147 Using Next Generation Sequencing (NGS) Method to Detect Circulating Free DNA (Cf-DNA) and Explore the Resistance and Prognosic Mechanism of Third Generation Epidermal Growth Factor Receptor (EGFR) Tyrosine-kinase Inhibitor (TKI) in Advanced Non-small Cell Lung Cancer (NSCLC) Patients: a Single Center Study

third generation of EGFR-TKIs is the newest target therapy for NSCLC. However, we did not known the specific mechanisms for those non-responders and patients grow resistance.Next generation sequencing is current the most sensitive and specific method to exam gene mutation, diversion etc. By consistently detect the cf-DNA, we could possibly find out the mechanisms of response and resistance.

NCT02738593
Conditions
  1. Non-small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- harboured with positive EGFR mutation (19 exon deletion, L858R, G719X, L861Q mutation) - reliable patients history data. --- L858R ---

Primary Outcomes

Description: Using next generation sequencing (NGS) method to detect circulating free DNA (cf-DNA) in patients receive third generation EGFR-TKI, periphereal blood sample were collected at baseline and every 2 months to disease progression.

Measure: cf-DNA change from baseline

Time: baseline and every 2 months up to 36 months or first documented progression disease.

148 Randomized, Open-label, Controlled Multicenter Study to Compare Bevacizumab in Combination With Erlotinib Versus Erlotinib Alone in Chinese NSCLC Patients Harbouring Activating EGFR Mutations(Artemis)

This is a randomized, open-label, controlled, multicenter, Phase III study. Patients will be randomly assigned to treatment group (1:1) through a dynamic randomization process with use of the following stratification factors: sex (female/male), disease stage (stage IIIb vs. stage IV vs. recurrence), and EGFR gene mutation (exon 19 deletion vs. exon 21 L858R).

NCT02759614
Conditions
  1. NSCLC
Interventions
  1. Drug: Bevacizumab
  2. Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Patients will be randomly assigned to treatment group (1:1) through a dynamic randomization process with use of the following stratification factors: sex (female/male), disease stage (stage IIIb vs. stage IV vs. recurrence), and EGFR gene mutation (exon 19 deletion vs. exon 21 L858R). --- L858R ---

An exon 19 deletion mutation or exon 21 L858R mutation has been found in high-sensitivity EGFR mutation tests by PCR using tumor tissue centrally confirmed. --- L858R ---

Primary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by independent review committee assessed progression-free survival using RECIST v1.1

Measure: Progression-free survival (PFS) by IRC

Time: The primary PFS analysis will be performed when approximately 224 PFS events (disease progression or death, whichever occurs first) have occurred, which is estimated to occur at approximately 18 months after enrollment of the last patient.

Secondary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed progression-free survival using RECIST v1.1

Measure: Progression-free survival (PFS) by investigator using RECIST v1.1

Time: The primary PFS analysis will be performed when approximately 224 PFS events (disease progression or death, whichever occurs first) have occurred, which is estimated to occur at approximately 18 months after enrollment of the last patient.

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by independent review committee assessed objective response rate using RECIST v1.1

Measure: Objective response rate (ORR) by IRC using RECIST v1.1

Time: baseline overall tumor assessment can be performed up to 28 days prior to randomization. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed objective response rate using RECIST v1.1

Measure: Objective response rate (ORR) by investigator using RECIST v1.1

Time: baseline overall tumor assessment can be performed up to 28 days prior to randomization. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: Disease control rate (DCR) will be analyzed using similar method as objective response rate.

Measure: Disease control rate (DCR) by IRC using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: Disease control rate (DCR) will be analyzed using similar method as objective response rate.

Measure: Disease control rate (DCR) by investigator using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: Duration of response(DOR) will be analyzed using similar method as objective response rate.

Measure: Duration of response(DOR) by IRC using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: Duration of response(DOR) will be analyzed using similar method as objective response rate.

Measure: Duration of response(DOR) by investigator using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed overall survival .

Measure: Overall survival(OS)

Time: That is expected to be approximately 57 months.

149 Phase II Trial of AZD9291 in First Line Treatment of Lung Cancer Harboring Activating EGFR Mutation From Circulating Tumor DNA and Second Line Treatment After Acquired Resistance With T790M Mutation Detected From Circulating Tumor DNA

Treatment efficacy of osimertinib will be assessed in patients with lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations (cohort 1) and those harboring T790M (cohort 2) which were detected from circulating tumor DNA

NCT02769286
Conditions
  1. Lung Neoplasms
  2. EGFR Gene Mutations
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

5. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test. --- L858R ---

6. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from tumor tissue or cytology specimen. --- L858R ---

5. Patients must fulfil one of the following: 5.1) Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) from tumor tissue or cytology or circulating tumor DNA 5.2) Must have experienced clinical benefit from prior EGFR-TKI, according to the Jackman criteria (Jackman 2010) followed by systemic objective progression (RECIST) while on continuous treatment with EGFR-TKI 6. T790M mutation detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test. --- L858R ---

Primary Outcomes

Description: RECIST v1.1

Measure: Response rate

Time: 2 months

Secondary Outcomes

Description: Percentage of positive cases among cases tested with Mutyper or Cobas

Measure: Sensitivity of testing methods

Time: 2 weeks

Measure: Progression free survival

Time: 2 years

Measure: Duration of response

Time: 2 years

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 2 years

150 Rapid Plasma Genotyping For Early Initiation Of Erlotinib In EGFR Mutant Lung Cancer

Patient with Non-Small Cell Lung Cancer (NSCLC) that might have a genetic change (mutation) in the Epidermal Growth Factor Receptor (EGFR) are invited to take part in this study. This research study is evaluating a new blood test that is capable of detecting an EGFR mutation in cancer without a biopsy.

NCT02770014
Conditions
  1. Epidermal Growth Factor Receptor
  2. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Biopsy requirement may be waived if not technically feasible and plasma genotyping reveals an eligible EGFR mutation (exon 19 del/L858R). --- L858R ---

Primary Outcomes

Description: Number of participants who were alive with evidence of complete or partial response, evaluated using RECIST 1.1 criteria. Patients that underwent rapid plasma genotyping and had an EGFR mutation and who were treated with erlotinib were included in this calculation.

Measure: Overall Response Rate

Time: From date of erlotinib initiation until the date of first documented disease progression or date of death from any cause, whichever came first. ORR was assessed up to 21 months after erlotinib initiation.

Secondary Outcomes

Description: The turnaround time from study registration to treatment initiation was recorded for the plasma genotyping strategy versus standard tumor genotyping. For rapid plasma genotyping, turnaround time is the time between ordering plasma genotyping and obtaining results; this time period was compared to the turnaround time of obtaining the tumor genotyping results.

Measure: Turnaround Time

Time: Maximum 38 days

Description: Concordance between results of plasma genotyping and tumor genotyping, among patients with tissue available for standard genotyping

Measure: Positive Predictive Value (PPV) And False Negative Rate Of Plasma Genotyping

Time: PPV and False Negative Rate can be assessed when plasma and tissue results are available for each patient; average plasma result turnaround time was 4 days, versus average of 20 days for tissue result turnaround time.

151 A Longitudinal Study Evaluating Molecular Changes Associated With Resistance to First and Third (AZD9291) Generation EGFR TKIs in Patients With EGFR Mutant NSCLC Using "Liquid Biopsy"

Based on the possibilities that both plasma and circulating tumor cells (CTCs) (the "liquid biopsy") may offer, we consider that it could be feasible to longitudinally monitor the genetic evolution and the biologic characteristics of CTCs, by using Circulating tumor DNA (ctDNA) and CTCs as a source of biologic material. This approach could provide information regarding the genetic/molecular changes associated with primary and acquired resistance to AZD9291 and, thus, to facilitate to more appropriately adapt the tailored treatment in this particular group of NSCLC patients. It has been recently reported that the detection of resistant clones, based on the tumor-associated genetic aberrations in the blood, can identify treatment resistance up to 10 months earlier than the radiological methods providing, thus, the potential for an early switch to a non cross-resistant therapy in order to improve patients' outcome.

NCT02771314
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Age >18 years 2. Both sexes 3. Histologically or cytologically documented NSCLC 4. Stage 3b (IIIb) not amenable to radical therapy or stage IV 5. Presence of EGFR activating mutations (exon 19 deletion or L858R in exon 21) 6. --- L858R ---

4. Severe or uncontrolled systemic liver disease, including those with known hepatitis B, hepatitis C, and Human Immunodeficiency virus (HIV) infection 5. Interstitial lung disease or pulmonary fibrosis 6. Pregnancy, lactation or other concomitant serious medical condition 7. Other concurrent active malignancy Inclusion Criteria: 1. Age >18 years 2. Both sexes 3. Histologically or cytologically documented NSCLC 4. Stage 3b (IIIb) not amenable to radical therapy or stage IV 5. Presence of EGFR activating mutations (exon 19 deletion or L858R in exon 21) 6. --- L858R ---

The patients will be followed every 3 months for the detection of mutations (T790M), (C797S), (L858R), del 19 EGFR mutations as well as the mutations [(KRAS)/(NRAS), (BRAF), (PI3K)] in the serum/plasma, the determination of the serum levels of Hepatocyte Growth Factor (HGF), the presence of T790M (+) and C797S(+) CTCs as well as the molecular (c-MET) and (HER2 amplification) and phenotypic characterization of CTCs using the filtration platform (ISET). --- T790M --- --- C797S --- --- L858R ---

Primary Outcomes

Measure: Biomarkers of resistance to first and third (AZD9291) generation EGFR TKIs, explored by studying baseline serial serum or plasma DNA specimens and baseline Circulating Tumor Cells (CTCs)

Time: Up to 2.5 years

Secondary Outcomes

Measure: Progression free survival (PFS)

Time: Up to 2.5 years

Measure: Overall Survival

Time: Up to 2.5 years

Measure: Response rate, assessed using RECIST 1.1

Time: Up to 2.5 years

152 MERIT - A Phase II Marker Identification Trial for Tarceva in Second Line NSCLC Patients

This study will assess potentially predictive markers of efficacy in participants with NSCLC receiving oral erlotinib (Tarceva) therapy. The anticipated time on study treatment is until disease progression, unacceptable toxicity or death.

NCT02774278
Conditions
  1. Non-Squamous Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Number of participants with EGFR mutation (L858R/ exon 19 deletion) and who achieved clinical benefit status was reported. --- L858R ---

Primary Outcomes

Description: Affymetrix gene expression profiles were primarily analyzed to identify differentially expressed genes between the participants who derived clinical benefit status and those who did not. Analysis was performed using a multivariate linear model (with clinical benefit status, histology, ethnicity, sex, RNA integrity number (RIN), smoking status and stage as predictors), and a False Discovery Rate criteria of below 0.3 as cut-off. Clinical benefit is defined in the Outcome Measure 5.

Measure: Number of Differentially Expressed Genes Associated With Clinical Benefit

Time: Baseline until disease progression, unacceptable toxicity or death, evaluated up to 4 years

Description: Affymetrix gene expression profiles were primarily analyzed to identify differentially expressed genes between the participants who derived clinical benefit status and those who did not. Analysis was performed using a multivariate linear model (with clinical benefit status, histology, ethnicity, sex, RNA integrity number (RIN), smoking status and stage as predictors), and a False Discovery Rate criteria of below 0.3 as cut-off. Number of participants with EGFR mutation (L858R/ exon 19 deletion) and who achieved clinical benefit status was reported. Clinical benefit is defined in the Outcome Measure 5.

Measure: Number of Epidermal Growth Factor Receptor (EGFR) Mutation Participants Who Achieved Clinical Benefit

Time: Baseline until disease progression, unacceptable toxicity or death, evaluated up to 4 years

Description: Affymetrix gene expression profiles were primarily analyzed to identify differentially expressed genes between the participants who derived clinical benefit status and those who did not. Analysis was performed using a multivariate linear model (with clinical benefit status, histology, ethnicity, sex, RNA integrity number (RIN), smoking status and stage as predictors), and a False Discovery Rate criteria of below 0.3 as cut-off. Number of participants with KRAS gene mutation and who achieved clinical benefit status was reported. Clinical benefit is defined in the Outcome Measure 5.

Measure: Number of KRAS Mutation Participants Who Achieved Clinical Benefit

Time: Baseline until disease progression, unacceptable toxicity or death, evaluated up to 4 years

Secondary Outcomes

Description: Tumor response was defined as either a CR or a PR prior to failure (disease progression, death from any cause, or a second malignancy). CR was defined as the complete disappearance on magnetic response imaging of all enhancing tumor and mass effect on a stable or decreasing dose of dexamethasone (or only receiving adrenal replacement doses) accompanied by a stable or improving neurologic examination that was maintained for at least 12 weeks. PR was defined as a greater than or equal to 50 percent (%) reduction in tumor size by bi-dimensional measurement on a stable or decreasing dose of dexamethasone accompanied by a stable or improving neurologic examination that was maintained for at least 12 weeks.

Measure: Percentage of Participants With Overall Response of Complete Response (CR) or Partial Response (PR) Using Response Evaluation Criteria in Solid Tumors (RECIST)

Time: Baseline until disease progression, unacceptable toxicity or death, evaluated up to 4 years

Description: Clinical benefit was defined as either a CR, PR, or SD prior to failure (disease progression, death from any cause, or a second malignancy). CR: complete disappearance on magnetic response imaging of all enhancing tumor and mass effect on a stable or decreasing dose of dexamethasone (or only receiving adrenal replacement doses) accompanied by a stable or improving neurologic examination that was maintained for at least 12 weeks. PR: greater than or equal to 50% reduction in tumor size by bi-dimensional measurement on a stable or decreasing dose of dexamethasone accompanied by a stable or improving neurologic examination that was maintained for at least 12 weeks. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) taking as reference smallest sum of longest dimensions since treatment started associated to non-progressive disease response for non-target lesions. PD: unequivocal progression of existing non-target lesions.

Measure: Percentage of Participants With Clinical Benefit (CR, PR, or Stable Disease [SD] for at Least 12 Weeks After Study Entry) Using RECIST

Time: Baseline until disease progression, unacceptable toxicity or death, evaluated up to 4 years

153 PANORAMA - Real World Molecular Testing, Treatment Patterns, and Clinical Outcomes in Patients With EGFR Mutation-Positive Locally Advanced or Advanced NSCLC

The objectives of this study are to assess molecular testing, treatment patterns, and associated outcomes among patients with EGFR (Epidermal Growth Factor Receptor) mutation-positive locally advanced or advanced NSCLC (Non-Small Cell Lung Cancer) who have progressed on or after EGFR-TKI (EGFR-Tyrosine Kinase Inhibitor) therapy post availability of a third-generation TKI (primary study cohort). Additionally, molecular testing and treatment patterns will be assessed among a secondary cohort of patients which will include patients diagnosed with de-novo EGFR T790M mutation-positive locally advanced or advanced NSCLC.

NCT02777658
Conditions
  1. Carcinoma, Non-Small-Cell Lung
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The de-novo T790M mutation can be alone or in combination with other mutations (e.g., L858R and T790M). --- T790M --- --- L858R ---

Primary Outcomes

Description: Molecular testing patterns including: Molecular testing rate defined as the number of patients identified as having received molecular testing divided by the number of patients in the primary study cohort (applicable to patients in the primary study cohort); Change in testing rates over time - testing rate over time will be described; Molecular testing details including sample type, method of biopsy, testing turnaround time, test type, reason for testing, testing laboratory type, reason for not performing a test; Molecular testing results including mutation status and type, test outcome, histologic/phenotypic transformation;

Measure: To evaluate molecular testing patterns among patients with EGFR mutation-positive locally advanced or advanced NSCLC

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Treatment patterns and associated clinical outcomes including: Overall survival measured from: date of initial diagnosis to date of death from any cause (for primary and secondary cohorts), date of progression to date of death from any cause (for primary cohort only); Time to initiation of new therapy defined as the time from start date of current therapy to start date of subsequent therapy; Treatment(s) received post diagnosis and post progression including chemotherapy, radiation, surgery, targeted therapy, immunotherapy; Treatment sequence patterns, line(s) of therapy, treatment regimen(s), treatment duration, number of cycles;

Measure: To assess treatment patterns and associated clinical outcomes among patients with EGFR mutation-positive locally advanced or advanced NSCLC

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Secondary Outcomes

Description: Health care utilization patterns will be presented by the following care settings: hospitalization and length of stay, emergency room and physician office visits

Measure: To assess health care utilization patterns

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Assessment of treatment related complications observed with chemotherapy and targeted therapies among patients with NSCLC.

Measure: To assess treatment related complications

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Assessment of biopsy related complications for each documented biopsy procedure

Measure: To assess biopsy related complications

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Measure: To document rate of central nervous system (CNS) metastases

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Health related quality of life (HRQoL): Assessment of general cancer-associated and specific lung cancer associated parameters by use of standardized HRQoL questionnaires: European Organization For Research And Treatment Of Cancer Quality Of Life Questionnaire - Core 30 (EORTC QLQ-C30) European Organisation For Research And Treatment Of Cancer Quality Of Life Questionnaire - Lung Cancer 13 (EORTC QLQ-LC13) (adminstered to patients included in primary study cohort)

Measure: Assessment of health-related quality of life (HRQoL)

Time: Date of first visit to last visit. HRQoL are collected every 6 months (plus or minus 1.5 months) up to 36 months

154 A Phase II Trial of Hypofractionated Radiotherapy Combined With Thymosin for Metastatic NSCLC Patients Who Showed Stable Disease After First Line TKI Therapy

The investigators postulated that the exploitation of the pro-immunogenic effects of radiotherapy with thymosin might result in abscopal responses among patients with metastatic cancer. The research is designed to evaluate the efficacy and toxicity of patients treated with hypofractionated radiotherapy combined with thymosin alpha 1. An exploratory biomarker analysis in blood and tumor samples is also planned.

NCT02787447
Conditions
  1. Lung Adenocarcinoma
Interventions
  1. Drug: TKI
  2. Radiation: Thoracic Hypofractionated Radiotherapy
  3. Drug: Thymosin Alpha 1
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma harboring sensitizing EGFR mutations (L858R, exon 19 deletion), and showed stable disease after 3 months TKI, evaluated twice by PET/CT scan, brain MRI, and abdomen ultrasound (≥3 measurable lesions, and these lesions haven't received local therapy) - Age 18 years or older - ECOG Performance Status 0-2 - Adequate bone marrow, liver and renal function, as specified below: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L; Hemoglobin ≥ 8 g/dL; Platelets ≥ 100 x 109/L; Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) ; AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present; Serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance ≥ 60ml/min for patients with creatinine levels above institutional normal - For women of child-bearing potential, negative pregnancy test within 14 days prior to starting treatment - Men and women of childbearing age must be willing to use effective contraception while on treatment and for at least 3 months thereafter - Patients and their family signed the informed consents Exclusion Criteria: - Received chemotherapy before TKI therapy - Brain parenchyma or leptomeningeal disease - Concurrent malignancies other than non-melanoma skin cancer that require active ongoing treatment - Any medical co-morbidities that would preclude radiation therapy. --- L858R ---

Primary Outcomes

Description: To assess the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion) at 1-6 months after the radiation therapy

Measure: The proportion of patients with an abscopal response assessed at 1-6 months after the radiation therapy

Time: 1-6 months

Secondary Outcomes

Description: FACT-E score at the 4 months after docetaxel consolidation therapy

Measure: To assess the short-term quality of life (QOL)

Time: 4 months

Description: The investigators will assess the rate of symptomatic radiation pneumonitis in patients who received the radiation therapy

Measure: Rate of CTCAE grade 2 or higher radiation pneumonitis

Time: 1 years

Measure: Overall Survival

Time: 2 years

155 A Phase II Trial of Hypofractionated Radiotherapy for Limited Metastatic NSCLC Harboring Sensitizing EGFR Mutations After First Line TKI Therapy

To evaluate the efficacy and toxicity of patients treated with hypofractionated radiotherapy for limited metastatic NSCLC harboring sensitizing EGFR mutations after first line TKI therapy. An exploratory biomarker analysis in blood and tumor samples is also planned.

NCT02788058
Conditions
  1. Lung Adenocarcinoma
  2. EGFR Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: EGFR-TKI
  2. Radiation: Thoracic Hypofractionated Radiotherapy
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma harboring sensitizing EGFR mutations (L858R, exon 19 deletion), and became oligometastatic disease after 3 months TKI, evaluated by PET/CT scan, brain MRI, and abdomen ultrasound (≤6 discrete lesions of disease, exclusive of the brain metastases, ≤3 lesions in the liver, ≤3 lesions in the lung); - All sites of disease must be amenable to definitive RT; - An intrathoracic lymph nodal station is considered 1 discrete lesion, according to IASLC lymph nodal station map; - Age 18 years or older; - ECOG Performance Status 0-2; - Adequate bone marrow, liver and renal function, as specified below: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L; Hemoglobin ≥ 8 g/dL; Platelets ≥ 100 x 109/L; Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) ; AST and ALT ≤ 2.5 x ULN or ≤ 5 x ULN if liver metastases are present; Serum creatinine ≤ 1.5 x upper limit of normal or creatinine clearance ≥ 60ml/min for patients with creatinine levels above institutional normal; - For women of child-bearing potential, negative pregnancy test within 14 days prior to starting treatment; - Men and women of childbearing age must be willing to use effective contraception while on treatment and for at least 3 months thereafter; - Patients and their family signed the informed consents; Exclusion Criteria: - Received chemotherapy before TKI therapy; - Brain parenchyma or leptomeningeal disease; - Any site of disease that is not amenable to definitive RT; - Concurrent malignancies other than non-melanoma skin cancer that require active ongoing treatment; - Any medical co-morbidities that would preclude radiation therapy. --- L858R ---

Primary Outcomes

Measure: Progression free survival

Time: 3 years

Secondary Outcomes

Measure: Frequency of T790M mutation before treatment detected by ctDNA

Time: 1 months

Measure: Abundance of T790M mutation before treatment detected by ctDNA

Time: 1 months

Measure: Frequency of T790M mutation after radiotherapy detected by ctDNA

Time: 3 months

Measure: Abundance of T790M mutation after radiotherapy detected by ctDNA

Time: 3 months

Measure: Frequency of T790M mutation after 1 year detected by ctDNA

Time: 1 year

Measure: Abundance of T790M mutation after 1 year detected by ctDNA

Time: 1 year

Description: We will assess the rate of symptomatic radiation pneumonitis in patients who received the radiation therapy.

Measure: Rate of CTCAE grade 2 or higher radiation pneumonitis

Time: 1 years

Description: FACT-E score at the 4 months after docetaxel consolidation therapy

Measure: To assess the short-term quality of life (QOL)

Time: 4 months

156 Adjuvant Erlotinib Intercalating Chemotherapy or Adjuvant Chemotherapy Alone in NSCLC With Common EGFR Mutation

This study will be performed as a local multicenter, randomized, phase III clinical study. It will compare the adjuvant chemotherapy in Stage IB-IIIA NSCLC with common EGFR mutation (Exon 19 deletion or L858R) who underwent total resection and the Erlotinib-Intercalation adjuvant chemotherapy with the chemotherapy alone. The patients will be randomly assigned to the Intercalation combination chemotherapy regimen and the chemotherapy alone regimen at the ratio of 1:1. The treatment regimen of each arm is as follows.

NCT02795884
Conditions
  1. NSCLC
Interventions
  1. Drug: intercalation therapy using pemetrexed, cisplatin and erlotinib
  2. Drug: Vinorelbine, cisplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

It will compare the adjuvant chemotherapy in Stage IB-IIIA NSCLC with common EGFR mutation (Exon 19 deletion or L858R) who underwent total resection and the Erlotinib-Intercalation adjuvant chemotherapy with the chemotherapy alone. --- L858R ---

- Stage IB-IIIA Non-squamous NSCLC (Based on AJCC Version 7 TNM Disease Stages) - Surgically complete resection - Confirmed with Exon 19 deletion or L858R EGFR mutation - Complete recovery from the surgery. --- L858R ---

Primary Outcomes

Description: Time from randomization to disease recurrence or death of any cause

Measure: Disease-free survival (DFS)

Time: 3 years

Secondary Outcomes

Measure: Overall survival (OS)

Time: 3 years

Measure: Treatment-related adverse events assessed by CTCAE v4.0

Time: 3 years

157 A Multi-centre Observational Study on Dynamic Changes of Circulating Tumor DNA in Late Stage NSCLC Patients Under Gefitinib Treatment

A multi-centre observational, non-interventional study is to dynamically monitor the changes of circulating tumor DNA (ctDNA) in late stage NSCLC patients under Gefitinib treatment.

NCT02804100
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Bronchial Neoplasms
  3. Carcinoma, Bronchogenic
  4. Lung Diseases
  5. Lung Neoplasms
MeSH:Carcinoma Neoplasms Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Lung Diseases
HPO:Abnormal lung morphology Bronchial neoplasm Carcinoma Neoplasm Neoplasm of the lung Non-small cell lung carcinoma

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Inclusion Criteria: - Provision of informed consent - Histologically confirmed stage IIIB/IV NSCLC. --- G719A --- --- L858R ---

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Carcinoma, Non-Small-Cell Lung Bronchial Neoplasms Carcinoma, Bronchogenic Lung Diseases Lung Neoplasms Carcinoma Neoplasms Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Lung Diseases null --- G719A --- --- L858R ---

Primary Outcomes

Measure: dynamic changes of circulating tumor DNA in late stage NSCLC patients under Gefitinib treatment

Time: 2 years

158 Phase II Study of AZD9291 in Patients With Advanced Stage Non-small Cell Lung Cancer Following Prior EGFR TKI Therapy With EGFR and T790M Mutations Detected in Plasma Circulating Tumor DNA (PLASMA)

Circulating tumor DNA (ctDNA) is a highly specific and effective biomarker for the detection of EGFR mutation status. We hypothesise AZD9291 is efficacious in patients with EGFR sensitizing mutations and T790M detected in plasma ctDNA. This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. Approximately 106 subjects will be enrolled. All patients must have documented radiological progression on EGFR-TKI treatment and on the last treatment administered prior to enrolling in the study.

NCT02811354
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. --- L858R ---

3. Locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy 4. Documentation of activating EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) at the time of initial diagnosis 5. Radiological documentation of disease progression: following 1st line EGFR TKI treatment but who have not received further treatment OR following prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy. --- L858R ---

7. Plasma sample must harbour an EGFR mutation known to be associated with EGFR TKI sensitivity (exon 19 deletion, L858R). --- L858R ---

This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions and exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. --- L858R ---

Target patient population: Patients will be > 18 years of age, with a diagnosis of locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy with documented activating EGFR mutations (exon 19 deletions and exon 21 L858R substitution mutations) at the time of initial diagnosis, have radiological disease progression following either 1st line EGFR TKI treatment OR following prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy. --- L858R ---

Plasma sample must harbour an EGFR mutation known to be associated with EGFR TKI sensitivity (exon 19 deletion, L858R as well as presence of T790M by central lab testing from a plasma sample taken after confirmation of disease progression on the most recent treatment regimen. --- L858R ---

Primary Outcomes

Measure: Objective response rate (ORR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Secondary Outcomes

Measure: Progression free survival (PFS)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Duration of response (DoR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Disease control rate (DCR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Tumour shrinkage

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Overall survival (OS)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

159 A Multicenter, Randomized,Double-Blind Study of Gefitinib in Combination With Apatinib or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Advanced Non-squamous Non-Small-Cell Lung Cancer

The main purpose of this study is to evaluate the safety and efficacy of Apatinib in combination with Gefitinib as compared to placebo in combination with Gefitinib in participants with stage ⅢB-IV Non-squamous non-small-cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). Safety and tolerability of Apatinib in combination with Gefitinib will be assessed in the first portion (Part A) before proceeding to the second portion of this study (Part B).

NCT02824458
Conditions
  1. EGFR Tyrosine Kinase Inhibitors Plus VEGFR Inhibitors
Interventions
  1. Drug: Apatinib
  2. Drug: Gefitinib
  3. Drug: Placebo
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Study of Gefitinib With or Without Apatinib in Patients With Advanced Non-squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations The main purpose of this study is to evaluate the safety and efficacy of Apatinib in combination with Gefitinib as compared to placebo in combination with Gefitinib in participants with stage ⅢB-IV Non-squamous non-small-cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Del19 and L858R). --- L858R ---

5. Documented evidence of tumor harboring an activating EGFR mutation (Example 19 del and L858R) . --- L858R ---

Primary Outcomes

Description: Determine the safety, tolerability and DLTs of Apatinib in Combination With Gefitinib

Measure: (Part A) Determine Dose-Limiting Toxicity (DLT) of Apatinib in combination with Gefitinib

Time: 1 months

Description: MTD was determined by testing increasing doses up to 750 mg daily (qd) on dose escalation cohorts 1 to 3 with 3 patients each. MTD reflects highest dose of drug that did not cause an unacceptable side effect (= Dose Limiting Toxicity (DLT) in more than 30% of patients; e.g., hematologic toxicities like Common Toxicity Criteria (CTC) Grade 4 Neutropenia in specific conditions, platelets < 25,000 cells/mL; specific non-hematologic/biochemical toxicities CTC Grade 3 or 4; additionally, any toxicity considered by the investigator severe enough was designated a DLT); CTC Version 2 were used.

Measure: (Part A) Maximum Tolerated Dose (MTD) of Apatinib in Combination With Gefitinib

Time: 1 months

Description: Time from the date of enrolment until documented progression or death, whichever occurs first.

Measure: (Part B) Progression Free Survival (PFS)

Time: Randomization to Measured Progressive Disease or Death from Any Cause (Estimated as 42 Months)

Secondary Outcomes

Description: Time from the date of enrolment until death from any cause.

Measure: (Part B) Overall Survival (OS)

Time: Randomization to Date of Death from Any Cause (Estimated as 50 Months)

Description: Best overall response (complete remission or partial remission) across all assessment time-points according to RECIST Criteria 1.1, during the period from enrolment to termination of trial treatment

Measure: (Part B) Objective Response Rate (ORR)

Time: Randomization to Disease Progression (Estimated as 42 Months)

Description: Achievement of objective response or stable disease for at least 6 weeks

Measure: (Part B) Disease Control Rate (DCR)

Time: Randomization to Disease Progression (Estimated as 42 Months)

Description: Interval from the date of first documentation of objective response by RECIST to the date of first documented progression or relapse

Measure: (Part B) Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated as 42 Months)

Description: Time to progression disease

Measure: (Part B) Time to progression disease (TTPD)

Time: Randomization to Measured Progressive Disease (Estimated as 42 Months)

Measure: (Part B) Quality of Life (QoL) questionnaire

Time: Baseline, End of Study (Estimated as 50 Months)

Description: including adverse events, physical examination, vital signs (including Blood Pressure(BP)), clinical chemistry and hematology

Measure: (Part A + B) Safety assessment : Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: Randomization to Measured Progressive Disease (Estimated as 50 Months)

Description: Area under the plasma concentration time profile from time zero to the time of the last quantifiable concentration

Measure: (Part A) Area Under roc Curve (last)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Area under the plasma concentration time profile after single dose from time zero to the next dose

Measure: (Part A) Area Under roc Curve (tau)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Maximum observed plasma concentration

Measure: (Part A) Cmax

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Time for Cmax

Measure: (Part A) Tmax

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Terminal half life

Measure: (Part A) t½a

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Predose concentration during multiple dosing

Measure: (Part A) Ctrough

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Apparent clearance

Measure: (Part A) The Apparent Clearance(CL/F)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Apparent volume of distribution

Measure: (Part A) The Apparent Volume of Distribution (Vd/F)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Metabolite to parent ratio for Area Under roc Curve (tau)

Measure: (Part A) The Metabolite to Parent Ratio of Area Under roc Curve (tau)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

Description: Metabolite to parent ratio for Cmax

Measure: (Part A) The Metabolite to Parent Ratio of Css,max(MRCmax)

Time: Apatinib & Gefitinib: Cycle1 Day 1 and 15

160 A Phase IIa Clinical Trial to Evaluate the Safety and Efficacy of Osimertinib (AZD9291) in First-line Patients With EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer and Concomitant EGFR T790M Mutation at Time of Diagnosis

The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.

NCT02841579
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally. --- L858R ---

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally. --- L858R ---

Primary Outcomes

Description: Defined as the rate of complete responses [CR] or partial responses [PR] to treatment in accordance to the guidelines of RECIST version 1.1 criteria

Measure: Objective response rate

Time: Baseline up to 78 weeks after patient entry

Secondary Outcomes

Description: Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4

Measure: Grade 3 or 4 adverse events and SAEs

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time of death due to any cause

Measure: Overall survival

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time at which the patient discontinues treatment due to any cause

Measure: Time to treatment failure

Time: Baseline up to 78 weeks after patient entry

Description: Time from the first documented response to documented disease progression or death

Measure: Duration of response

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks after patient entry

Measure: Disease control rate

Time: Baseline up to 78 weeks after patient entry

Measure: Tumor shrinkage

Time: Baseline up to 78 weeks after patient entry

Description: Correlation ratio of mutational status and documented clinical response

Measure: Correlation ratio between mutational status and clinical response

Time: Baseline up to 78 weeks after patient entry

Measure: Tumour EGFR mutation status by histology

Time: Baseline up to 78 weeks after patient entry

Description: Measured by Percentage of patients with a positive EGFR mutation in plasma

Measure: Overall plasma EGFR mutation status

Time: Baseline up to 78 weeks after patient entry

Measure: BIM mRNA levels

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in tumour tissue

Measure: Acquired resistance to osimertinib (AZD9291) by histology

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in plasma

Measure: Overall plasma acquired resistance to osimertinib (AZD9291)

Time: Baseline up to 78 weeks after patient entry

161 Exploratory Phase 0/1 of Positron Emission Tomography (PET) Imaging Agent [18F]-ODS2004436 as a Marker of EGFR Mutation in Subjects With NSCLC

The development of biomarkers will lead the dynamic of personalized medicine and fill the unsatisfied needs in oncology for prediction of therapeutic response. Molecular imaging enables non invasive quantification of biomarkers. The development of molecular imaging biomarkers is closely related to the development of therapeutic molecules. Among the potential targets, kinases offer a lot of advantages: (i) they play a central role in cellular regulation, (ii) numerous kinase-specific small molecule libraries exist in biotech and pharma industry, (iii) several kinase-targeted therapies are used in clinic (imatinib, sorafenib, sunitinib…) with application across a variety of therapeutic indications. Among the imaging technologies, the Positron Emission Tomography (PET) is the most sensitive and dedicated to evaluate small molecules. However few radiotracers are available and their specificity limits their clinical use. The IMAkinib® approach is an innovative method proposed to develop new PET radiotracers adapted to current medical and economical challenges. The epidermal growth factor receptor (EGFR) is an established target for the treatment of advanced non-small cell lung cancer (NSCLC). The EGFR tyrosine kinase inhibitors (TKIs) Gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®) have already been approved for treatment of NSCLC harboring EGFR activating mutations (L858R or del exon 19). Unfortunately the majority of patients will develop a resistance to the TKI in the long term (6-12 months). If the mechanism of resistance is not yet fully characterized, most patients (50%) will acquire an additional T790M mutation of EGFR. TKI PET-imaging can provide a tool to determine and predict responsiveness to EGFR TKI in vivo. That is why, the investigators have selected and radiolabeled (18-Fluor) a compound targeting specifically EGFR mutated ([18F]-ODS2004436) which was further evaluated in a preclinical imaging study to determine the feasibility of TKI-PET. The investigators proved in vivo that [18F]-ODS2004436 a compound is a good candidate to evaluate the EGFR activity in human lung tumours using PET imaging.

NCT02847377
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Other: Injection of [18F]-ODS2004436 radiotracer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The EGFR tyrosine kinase inhibitors (TKIs) Gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®) have already been approved for treatment of NSCLC harboring EGFR activating mutations (L858R or del exon 19). --- L858R ---

Primary Outcomes

Description: Sensibility will be evaluated by positron emission tomography (PET) performed on EGFR mutant patient

Measure: Evaluation of sensibility of [18F] ODS2004436

Time: 1 day

Description: Specificity will be evaluated by positron emission tomography (PET) performed on EGFR wild type patient

Measure: Evaluation of specificity of [18F] ODS2004436

Time: 1 day

Other Outcomes

Description: A follow up visit will be performed 3 days after each PET has been performed in order to register adverse events

Measure: Security

Time: 10 days

162 APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients

The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC patients. Finally, the trial will also explore the mechanisms of acquired resistance to Osimertinib based on the results of an optional biopsy upon progression.

NCT02856893
Conditions
  1. NSCLC
Interventions
  1. Drug: Osimertinib
  2. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Adverse events, serious adverse events and adverse reactions will be monitored.. Inclusion: Registration: - Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. --- L858R ---

Inclusion: Registration: - Pathological diagnosis of adenocarcinoma of the lung carrying common EGFR activating mutations associated with EGFR-TKI sensitivity (Del19 or L858R); performed locally; no other EGFR mutations will be allowed. --- L858R ---

Primary Outcomes

Measure: PFS Rate at 18 months

Time: 24 months after first patient in

Secondary Outcomes

Measure: PFS measured from switching to Osimertinib by RECIST criteria 1.1

Time: 24 months after first patient in

Measure: Proportion of patients receiving Osimertinib based on the determination of cfDNA T790M mutation positive

Time: 24 months after first patient in

Measure: Time to progression on Osimertinib

Time: through study completion

Measure: Time to symptomatic brain metastases in patients with presence of brain metastases at study entry

Time: 24 months after first patient in

Measure: Overall Response Rate (ORR) to Osimertinib

Time: 24 months after first patient in

Measure: Treatment duration

Time: 24 months after first patient in

Measure: Overall Survival (OS)

Time: 24 months after first patient in

Measure: Time to brain progression (TTBP)

Time: 24 months after first patient in

Description: Number of participants with treatment-related adverse events by CTCAE version 4.0. Adverse events, serious adverse events and adverse reactions will be monitored.

Measure: Safety

Time: 24 months after first patient in

163 EGFR-TKIs Combine Chemotherapy as First-line Therapy for Patients With Advanced EGFR Mutation-positive NSCLC

The aim of this study was to compare the efficacy of EGFR-TKIs(Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors) treatment plus concurrent chemotherapy versus sequential treatment with EGFR-TKIs and chemotherapy in patients with EGFR(Epidermal Growth Factor Receptor)-mutant non-small-cell lung cancer (NSCLC).

NCT02886195
Conditions
  1. EGFR Gene Mutation
Interventions
  1. Drug: pemetrexed
  2. Drug: cisplatin
  3. Drug: Erlotinib

Inclusion Criteria: - Stage Ⅳ EGFR mutation-positive NSCLC - Initial therapy - ECOG performance status 0-1 Exclusion Criteria: - EGFR mutation-negative - Previous systemic antitumour treatment Inclusion Criteria: - Stage Ⅳ EGFR mutation-positive NSCLC - Initial therapy - ECOG performance status 0-1 Exclusion Criteria: - EGFR mutation-negative - Previous systemic antitumour treatment EGFR Gene Mutation This is an open-label, randomized, parallel-group controlled clinical trial, and the study subjects recruited in this study are NSCLC patients mutant for EGFR gene (19del or L858R). --- L858R ---

Primary Outcomes

Measure: Progression-Free Survival (PFS)

Time: 6 months

Secondary Outcomes

Measure: Response Rate (RR)

Time: 2 months

Measure: Overall Survival (OS)

Time: 6 months

Description: NCI CTC 4.03

Measure: Adverse Event (AE)

Time: 2 months

164 Tyrosine-kinase Inhibitor (TKI) With or Without SBRT in Newly Diagnosed EGFRm Advanced Staged Lung Adenocarcinoma

To tested if the adding of consolidative SBRT to TKI in EGFR mutated patients with less than or equal to 5 metastatic sites (primary + 5) will improve progression free survival (PFS) compared to TKI alone.

NCT02893332
Conditions
  1. Stage IV EGFR Mutated Non-Small Cell Lung Cancer
Interventions
  1. Radiation: Radiation: SBRT
  2. Drug: TKI (Gefitinib or Tarceva )
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

- Any medical co-morbidities that would preclude surgery or radiation therapy Inclusion Criteria: - Newly diagnosed metastatic lung adenocarcinoma (recurrent or de novo) harboring sensitizing EGFR mutations (L858R, exon 19 deletion, G719A, L861Q, S768I, exon 19 insertions) with oligometastatic disease (≤5 discrete lesions of disease irrespective of location, inclusive of the primary lesion): - all sites of disease must be amenable to definitive treatment with a local therapy (surgical resection, stereotactic radiosurgery, ablation and conventional radiation therapy) as determined by surgery, interventional radiology and radiation oncology - all intrathoracic lymph nodes (including hilar, mediastinal, and supraclavicular nodal disease) are considered 1 discrete lesion. --- L858R ---

Primary Outcomes

Description: Evaluate the effect of TKI with or without SBRT on progression free survival,to describe local control and out-of-field disease progression

Measure: Progression free survival

Time: 4 years

Secondary Outcomes

Description: To evaluate overall survival after SBRT followed by maintenance chemotherapy in comparison to maintenance chemotherapy alone.

Measure: Overall survival

Time: 4 years

Description: Using CTCAE system to evaluate toxicity profile

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])

Time: 4 years

165 A Phase 1 Study of BPI-15086 in Patients With Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed on Previous EGFR Tyrosine Kinase Inhibitor Therapy

The main objective of this study is to evaluate the safety and tolerability of BPI-15086.

NCT02914990
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: BPI-15086
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

icotinib, gefitinib, afatinib, neratinib, dacomitnib, or erlotinib) treatment - Patients must fulfil one of the following: - Confirmation that the tumour harbours EGFR sensitivity mutation (exon 19 deletion, L858R and L861R, G719X) - Must have experienced clinical benefit from EGFR TKIs, according to the Jackman criteria - Confirmation of T790M mutation positive after disease progression on EGFR TKIs - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and estimated life expectancy of at least 12 weeks - Measurable lesion per Response Evaluation Criteria in Solid Tumors(RECIST1.1) --- L858R ---

Primary Outcomes

Description: Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03

Measure: Adverse events

Time: 18 months

Secondary Outcomes

Measure: Cmax

Time: 4 weeks

Measure: Half life

Time: 4 weeks

Measure: AUC

Time: 4 weeks

Measure: Objective Response Rate

Time: 12 weeks

Measure: Progression-Free Survival

Time: 18 months

166 An Open-Label Phase 1/2 Study of Itacitinib in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

The purpose of this study is to evaluate the safety and tolerability of itacitinib in combination with osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC).

NCT02917993
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Itacitinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Documented evidence of somatic activating mutation in EGFR (eg, G719X, exon 19 deletion, L858R, L861Q) in a tumor tissue sample. --- L858R ---

Primary Outcomes

Measure: Phase 1: Frequency, severity, and duration of adverse events (AEs)

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

Measure: Phase 1: Number of subjects with dose-limiting toxicities (DLTs)

Time: Day 1 through Day 28

Description: ORR defined as the percentage of subjects who have a confirmed best overall response of complete response (CR) or partial response (PR).

Measure: Phase 2: Objective response rate (ORR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Secondary Outcomes

Measure: Phase 1 and Phase 2: Maximum plasma concentration (Cmax) of itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Measure: Phase 1 and Phase 2: Area under the plasma concentration-time curve (AUC) of Itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Description: Defined as the percentage of maximal tumor shrinkage observed at the lowest point (nadir) compared with baseline.

Measure: Phase 2: Depth of response (DpR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Measure: Phase 2: Progression-free survival (PFS)

Time: Interval from the first day of study treatment until disease progression or death due to any cause, approximately 3 years.

Measure: Phase 2: Overall survival (OS)

Time: Interval from the first day of study treatment until death due to any cause, approximately 3 years.

Measure: Phase 2: Frequency, severity, and duration of AEs

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

167 A Phase I/II, Open-Label, Safety, Pharmacokinetic and Efficacy Study of Ascending Doses of Oral CK-101 in Patients With Advanced Solid Tumors

CK-101 is a novel, potent, small molecule tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral CK-101; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral CK-101; to assess the safety and efficacy of CK-101 in treatment-naive NSCLC patients known to have activating EGFR mutations and previously treated NSCLC patients known to have the T790M EGFR mutation.

NCT02926768
Conditions
  1. Lung Neoplasms
  2. Carcinoma, Non-Small-Cell Lung
  3. Lung Diseases
  4. Adenocarcinoma
Interventions
  1. Drug: CK-101
MeSH:Carcinoma, Non-Small-Cell Lung Lung Neoplasms Lung Diseases
HPO:Abnormal lung morphology Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Measureable disease according to RECIST Version 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Minimum age of 18 years - Adequate hematological, hepatic and renal function - Written consent on an Institutional Review Board-approved informed consent form prior to any study-specific evaluation - Histologically or cytologically confirmed diagnosis of one of the following: 1. Metastatic or unresectable locally advanced NSCLC with documented evidence that the tumor harbors one of the two common EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (exon 19 deletion, L858R), either alone or in combination with other EGFR mutations, determined by PCR-based testing of the tumor tissue or plasma sample, and without prior exposure to an EGFR-TKI therapy; OR 2. Metastatic or unresectable locally advanced NSCLC: 1. with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and 2. with evidence of radiological disease progression while on a previous continuous treatment with a first-generation EGFR TKI. --- L858R ---

Inclusion Criteria: - Measureable disease according to RECIST Version 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Minimum age of 18 years - Adequate hematological, hepatic and renal function - Written consent on an Institutional Review Board-approved informed consent form prior to any study-specific evaluation - Histologically or cytologically confirmed diagnosis of one of the following: 1. Metastatic or unresectable locally advanced NSCLC with documented evidence that the tumor harbors one of the two common EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (exon 19 deletion, L858R), either alone or in combination with other EGFR mutations, determined by PCR-based testing of the tumor tissue or plasma sample, and without prior exposure to an EGFR-TKI therapy; OR 2. Metastatic or unresectable locally advanced NSCLC: 1. with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and 2. with evidence of radiological disease progression while on a previous continuous treatment with a first-generation EGFR TKI. --- L858R --- --- L858R ---

- Refusal to use adequate contraception for fertile patients (females and males) - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection Inclusion Criteria: - Measureable disease according to RECIST Version 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Minimum age of 18 years - Adequate hematological, hepatic and renal function - Written consent on an Institutional Review Board-approved informed consent form prior to any study-specific evaluation - Histologically or cytologically confirmed diagnosis of one of the following: 1. Metastatic or unresectable locally advanced NSCLC with documented evidence that the tumor harbors one of the two common EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (exon 19 deletion, L858R), either alone or in combination with other EGFR mutations, determined by PCR-based testing of the tumor tissue or plasma sample, and without prior exposure to an EGFR-TKI therapy; OR 2. Metastatic or unresectable locally advanced NSCLC: 1. with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and 2. with evidence of radiological disease progression while on a previous continuous treatment with a first-generation EGFR TKI. --- L858R ---

- Refusal to use adequate contraception for fertile patients (females and males) - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection Inclusion Criteria: - Measureable disease according to RECIST Version 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Minimum age of 18 years - Adequate hematological, hepatic and renal function - Written consent on an Institutional Review Board-approved informed consent form prior to any study-specific evaluation - Histologically or cytologically confirmed diagnosis of one of the following: 1. Metastatic or unresectable locally advanced NSCLC with documented evidence that the tumor harbors one of the two common EGFR mutations known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (exon 19 deletion, L858R), either alone or in combination with other EGFR mutations, determined by PCR-based testing of the tumor tissue or plasma sample, and without prior exposure to an EGFR-TKI therapy; OR 2. Metastatic or unresectable locally advanced NSCLC: 1. with documented evidence that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q); and 2. with evidence of radiological disease progression while on a previous continuous treatment with a first-generation EGFR TKI. --- L858R --- --- L858R ---

Primary Outcomes

Measure: Phase I: Incidence of dose-limiting toxicities (DLTs)

Time: From baseline (first dose) to 28 days after last dose, expected average 6 months

Measure: Phase II: Objective response rate (ORR): Defined as the rate of complete responses [CR] or partial responses [PR] per RECIST Version 1.1 as assessed by an independent central review

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Secondary Outcomes

Measure: Phase II: Evaluation of tumor response based on disease control rate as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on duration of response as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on tumor shrinkage as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on progression free survival as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase I: Change from baseline in QT/QTc interval

Time: Cycle 1 Day 1 until disease progression or withdrawal from study, expected average 10 months

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by area under the curve

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by maximum concentration

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by elimination half-life

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

168 Combination of Gefitinib With Chemotherapy or Anti-angiogenesis as 1st Line Treatment in Advanced NSCLC Patients Detected With Bim Deletion or Low EGFR Activating Mutation Abundance

This is a single arm phase II clinical trial, which aims to evaluate the effectiveness of combination of gefitinib and doublet chemotherapy or antiangiogenesis in advanced non-small cell lung cancer patients with EGFR activating mutation, accompanied with Bim deletion or low activating EGFR mutation abundance.

NCT02930954
Conditions
  1. Non-small-cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: pemetrexed or gemcitabine plus carboplatin,
  3. Drug: bevacizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Histologically documented, locally advanced or recurrent (stage IIIb and not amenable to combined modality treatment) or metastatic (stage IV) non-small cell lung cancer, anti-cancer treatment naiive - EGFR exon 19 deletion or exon 21 L858R. --- L858R ---

- Bim deletion by realtime PCR, or low abundance for EGFR mutation, for 19Del less than 4.9%, for L858R less than 9.5%. --- L858R ---

- Unhealed bone fracture or wound for long time Inclusion Criteria: - Histologically documented, locally advanced or recurrent (stage IIIb and not amenable to combined modality treatment) or metastatic (stage IV) non-small cell lung cancer, anti-cancer treatment naiive - EGFR exon 19 deletion or exon 21 L858R. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy untill progression or death

Measure: Progression free survival

Time: 8 weeks

Secondary Outcomes

Description: evaluated in the 36th since treatment begain

Measure: overall survival

Time: 36 months

Description: toxicities related to anti-cancer therapy

Measure: side effect

Time: 8 weeks

Description: evaluated since treatment began

Measure: quality of life

Time: 24 months

169 Phase I/II Study of Dasatinib and Osimertinib (AZD9291) in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations

This is a study for patients with advanced non-small cell lung cancer with changes to their cancer cells called EGFR mutations. Mutated EGFR is important in the growth of cancer cells. Medical studies have shown that patients with EGFR mutation-positive lung cancer gain more benefit from targeted therapy drugs such as EGFR inhibitors than with standard chemotherapy. However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first-generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through activation of the SRC oncogene. They have also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a Src inhibitor are synergistic in Cripto-1 overexpressing tumors in the laboratory. This study will be testing a combination of two drugs, dasatinib and osimertinib, to overcome resistance to EGFR-TKIs. Osimertinib (AZD9291) is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants, but spares that of wild type. The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors. The first part of the study will involve finding the highest dose of dasatinib that can be given with osimertinib without causing severe side effects, finding out the side effects seen by giving dasatinib at different dose levels with osimertinib, and measuring the levels of dasatinib and osimertinib in blood at different dose levels. The second part will determine the effects of the combination of dasatinib and osimertinib and determine if the amount of Cripto-1 protein in your tumor or blood makes you more likely to have a good response to the combination of dasatinib and osimertinib.

NCT02954523
Conditions
  1. EGFR Gene Mutation
  2. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: Dasatinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Presence of sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q). --- L858R ---

The most predominant EGFR mutations are in-frame deletions in exon-19 and L858R missense mutation, and patients carrying these mutations are mostly sensitive to the EGFR-targeted tyrosine kinase inhibitors (TKIs). --- L858R ---

The advantage of using AZD9291 is that it inhibits not only the mutants of exon-19 deletion and L858R, but also the T790M mutant, which is the most common mechanism of acquired resistance. --- L858R ---

Primary Outcomes

Description: Number of patients with drug related adverse events and number of patients who can tolerate dosing of dasatinib when given in combination with osimertinib

Measure: Phase I : Number of patients with drug-related adverse events as assessed by CTCAEv4.0

Time: 9 months

Description: The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib

Measure: Phase II : Number of patients that do not progress according to RECIST v1.1

Time: 9 months

Secondary Outcomes

Description: Number of patients with treatment-related adverse events in the phase II study, who are treated at the same dose that has been selected based on the phase I part

Measure: Number of patients with treatment-related adverse events in the phase II study

Time: 18 months

Description: To describe the concentration of osimertinib when administered with dasatinib. Blood is obtained from patients before each cycle and 4 hours after start of the first 2 cycles.

Measure: Concentration of orimertinib in blood

Time: 18 months

Description: Determination of the time between the start of the experimental treatment and progression of the tumor

Measure: Progression-free survival

Time: 3 years

Description: Determination of the time between start of the experimental treatment and death

Measure: Overall survival

Time: 3 years

Description: Determination of the duration of the response to the treatment, calculated from start of treatment in case of partial response and from the declaration of complete response in case of complete response. The end of the response will be when the tumor progresses

Measure: Duration of response

Time: 3 years

170 Clinical Activity of Icotinib in Patients With Advanced Non-small-cell Lung Cancer Harbouring Uncommon EGFR Mutations: a Single-arm, Prospective, Phase 2 Study

This study aims to evaluate the efficacy of icotinib, a first generation EGFR TKI, in non-small cell lung cancer patients harboring uncommon EGFR mutation

NCT02961270
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Icotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Inclusion Criteria: - Patients with stage IIIB/IV non-small cell lung cancer - Patients with uncommon epidermal growth factor receptor (EGFR) mutation - Targeted-therapy-naive patients - Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 - Evaluable target lesions according to RECIST 1.1 for tumour response assessment Exclusion Criteria: - Wild-type EGFR - Positive 19 del and/or 21 L858R mutation - Previous treatment with EGFR TKIs such as gefitinib, erlotinib, and afatinib - Patients who have documented history of interstitial lung disease Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L858R ---

Primary Outcomes

Measure: progression-free survival

Time: 10 months

Secondary Outcomes

Measure: tumor response rate

Time: 2 months

Measure: overall survival

Time: 24 months

171 A Phase II Trial of AZD9291 (Osimertinib) With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases

This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may stop or slow non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.

NCT02971501
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Metastatic Malignant Neoplasm in the Brain
  3. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Bevacizumab
  2. Other: Laboratory Biomarker Analysis
  3. Drug: Osimertinib
MeSH:Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm Non-small cell lung carcinoma

Analysis will be completed using Lasso-based elastic net method.. Inclusion Criteria: - Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory - No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for early-stage or advanced disease but this is not required; prior immunotherapy is not allowed - Patients must have at least one measurable CNS lesion that is asymptomatic, untreated, and does not require local therapy at the time of enrollment; measurable CNS disease is defined as a brain metastasis that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain magnetic resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment - Patients are not required to have measurable systemic (i.e. --- L858R ---

aortic aneurysm, history of aortic dissection) - Clinically significant peripheral vascular disease - Any of the following cardiac criteria: - Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) > 470 ms obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived corrected QT (QTc) value - Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Evidence of bleeding diathesis or coagulopathy (including clinically significant hemoptysis) - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9291 (osimertinib) - Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4 - Any evidence of severe or uncontrolled systemic diseases, including, but not limited to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening for chronic conditions is not required - History of hypersensitivity active or inactive excipients of AZD9291 (osimertinib) or drugs with a similar chemical structure or class to AZD9291 (osimertinib) - Absolute neutrophil count < 1.5 x 10^9/L - Platelet count < 100 x 10^9/L - Hemoglobin < 90 g/L - Alanine aminotransferase > 2.5 times upper limit of normal (ULN) if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases; aspartate aminotransferase > 2.5 times ULN if no demonstrable liver metastases or > 5 times ULN in the presence of liver metastases - Total bilirubin > 1.5 times ULN if no liver metastases or > 3 times ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases - Serum creatinine > 1.5 times ULN concurrent with creatinine clearance < 50 mL/min (measured or calculated by Cockcroft and Gault equation)-confirmation of creatinine clearance is only required when creatinine is > 1.5 times ULN - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: - Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory - No prior treatment with an EGFR TKI; patient may have received prior chemotherapy for early-stage or advanced disease but this is not required; prior immunotherapy is not allowed - Patients must have at least one measurable CNS lesion that is asymptomatic, untreated, and does not require local therapy at the time of enrollment; measurable CNS disease is defined as a brain metastasis that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain magnetic resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment - Patients are not required to have measurable systemic (i.e. --- L858R ---

Primary Outcomes

Description: The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: Progression free survival (PFS)

Time: From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 2 years

Secondary Outcomes

Description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: Overall survival (OS)

Time: From start of treatment to death, assessed up to 2 years

Description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: OS rate

Time: At 12 months

Description: Assessed by Common Terminology Criteria for Adverse Events. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.

Measure: Incidence of adverse events

Time: Up to 2 years

Description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.

Measure: Overall response rate

Time: Up to 2 years

Description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.

Measure: Intracranial response rate

Time: Up to 2 years

Description: Will be assessed by Response Assessment in Neuro-Oncology Brain Metastases.

Measure: Time to intracranial progression

Time: Up to 2 years

Measure: Brain metastasis response rate

Time: Up to 2 years

Measure: Time to central nervous system (CNS) progression

Time: From start of treatment to time of progression in the CNS, assessed up to 2 years

Description: Assessed by Response Assessment in Neuro-Oncology Criteria-Glioblastoma Multiforme. Will be estimated using the 95% confidence interval CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratios will be reported.

Measure: Intracranial response

Time: Up to 2 years

Description: Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

Measure: Objective response defined as a complete or partial response

Time: Up to 2 years

Other Outcomes

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Molecular characterization

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Circulating tumor deoxyribonucleic acid assessed in plasma

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Angiogenic signature assessed in plasma by multiplex panel array

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Biomarker analysis of angiogenesis and signaling pathways

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Changes in the tumor immune microenvironment

Time: Baseline to 2 years

172 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Alflutinib in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

Alflutinib Mesylate Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT02973763
Conditions
  1. NSCLC
Interventions
  1. Drug: Alflutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) 5. Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- L858R ---

Primary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Secondary Outcomes

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out Cmax.

Measure: Maximum Plasma Concentration [Cmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out tmax.

Measure: Peak Plasma Time [tmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day1 to figure out AUC.

Measure: Area under the plasma concentration versus time curve (AUC) of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out terminal rate constant.

Measure: Terminal rate constant of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out clearance.

Measure: Clearance of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out half life.

Measure: Half life of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out volume of distribution.

Measure: Volume of distribution of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out mean resistance time.

Measure: Mean resistance time of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state tmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state AUC of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.

Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Time dependency of Alflutinib and 2 metabolites following multiple doses.

Measure: Time dependency of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease progression rate

Measure: Disease progression rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1

Measure: Clinical benefit rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

173 A Phase 1/2, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10296 in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

This is a Phase 1/2, open-label, multicenter study of HS-10296 with dose escalation, dose expansion and extension cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent. The study is designed to evaluate safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of once-daily and orally (PO) administered HS-10296. The overall study design is shown in the flow chart below, which consists of 3 phases: dose escalation, dose expansion and extension cohort.

NCT02981108
Conditions
  1. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: HS-10296
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5. Patients must fulfill one of the following: - Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria (followed by systemic objective progression (RECIST or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 6. --- L858R ---

Primary Outcomes

Measure: Incidence of Dose Limiting Toxicity (DLT) Phase I Part

Time: 4 weeks

Measure: Overall Response Rate (ORR) Phase II Part

Time: 12 months

Measure: Progression-free survival (Phase I Part)

Time: 12 months

Measure: Overall Response Rate (Phase I Part)

Time: 6 weeks

Measure: Incidence and severity of AEs, changes in laboratory values, vital signs & ECGs

Time: 12 months

Measure: Area under the plasma concentration versus time curve (AUC) of HS-10296

Time: 4 weeks

Measure: Elimination half-life(T1/2) of HS-10241

Time: 4 weeks

174 Nivolumab in Treating Patients With Stage IV or Recurrent Lung Cancer With High Mutation Loads

This phase II trial studies how well nivolumab works in treating patients with stage IV lung cancer or that has come back after initial treatment who has high mutation loads. Monoclonal antibodies, such as nivolumab, may block tumor growth in different ways by targeting certain cells.

NCT03023904
Conditions
  1. Recurrent Non-Small Cell Lung Carcinoma
  2. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Biological: Nivolumab
  2. Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - • Signed written informed consent - Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol related procedures that are not part of normal subject care - Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing - Eastern Cooperative Oncology Group (ECOG) performance status of =< 1 - Subjects with histologically confirmed stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification squamous or nonsquamous histology, with no prior systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease - Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration is at least 2 months prior to enrollment - Prior definitive chemoradiation for locally advanced disease is also permitted as long as the last administration of chemotherapy or radiotherapy (whichever was given last) occurred at least 2 months prior to enrollment - Mutation load determined by FoundationOne of >= 20 mutations/MB tested on archival tumor sample; the mutation load metric will be displayed on the FoundationOne report for all participating sites as "tumor mutation burden (TMB) - high" or may be obtained from Foundation Medicine from older reports using the Insights Portal, which will be available to all participating sites, or by emailing Foundation Medicine - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria - Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site after the completion of radiation therapy - Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been completed at least 2 weeks prior to enrollment; subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of enrollment are strongly encouraged to receive palliative radiotherapy prior to enrollment - White blood cell (WBC) > 2000/uL - Neutrophils > 1500/uL - Platelets > 100 x 10^9/uL - Hemoglobin > 9.0 g/dL - Serum creatinine =< 2 x upper limit normal (ULN) or creatinine clearance (CrCl) >= 30 mL/min using the Cockcroft-Gault formula - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (unless liver metastases, who can have AST/ALT =< 5 x ULN) - Total bilirubin =< 3 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL) - Women must not be breastfeeding - Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of nivolumab - "Women of childbearing potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal - Menopause is defined as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; if menopausal status is considered for the purpose of evaluating childbearing potential, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level > 40 mIU/mL, in order to be considered postmenopausal and not of childbearing potential • Women of child bearing potential (WOCBP) and men able to father children who are sexually active with WOCBP must agree to use acceptable contraception - Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception - Women of childbearing potential receiving nivolumab will be instructed to use and must be willing to use appropriate method(s) of contraception for a period of 23 weeks after the last dose of investigational product - Men receiving nivolumab who are sexually active with WOCBP will be instructed to use and must be willing to use acceptable contraception for a period of 31 weeks after the last dose of investigational product Exclusion Criteria: - Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded; all subjects with non-squamous histology must have been tested for EGFR mutation status; use of a Food and Drug Administration (FDA)-approved test is strongly encouraged - Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded; if tested, use of an FDA-approved test is strongly encouraged; subjects with unknown or indeterminate ALK status may be enrolled - Active brain metastases or leptomeningeal metastases (carcinomatous meningitis); subjects with brain metastases are eligible if these have been treated and there is no evidence of progression for at least 2 weeks after treatment is complete and corticosteroid dose is stable (and equivalent dose of < 10 mg prednisone) for at least 2 weeks - Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before enrollment - Subjects with an active, known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first study treatment with nivolumab; inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease - Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection) - Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration - Subjects with previous or active malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to enrollment and no additional therapy is required or anticipated to be required during the study period - History of allergy to study drug components or of severe hypersensitivity reaction to any monoclonal antibody - Prisoners or subjects who are involuntarily incarcerated - Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Inclusion Criteria: - • Signed written informed consent - Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol related procedures that are not part of normal subject care - Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing - Eastern Cooperative Oncology Group (ECOG) performance status of =< 1 - Subjects with histologically confirmed stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification squamous or nonsquamous histology, with no prior systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease - Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration is at least 2 months prior to enrollment - Prior definitive chemoradiation for locally advanced disease is also permitted as long as the last administration of chemotherapy or radiotherapy (whichever was given last) occurred at least 2 months prior to enrollment - Mutation load determined by FoundationOne of >= 20 mutations/MB tested on archival tumor sample; the mutation load metric will be displayed on the FoundationOne report for all participating sites as "tumor mutation burden (TMB) - high" or may be obtained from Foundation Medicine from older reports using the Insights Portal, which will be available to all participating sites, or by emailing Foundation Medicine - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria - Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site after the completion of radiation therapy - Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been completed at least 2 weeks prior to enrollment; subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of enrollment are strongly encouraged to receive palliative radiotherapy prior to enrollment - White blood cell (WBC) > 2000/uL - Neutrophils > 1500/uL - Platelets > 100 x 10^9/uL - Hemoglobin > 9.0 g/dL - Serum creatinine =< 2 x upper limit normal (ULN) or creatinine clearance (CrCl) >= 30 mL/min using the Cockcroft-Gault formula - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (unless liver metastases, who can have AST/ALT =< 5 x ULN) - Total bilirubin =< 3 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL) - Women must not be breastfeeding - Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of nivolumab - "Women of childbearing potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal - Menopause is defined as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; if menopausal status is considered for the purpose of evaluating childbearing potential, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level > 40 mIU/mL, in order to be considered postmenopausal and not of childbearing potential • Women of child bearing potential (WOCBP) and men able to father children who are sexually active with WOCBP must agree to use acceptable contraception - Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception - Women of childbearing potential receiving nivolumab will be instructed to use and must be willing to use appropriate method(s) of contraception for a period of 23 weeks after the last dose of investigational product - Men receiving nivolumab who are sexually active with WOCBP will be instructed to use and must be willing to use acceptable contraception for a period of 31 weeks after the last dose of investigational product Exclusion Criteria: - Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded; all subjects with non-squamous histology must have been tested for EGFR mutation status; use of a Food and Drug Administration (FDA)-approved test is strongly encouraged - Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded; if tested, use of an FDA-approved test is strongly encouraged; subjects with unknown or indeterminate ALK status may be enrolled - Active brain metastases or leptomeningeal metastases (carcinomatous meningitis); subjects with brain metastases are eligible if these have been treated and there is no evidence of progression for at least 2 weeks after treatment is complete and corticosteroid dose is stable (and equivalent dose of < 10 mg prednisone) for at least 2 weeks - Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before enrollment - Subjects with an active, known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first study treatment with nivolumab; inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease - Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection) - Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration - Subjects with previous or active malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to enrollment and no additional therapy is required or anticipated to be required during the study period - History of allergy to study drug components or of severe hypersensitivity reaction to any monoclonal antibody - Prisoners or subjects who are involuntarily incarcerated - Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess the objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. --- L858R ---

Inclusion Criteria: - • Signed written informed consent - Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol related procedures that are not part of normal subject care - Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing - Eastern Cooperative Oncology Group (ECOG) performance status of =< 1 - Subjects with histologically confirmed stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification squamous or nonsquamous histology, with no prior systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease - Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration is at least 2 months prior to enrollment - Prior definitive chemoradiation for locally advanced disease is also permitted as long as the last administration of chemotherapy or radiotherapy (whichever was given last) occurred at least 2 months prior to enrollment - Mutation load determined by FoundationOne of >= 20 mutations/MB tested on archival tumor sample; the mutation load metric will be displayed on the FoundationOne report for all participating sites as "tumor mutation burden (TMB) - high" or may be obtained from Foundation Medicine from older reports using the Insights Portal, which will be available to all participating sites, or by emailing Foundation Medicine - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria - Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site after the completion of radiation therapy - Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been completed at least 2 weeks prior to enrollment; subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of enrollment are strongly encouraged to receive palliative radiotherapy prior to enrollment - White blood cell (WBC) > 2000/uL - Neutrophils > 1500/uL - Platelets > 100 x 10^9/uL - Hemoglobin > 9.0 g/dL - Serum creatinine =< 2 x upper limit normal (ULN) or creatinine clearance (CrCl) >= 30 mL/min using the Cockcroft-Gault formula - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (unless liver metastases, who can have AST/ALT =< 5 x ULN) - Total bilirubin =< 3 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL) - Women must not be breastfeeding - Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of nivolumab - "Women of childbearing potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal - Menopause is defined as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; if menopausal status is considered for the purpose of evaluating childbearing potential, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level > 40 mIU/mL, in order to be considered postmenopausal and not of childbearing potential • Women of child bearing potential (WOCBP) and men able to father children who are sexually active with WOCBP must agree to use acceptable contraception - Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception - Women of childbearing potential receiving nivolumab will be instructed to use and must be willing to use appropriate method(s) of contraception for a period of 23 weeks after the last dose of investigational product - Men receiving nivolumab who are sexually active with WOCBP will be instructed to use and must be willing to use acceptable contraception for a period of 31 weeks after the last dose of investigational product Exclusion Criteria: - Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded; all subjects with non-squamous histology must have been tested for EGFR mutation status; use of a Food and Drug Administration (FDA)-approved test is strongly encouraged - Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded; if tested, use of an FDA-approved test is strongly encouraged; subjects with unknown or indeterminate ALK status may be enrolled - Active brain metastases or leptomeningeal metastases (carcinomatous meningitis); subjects with brain metastases are eligible if these have been treated and there is no evidence of progression for at least 2 weeks after treatment is complete and corticosteroid dose is stable (and equivalent dose of < 10 mg prednisone) for at least 2 weeks - Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before enrollment - Subjects with an active, known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first study treatment with nivolumab; inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease - Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection) - Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration - Subjects with previous or active malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to enrollment and no additional therapy is required or anticipated to be required during the study period - History of allergy to study drug components or of severe hypersensitivity reaction to any monoclonal antibody - Prisoners or subjects who are involuntarily incarcerated - Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Inclusion Criteria: - • Signed written informed consent - Subjects must have signed and dated an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent form in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol related procedures that are not part of normal subject care - Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing - Eastern Cooperative Oncology Group (ECOG) performance status of =< 1 - Subjects with histologically confirmed stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification squamous or nonsquamous histology, with no prior systemic anticancer therapy (including EGFR and ALK inhibitors) given as primary therapy for advanced or metastatic disease - Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration is at least 2 months prior to enrollment - Prior definitive chemoradiation for locally advanced disease is also permitted as long as the last administration of chemotherapy or radiotherapy (whichever was given last) occurred at least 2 months prior to enrollment - Mutation load determined by FoundationOne of >= 20 mutations/MB tested on archival tumor sample; the mutation load metric will be displayed on the FoundationOne report for all participating sites as "tumor mutation burden (TMB) - high" or may be obtained from Foundation Medicine from older reports using the Insights Portal, which will be available to all participating sites, or by emailing Foundation Medicine - Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria - Target lesions may be located in a previously irradiated field if there is documented (radiographic) disease progression in that site after the completion of radiation therapy - Prior palliative radiotherapy to non-central nervous system (CNS) lesions must have been completed at least 2 weeks prior to enrollment; subjects with symptomatic tumor lesions at baseline that may require palliative radiotherapy within 4 weeks of enrollment are strongly encouraged to receive palliative radiotherapy prior to enrollment - White blood cell (WBC) > 2000/uL - Neutrophils > 1500/uL - Platelets > 100 x 10^9/uL - Hemoglobin > 9.0 g/dL - Serum creatinine =< 2 x upper limit normal (ULN) or creatinine clearance (CrCl) >= 30 mL/min using the Cockcroft-Gault formula - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (unless liver metastases, who can have AST/ALT =< 5 x ULN) - Total bilirubin =< 3 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL) - Women must not be breastfeeding - Women of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to the start of nivolumab - "Women of childbearing potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal - Menopause is defined as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; if menopausal status is considered for the purpose of evaluating childbearing potential, women under the age of 62 must have a documented serum follicle stimulating hormone (FSH) level > 40 mIU/mL, in order to be considered postmenopausal and not of childbearing potential • Women of child bearing potential (WOCBP) and men able to father children who are sexually active with WOCBP must agree to use acceptable contraception - Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) and azoospermic men do not require contraception - Women of childbearing potential receiving nivolumab will be instructed to use and must be willing to use appropriate method(s) of contraception for a period of 23 weeks after the last dose of investigational product - Men receiving nivolumab who are sexually active with WOCBP will be instructed to use and must be willing to use acceptable contraception for a period of 31 weeks after the last dose of investigational product Exclusion Criteria: - Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded; all subjects with non-squamous histology must have been tested for EGFR mutation status; use of a Food and Drug Administration (FDA)-approved test is strongly encouraged - Subjects with known ALK translocations which are sensitive to available targeted inhibitor therapy are excluded; if tested, use of an FDA-approved test is strongly encouraged; subjects with unknown or indeterminate ALK status may be enrolled - Active brain metastases or leptomeningeal metastases (carcinomatous meningitis); subjects with brain metastases are eligible if these have been treated and there is no evidence of progression for at least 2 weeks after treatment is complete and corticosteroid dose is stable (and equivalent dose of < 10 mg prednisone) for at least 2 weeks - Subjects must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before enrollment - Subjects with an active, known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll - Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first study treatment with nivolumab; inhaled or topical steroids, and adrenal replacement steroid > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease - Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study (e.g., uncontrolled hypertension and/or diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection) - Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration - Subjects with previous or active malignancies (except non-melanoma skin cancers, and in situ cancers such as the following: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to enrollment and no additional therapy is required or anticipated to be required during the study period - History of allergy to study drug components or of severe hypersensitivity reaction to any monoclonal antibody - Prisoners or subjects who are involuntarily incarcerated - Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess the objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. --- L858R --- --- L858R ---

Primary Outcomes

Measure: Objective Response Rate defined as the number of subjects with a best overall response of complete response or partial response divided by the number of subjects that receive nivolumab as assessed by RECIST 1.1

Time: Up to 6 months

Secondary Outcomes

Measure: Overall survival

Time: From date of enrollment to date of death due to any cause, assessed up to 2 years

Measure: Progression Free Survival as determined by RECIST 1.1

Time: From date of enrollment until first date of documented progression or death due to any cause, assessed up to 2 years

Measure: Mutation load as determined by FoundationOne testing

Time: Up to 2 years

Measure: Incidence of adverse events (AEs) graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Time: Up to 100 days after the last dose of study drug

Measure: PD-L1 expression as determined by immunohistochemistry

Time: Up to 2 years

175 Early Rebiopsy to Identify Mechanisms and Biomarkers of Tumor Cell Survival Following Targeted Therapy in Patients With EGFR, ALK, ROS1 or BRAF Mutations.

A comparison of baseline tumor characteristics in oncogene-driven cancers to tumor characteristics after early response to Tyrosine Kinase Inhibitor (TKI) targeted treatment will allow identification of early adaptive mechanisms of cell survival. This will facilitate targeting and termination of these survival/ resistance pathways before they develop with rational combinations of therapeutic agents to improve outcomes.

NCT03042221
Conditions
  1. Non-Small Cell Carcinoma of Lung, TNM Stage 4
  2. Non-Small Cell Lung Cancer
  3. EGFR Gene Mutation
  4. ALK Gene Mutation
  5. ROSE Cluster 1
  6. BRAF V600E
MeSH:Carcinoma, Non-Small-Cell Lung Lung Neoplasms
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Aged 18 - 85 years or older - ECOG 0-2 - Have a histologically confirmed diagnosis of lung adenocarcinoma harboring an EGFR sensitizing mutation (including, but not limited to: G719X, del exon 19, or L858R). --- L858R ---

Primary Outcomes

Description: change from baseline of tumor gene expression profile at 2 weeks. Global gene expression data will be collected using RNAseq

Measure: gene expression changes

Time: baseline and 2 weeks (+/- 1 week) for each patient.

Description: change from baseline of protein gene expression profile at 2 weeks as measured by multiplex protein assay (proteins to be assayed include: e-cadherin, vimentin, fibronectin, CD4, CD8, CD14, CD16, CD206, PDL1, and CSF1R)

Measure: protein expression change

Time: baseline and 2 weeks (+/- 1 week) for each patient.

Secondary Outcomes

Description: Correlation between the depths of tumor response (by RECIST v1.1) (percentage decrease in tumor size) with the presence of an EMT signature.

Measure: Depth of Response

Time: Study startup through 36 months

Other Outcomes

Description: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0

Measure: Evaluation of Adverse Events

Time: Study startup through 36 months

Description: Success rate of early rebiopsy in obtaining tumor samples that have evaluable material for RNA Seq and other analyses

Measure: Success rate of Repeat Biopsy

Time: Study startup through 36 months

Description: Length of PFS as per RECIST 1.1

Measure: Progression Free Survival

Time: Study startup through 36 months

176 A Randomized, Open Label, Phase II Study Comparing Pemetrexed Plus Cisplatin Followed by Pemetrexed Until Progression Versus Pemetrexed Alone Until Progression in Non-small Cell Lung Cancer Patients Who Have Progressed on First Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI)

It has not been established whether platinum-based doublets is better than single agent chemotherapy in EGFR mutant NSCLC patients who failed first-line EGFR TKI. In this prospective trial, the investigators try to evaluate whether the progression-free survival of pemetrexed/cisplatin (PC) regimen is longer than that of pemetrexed single(P) regimen in NSCLC patients who have progressed after first line treatment of EGFR-TKI.

NCT03050437
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Cisplatin
  2. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Histologically confirmed nonsquamous NSCLC with activating EGFR mutation (on exon 19 deletion or exon 21 L858R mutation) - Stage IIIb, IV or recurrent NSCLC (AJCC 7th criteria) - Age ≥ 20 years - ECOG performance status of 0 or 1 - At least one measurable lesion by RECIST 1.1 - Progression after first line treatment with EGFR TKIs for advanced NSCLC - Asymptomatic brain metastasis or symptomatic brain metastasis treated with local treatment such as operation, whole brain radiotherapy, or gamma-knife surgery - At least 2 weeks later after whole brain radiotherapy or palliative radiotherapy - Adequate renal function: estimated creatinine clearance ≥ 45 mL/min - Organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 3 UNL, in case of known hepatic metastasis, AST/ALT< 5 UNL - Written informed consent form - No other previous systemic chemotherapy Exclusion Criteria: - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Patients with post-obstructive pneumonia or uncontrolled serious infection - Pregnant or nursing women (Women of reproductive potential have to agree to use an effective contraceptive method) - Uncontrolled symptomatic brain metastasis - Presence of third space fluid which cannot be controlled by drainage - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, well-treated thyroid cancer. --- L858R ---

Primary Outcomes

Measure: progression-free survival

Time: 2 years

177 A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI

A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI.

NCT03058094
Conditions
  1. NSCLC
Interventions
  1. Drug: Pemetrexed
  2. Drug: Cisplatin 75mg/m2
  3. Drug: AC0010
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

6. Confirmation of tumor EGFR sensitive mutation positive in previous tumor samples, including G719X, exon 19 deletion, L858R, L861Q. --- L858R ---

Primary Outcomes

Description: To assess the Progression-Free Survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Progression-Free Survival (PFS)

Time: From the date of randomization until the date of first documented progression or the date of death from any cause, whichever came first, assessed up to 24 months.

Secondary Outcomes

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Objective Response Rate (ORR)

Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Duration of Response (DoR)

Time: From occurring of CR or PR until progression or the date of death from any cause, whichever came first, assessed up to 24 months.

Description: To assess the Disease Control Rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Disease Control Rate (DCR)

Time: From the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

Description: To assess the Overall Survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Overall Survival (OS)

Time: From the date of randomization to death or end of study, which is assessed up to 36 months.

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Patient Reported Outcomes by EORTC QLQ-C30 Questionnaire

Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.

Other Outcomes

Description: Clinical chemistry, hematology, urinalysis, vital signs, physical examination, weight, ECG and ECOG Performance status and adverse event will be used to assess safety endpoints.

Measure: Incidence of toxicity, grading with CTCAE 4.03

Time: From the date of randomization until end of treatment,which is assessed up to 24 months

178 Effect of Metformin in Combination With Tyrosine Kinase Inhibitors (TKI) on Clinical, Biochemical and Nutritional in Patients With Non-Small Cell Lung Carcinoma (NSCLC): Randomized Clinical Trial

Treatment for patients with mutation in the epidermal growth factor receptor (EGFR) with specific domain tyrosine kinase inhibitors (TKIs) has given place to objective clinical response, increase in progression-free survival (PFS) compared to cytotoxic chemotherapy. However, despite clinical success with different TKIs, most patients eventually develop acquired resistance to these agents after an average period of time of 10 months. Recently metformin, an oral hypoglycemic agent, has been associated with reduction in the global risk of incidence and mortality of different types of cancer, by exercising anti-tumor properties. Its role as a chemo-preventive and adjuvant drug in overcoming acquired resistance to chemotherapy, target therapy and immunotherapy in NSCLC is still under discussion. However, preclinical data support the role as an adjuvant drug in the treatment of NSCLC in combination with chemotherapy or EGFR-TKIs. This evidence led to examine the effects of metformin in combination with EGFR-TKIs in a NSCLC cellular line panel, obtaining a different sensibility to the unique use with EGFR-TKIs. The combination of metformin and TKIs reduced the colony forming capacity and proliferation, and induced a huge pro-apoptotic effect in NSCLC cellular lines and resistance in EGFR-TKIs. This suggests that metformin may reduce the resistance to TKIs. A retrospective study in patients from our institution from 2008 to 2014, showed significant clinical benefit in patients who used metformin, improving the global survival. Based on these considerations, we propose a phase II randomized study to assess the effect and safety of metformin in combination with TKIs as second line therapy in patients with NSCLC in advanced stages with EGFR mutation. The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone.

NCT03071705
Conditions
  1. Non-Small Cell Adenocarcinoma
  2. Tyrosine Kinase Mutation
  3. EGFR Gene Mutation
Interventions
  1. Drug: Metformin
  2. Drug: TKI
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

T790M mutation may be present before exposition to TKI and it's generally found with other activating mutations in EGFR (exon 19 deletion and punctual L858R mutation). --- T790M --- --- L858R ---

Primary Outcomes

Measure: Overall Survival

Time: Start of treatment until 1-year follow-up

Secondary Outcomes

Description: Inflammatory markers (IL-6, IL-12, TNF-alpha)

Measure: Response Rate

Time: 3 month evaluation after start of treatment

179 Understanding Evidence-Based Practice Patterns in Advanced NSCLC: An Educational/Research Initiative in Mid-Atlantic States

The overarching objective of this study is to close clinical knowledge and performance gaps by providing oncology clinicians with the latest advances and emerging research in the evidence-base and personalized treatment of advanced NSCLC patients. In addition, the research team seeks to meet quality measures relevant to value-based care delivery through IT infrastructure and clinical workflow processes. The research team also hopes to gain insights on clinician practice patterns related to advanced NSCLC, and the correlation between advanced NSCLC patients reported goals of care and advanced NSCLC patients' fit/frailty status and treatment decisions.

NCT03107156
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Behavioral: Carevive CPS
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

For example, the NCCN notes that there is a significant association between EGFR mutations-especially exon 19 deletion and exon 21 (L858R, L861) and exon 18 (G719X, G719) mutations-and sensitivity to TKIs, and that the exon 20 insertion mutation may predict resistance to clinically achievable levels of TKIs. --- L858R ---

Primary Outcomes

Description: Data collected on the Carevive CPS will be analyzed in order to correlate the patient biomarker testing results with treatment selections.

Measure: Adherence (by providers) to evidence-based treatment recommendations for patients with advanced NSCLC

Time: Year 1

Secondary Outcomes

Description: An in-person workshop will be held at which clinicians treating patients with NSCLC will gather in discussion regarding what value-based care is and how it affects their patients.

Measure: Components of value-based NSCLC cancer care.

Time: Year 1

Description: Clinician practice patterns of medical oncologists managing older patients with advanced NSCLC, including sub-analyses of practice patterns for those who are considered "fit", "intermediate fit", and "frail," will occur.

Measure: Clinical practice patterns in medical oncologists managing older patients with advanced NSCLC.

Time: Year 1

Other Outcomes

Description: To explore how frequently older adults with lung cancer are hospitalized or visit the ER as a result of their lung cancer.

Measure: ER utilization and hospitalization in elderly patients with lung cancer

Time: Year 1

180 A Multicenter, Randomized, Double-Blind Trial in Subjects With Non-Squamous Non-Small Cell Lung Cancer (TASUKI-52)

The purpose of study is to compare the efficacy and safety of ONO-4538 in combination with carboplatin, paclitaxel, and bevacizumab (ONO-4538 group) to placebo in combination with carboplatin, paclitaxel, and bevacizumab (placebo group) in chemotherapy-naïve subjects with stage IIIB/IV or recurrent non-squamous non-small cell lung cancer unsuitable for radical radiation in a multicenter, randomized, double-blind study.

NCT03117049
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: ONO-4538
  2. Drug: Carboplatin
  3. Drug: Paclitaxel
  4. Drug: Bevacizumab
  5. Drug: Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1 Exclusion Criteria: - Subjects with known EGFR mutations, including deletions in exon 19 and exon 21 (L858R) substitution mutations. --- L858R ---

Primary Outcomes

Measure: Progression Free Survival (PFS) as assessed by the Independent Radiology Review Committee (IRRC)

Time: Up to approximately 3 years

Secondary Outcomes

Measure: Overall survival (OS)

Time: At least 3 years

Measure: PFS (as assessed by the study site's investigator)

Time: Up to approximately 3 years

Measure: Objective response rate (ORR [as assessed by the IRRC and study site's investigator])

Time: Up to approximately 3 years

Measure: Disease control rate (DCR [as assessed by the IRRC and study site's investigator])

Time: Up to approximately 3 years

Measure: Duration of response (DOR [as assessed by the IRRC])

Time: Up to approximately 3 years

Measure: Time to response (TTR [as assessed by the IRRC])

Time: Up to approximately 3 years

Measure: Best overall response (BOR [as assessed by the IRRC and study site's investigator])

Time: Up to approximately 3 years

Measure: Maximum percentage of change in the sum of diameters of target lesions (as assessed by the IRRC)

Time: Up to approximately 3 years

Measure: Safety will be analyzed through the incidence of adverse events, serious adverse events

Time: Up to 100 days from last dose

Measure: Patient reported outcome (PRO)

Time: Up to approximately 5 years

181 A Phase 1/2 Study of Osimertinib in Combination With Gefitinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer

This research study is studying a combination of two drugs as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The interventions involved in this study are: - Osimertinib (Tagrisso) - Gefitinib (Iressa)

NCT03122717
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The Kaplan-Meier method will be used to calculate overall survival.. Inclusion Criteria: - Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a CLIA-approved laboratory. --- L858R ---

Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with gefitinib or osimertinib, breastfeeding should be discontinued if the mother is treated with these agents Inclusion Criteria: - Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a CLIA-approved laboratory. --- L858R ---

Primary Outcomes

Description: The feasibility of combination gefitinib/osimertinib dosing will be determined through evaluation of the number of patients in each cohort who are able to remain on combination therapy for 6 x 28 day cycles.

Measure: Number of patients completing combination therapy with gefitinib and osimertinib for 6 x 28 day cycles

Time: 3 years

Secondary Outcomes

Description: CTCAE v4.0 will be used to monitor toxicities in patients on combination therapy with gefitinib and osimertinib.

Measure: Rate of treatment-related Grade 3-5 adverse events

Time: 3 years

Description: RECIST 1.1 measurements of CT scans of the chest/abdomen/pelvis will be measured every 2 cycles on treatment to determine the objective response rate for patients being treated with combination gefitinib and osimertinib.

Measure: Objective response rate

Time: 3 years (each cycle is 28 days)

Description: The Kaplan-Meier method will be used to determine the progression-free survival of patients enrolled on protocol and treated with combination gefitinib and osimertinib.

Measure: Progression free survival

Time: 3 years

Description: Survival follow-up with clinic visits or phone calls will be used to monitor for overall survival from time of study randomization to death from any cause. The Kaplan-Meier method will be used to calculate overall survival.

Measure: Overall Survival

Time: 3 years

182 A Randomized Phase II Study of Erlotinib Alone Versus Erlotinib Plus Bevacizumab for Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Activating Mutations

Korean data of treating EGFR mutation positive NSCLC patients with Erlotinib and Bevacizumab is significantly necessary for developing new standard treatment in first-line therapy in Korean EGFR mutant NSCLC patients. In this study, The investigators will investigate the efficacy and safety of Erlotinib and Bevacizumab combination compare to Erlotinib alone in Korean EGFR-mutant NSCLC patients.

NCT03126799
Conditions
  1. EGFR Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib plus Bevacizumab
  2. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Pathologically confirmed stage IIIB & IV non-small cell lung cancer other than squamous cell carcinoma - Patients with one or more measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Locally diagnosed sensitive EGFR mutation positive (Exon 19 deletion or L858R) - ECOG performance 0~1 - Age ≥ 19 years and - No previous treatment Adequate organ function by following: - ANC ≥1,500/uL, hemoglobin ≥9.0g/dL, platelet ≥100,000/uL - Serum bilirubin < 1 x UNL, AST (SGOT) and ALT (SGPT) < 2.5 x UNL, If Liver metastasis, Serum bilirubin < 3 x UNL, AST (SGOT) and ALT (SGPT) < 5 x UNL - Serum Cr ≤ 1 x UNL - Patients who have had undergone radiotherapy are acceptable if patients meet all of the following criteria: - No history of irradiation to pulmonary tumor lesions. --- L858R ---

- In case of irradiation to non-pulmonary sites: at least two weeks must have passed at the date of inclusion since the last irradiation of the sites - At the time of registration, at least the following period has passed since last date of the prior therapy or procedure: - Surgery(including exploratory/ examination thoracotomy): 4 weeks - Pleural cavity drainage: 1 weeks - Pleurodesis without anti-neoplastic agents (inclusive of BRM such as Picibanil): 2 week - Biopsy accompanied by incision (including thoracoscopic biopsy): 2 week - Procedure for trauma (exclusive of patients with unhealed wound): 2 weeks - Transfusion of blood, preparation of hematopoietic factor: 2 week - Puncture and aspiration cytology: 1 week - Other investigational product: 4 weeks - Written informed consent form Exclusion Criteria: - Previous history of malignancy within 3 years from study entry except treated non-melanomatous skin cancer, uterine cervical cancer in situ, or thyroid cancer - Prior chemotherapy or systemic anti-cancer therapy for metastatic disease but postoperative adjuvant or neoadjuvant therapy of 6 months or more previously is allowed - Patients who received previous treatment for lung cancer with drugs - Symptomatic or uncontrolled central nervous system (CNS) metastases - Patients with increased risk of bleeding, clinically significant cardiovascular diseases, a history of thrombosis or thromboembolism in the 6 months prior to treatment, gastrointestinal problems, and neurologic problems - Any significant ophthalmologic abnormality - Pre-existing parenchymal lung disease such as pulmonary fibrosis - Known allergic history of Erlotinib or Bevacizumab - Interstitial lung disease or fibrosis on chest radiogram - Active infection, uncontrolled systemic disease (cardiopulmonary insufficiency, fatal arrhythmias, hepatitis) - Pregnant or nursing women Inclusion Criteria: - Pathologically confirmed stage IIIB & IV non-small cell lung cancer other than squamous cell carcinoma - Patients with one or more measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Locally diagnosed sensitive EGFR mutation positive (Exon 19 deletion or L858R) - ECOG performance 0~1 - Age ≥ 19 years and - No previous treatment Adequate organ function by following: - ANC ≥1,500/uL, hemoglobin ≥9.0g/dL, platelet ≥100,000/uL - Serum bilirubin < 1 x UNL, AST (SGOT) and ALT (SGPT) < 2.5 x UNL, If Liver metastasis, Serum bilirubin < 3 x UNL, AST (SGOT) and ALT (SGPT) < 5 x UNL - Serum Cr ≤ 1 x UNL - Patients who have had undergone radiotherapy are acceptable if patients meet all of the following criteria: - No history of irradiation to pulmonary tumor lesions. --- L858R ---

Primary Outcomes

Description: Progression Free Survival

Measure: PFS

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to at least 36 months.

Secondary Outcomes

Description: Overall Response Rate

Measure: ORR

Time: through study completion, and average of 2 years

Description: Overall Survival

Measure: OS

Time: From date of randomization until the date of death or date of last visit/contact, whichever came first, assessed to at least 36 months

183 Multiple-Centered Study of AST2818 in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations

This study is conducted to assess the safety, tolerability and preliminary efficacy of AST2818 in patients with advanced Non Small Cell Lung Cancer (NSCLC).

NCT03127449
Conditions
  1. Advanced NSCLC
Interventions
  1. Drug: Alflutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Documented evidence of definitely EGFR T790M+ state in the tumor tissue after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- L858R ---

Primary Outcomes

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Secondary Outcomes

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1

Measure: Clinical benefit rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease control rate

Measure: Disease control rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks.

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses

Measure: Steady state Maximum Plasma Concentration [Cmax] of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state peak plasma time [tmax] of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state area under the plasma concentration versus time curve [AUC] of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.

Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

184 A Randomised Phase II Trial of Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M

BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation.

NCT03133546
Conditions
  1. Non Small Cell Lung Cancer Metastatic
Interventions
  1. Drug: Osimertinib
  2. Drug: Bevacizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M (BOOSTER) BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation. --- T790M --- --- L858R ---

Primary Outcomes

Description: PFS in patients with locally advanced or metastatic NSCLC will be assessed according to RECIST 1.1 criteria.The two treatment arms will be compared using the Kaplan-Meier method.

Measure: Progression Free Survival (PFS)

Time: PFS will be measured from date of patient enrolment until documented progression, or death, if progression is not documented, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.

Secondary Outcomes

Description: ORR, defined as the percentage of patients reaching a complete or partial response, based on evaluation using RECIST 1.1 criteria and disease control rate.

Measure: Objective Response Rate (ORR)

Time: ORR will be evaluated from date of patient enrolment until termination of trial treatment across all assessment timepoints, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.

Description: Disease control, defined as complete or partial response, or disease stabilisation confirmed at subsequent radiological assessment.

Measure: Disease Control

Time: Evaluated across all assessment timepoints from date of patient enrolment to termination of trial treatment, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.

Description: Adverse events, graded by CTCAE 4.0, will be recorded from date of signature of informed consent until 30 days after all trial treatment discontinuation.

Measure: Adverse Events

Time: From date of signature of informed consent until 30 days after all trial treatment discontinuation, for a maximum of 48 months from enrolment of the first patient

Description: Defined as the time from date of randomisation until death from any cause.

Measure: Overall Survival (OS)

Time: Evaluated from date of enrolment until death from any cause, assessed at 48 months from enrolment of the first patient.

Other Outcomes

Description: For this correlative studie tumour tissue blocks, plasma and serum samples will be collected at trial entry and at disease progression on trial treatment.

Measure: T790M evolution in tissue and plasma/serum between baseline and disease progression on trial treatment

Time: Assessed at baseline and disease progression on trial treatment (maximum 48 months)

185 A Prospective,Multi-center, Open-labeled Phase 2 Randomized and Comparative Clinical Study of First Line Intermittent and Maintenance of Icotinib in Combination With Pemetrexed/Carboplatin Compared With Icotinib Single Drug in ⅢB/IV Non Small Cell Lung Cancer With Epidermal Growth Factor Receptor (EGFR) Mutation

EGFR-tyrosine kinase inhibitor(TKI)- ie, erlotinib, gefitinib, icotinib,has been recommended as the first option for EGFR-mutated IIIb/IV NSCLC by serial trials as it prolonged patients' progression-free survival. The OPTIMAl trial indicated that those who received TKI and chemotherapy during the whole treatment window survived longest. Unfortunately, previous studies(INTACT, TRIBUTE et al) that concurrently combined TKI and cytotoxic regimens failed to improve survival in unselected patients. To avoid the potential synergistic antagonism, the FAST-ACT II trial committed a sequential strategy and find a superiority in the combination arm upon chemotherapy even in EGFR-mutated group. However, pharmaceutically, the continuous administration of an EGFR-TKI before subsequent chemotherapy in FAST-ACT II could obviate the effects of cytotoxic agents due to the erlotinib-induced G1 arrest. On the basis of these and other studies, the investigators hypothesized that a better sequential combination strategy of EGFR-TKI and chemotherapy (adding a EGFR-TKI wash-out window before chemotherapy) would be more efficacious than chemotherapy alone. In this study, the investigators investigate the efficacy(PFS:progression free survival), safety, and adverse-event profile of chemotherapy plus intermittent and maintenance of icotinib compared with icotinib single drug, when these drugs were used as first-line treatment in who had non-squamous lung carcinoma with EGFR gene mutation in China.

NCT03151161
Conditions
  1. Lung, Carcinoma
Interventions
  1. Drug: Icotinib,Pemetrexed,Carboplatin
  2. Drug: Icotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmed activating mutation of EGFR-ie, an exon 19 deletion or an exon 21 L858R point mutation. --- L858R ---

Primary Outcomes

Description: Patients were images with computed tomography (CT) scan

Measure: Response Evaluation Criteria in Solid Tumors(RECIST) 1.1

Time: eight weeks

186 A Phase III, Open-Label, Multicenter, Randomized Study to Investigate the Efficacy and Safety of Atezolizumab Compared With Chemotherapy in Patients With Treatment Naïve Advanced or Recurrent (Stage IIIb Not Amenable for Multimodality Treatment) or Metastatic (Stage IV) Non-Small Cell Lung Cancer Who Are Deemed Unsuitable for Platinum-Containing Therapy

This Phase III, global, multicenter, open-label, randomized, controlled study will evaluate the efficacy and safety of atezolizumab (an anti-programmed death-ligand 1 [anti-PD-L1] antibody) compared with a single agent chemotherapy regimen by investigator choice (vinorelbine or gemcitabine) in treatment-naïve participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) who are deemed unsuitable for any platinum-doublet chemotherapy due to poor performance status (Eastern Cooperative Oncology Group [ECOG] performance status of 2-3).

NCT03191786
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Atezolizumab (MPDL3280A), an engineered anti-PD-L1 antibody
  2. Drug: Vinorelbine
  3. Drug: Gemcitabine
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Investigator-assessed PFS according to RECIST v1.1 will be assessed in participants whose tumors express PD-L1 protein as measured by PD-L1 SP263 IHC assay.. Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American Joint Committee on Cancer (AJCC) 7th edition - No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 19 deletions) or anaplastic lymphoma kinase (ALK) fusion oncogene detected - No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th edition - Life expectancy greater than or equal to (>/=) 8 weeks - Deemed unsuitable by the investigator for any platinum-doublet chemotherapy due to poor performance status (ECOG performance status of 2-3). --- L858R ---

Grade 3 or higher toxicities due to any prior therapy (example [e.g.], radiotherapy) (excluding alopecia), which have not shown improvement and are strictly considered to interfere with current study medication - Participants who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from randomization since the last chemotherapy, radiotherapy, or chemoradiotherapy General Medical Exclusion Criteria: - History of autoimmune disease except autoimmune-related hypothyroidism and controlled Type I diabetes mellitus - History of idiopathic pulmonary fibrosis (IPF), organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis - Known positivity for human immunodeficiency virus (HIV) - Known active hepatitis B or hepatitis C - Active tuberculosis - Severe infections within 4 weeks prior to randomization - Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina - Major surgical procedure other than for diagnosis within 4 weeks prior to randomization or anticipation of need for a major surgical procedure during the course of the study - Prior allogeneic bone marrow transplantation or solid organ transplant - Participants with an illness or condition that may interfere with capacity or compliance with the study protocol, as per investigator's judgment - Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 28 days prior to randomization Exclusion Criteria Related to Atezolizumab: - History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins - Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation - Oral or IV antibiotic treatment - Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study - Prior treatment with cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies, anti-programmed death-1 (anti-PD-1), and anti-PD-L1 therapeutic antibodies - Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to randomization - Treatment with systemic corticosteroids or other immunosuppressive medications - Participants not willing to stop treatment with traditional herbal medicines Exclusion Criteria Related to Chemotherapy: - Known sensitivity and contraindications to the 2 comparative chemotherapy agents (that is [i.e.] vinorelbine, oral or intravenous, and gemcitabine, intravenous) Inclusion Criteria: - Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the American Joint Committee on Cancer (AJCC) 7th edition - No sensitizing epidermal growth factor receptor (EGFR) mutation (L858R or exon 19 deletions) or anaplastic lymphoma kinase (ALK) fusion oncogene detected - No prior systemic treatment for advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC as per the AJCC 7th edition - Life expectancy greater than or equal to (>/=) 8 weeks - Deemed unsuitable by the investigator for any platinum-doublet chemotherapy due to poor performance status (ECOG performance status of 2-3). --- L858R ---

Primary Outcomes

Measure: Overall Survival

Time: From randomization up to death from any cause (up to approximately 3.5 years)

Secondary Outcomes

Measure: Percentage of Participants Who Are Alive at Specified Timepoints

Time: 6, 12, 18 and 24 months

Description: Objective response is defined as partial response (PR) plus complete response (CR).

Measure: Percentage of Participants With Objective Response, as Determined by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 (v1.1)

Time: From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 3.5 years)

Measure: Progression-Free Survival (PFS), as Determined by the Investigator Using RECIST v1.1

Time: From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 3.5 years)

Measure: Duration of Response, as Determined by the Investigator Using RECIST v1.1

Time: Time from the first occurrence of a documented objective response to the time of disease progression or death from any cause, whichever occurs first (up to approximately 3.5 years)

Measure: Percentage of Participants With Adverse Events (AEs)

Time: From randomization up to approximately 3.5 years

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC-QLQ-C30) Score

Time: Baseline, Day 1 of each treatment cycle up to 30 days after last dose (up to approximately 3.5 years) (Cycle length = 21 days)

Measure: Change From Baseline in EORTC QLQ Supplementary Lung Cancer Module 13 (EORTC QLQ-LC13) Score

Time: Baseline, Day 1 of each treatment cycle up to 30 days after last dose (up to approximately 3.5 years) (Cycle length = 21 days)

Measure: Time to Deterioration in Patient-Reported Lung Cancer Symptoms as Assessed by EORTC QLQ-C30 Score

Time: From baseline up to approximately 3.5 years

Measure: Time to Deterioration in Patient-Reported Lung Cancer Symptoms As Assessed by EORTC QLQ-LC13 Score

Time: From baseline up to approximately 3.5 years

Description: Overall survival will be assessed in participants whose tumors express PD-L1 protein as measured by PD-L1 SP263 IHC assay.

Measure: Overall Survival in Participants With PD-L1 Positive Status

Time: From randomization up to death from any cause (up to approximately 3.5 years)

Description: Investigator-assessed PFS according to RECIST v1.1 will be assessed in participants whose tumors express PD-L1 protein as measured by PD-L1 SP263 IHC assay.

Measure: Progression-Free Survival (PFS), as Determined by the Investigator Using RECIST v1.1 in Participants With PD-L1 Positive Status

Time: From randomization to the first occurence of disease progression or death from any cause, whichever occurs first (up to approximately 3.5 years)

187 A Phase 3, Randomized Study of Nivolumab Plus Ipilimumab in Combination With Chemotherapy vs Chemotherapy Alone as First Line Therapy in Stage IV Non-Small Cell Lung Cancer

The purpose of this study is to determine whether Nivolumab, Ipilimumab combined with chemotherapy is more effective than chemotherapy by itself when treating stage IV NSCLC as the first treatment given for the disease

NCT03215706
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Biological: Ipilimumab
  2. Biological: Nivolumab
  3. Drug: Carboplatin
  4. Drug: Paclitaxel
  5. Drug: Pemetrexed
  6. Drug: Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Participants with histologically confirmed Stage IV or recurrent NSCLC squamous or non-squamous histology, with no prior systemic anticancer therapy - Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 - Measurable disease by CT or MRI per response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) criteria - Participants must have PD-L1 IHC testing with results performed by a central laboratory during the screening period Exclusion Criteria: - Participants with known epidermal growth factor receptor (EGFR) mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded - Participants with known anaplastic lymphoma kinase (ALK) translocations which are sensitive to available targeted inhibitor therapy are excluded - Participants with untreated CNS metastases are excluded. --- L858R ---

Primary Outcomes

Description: OS was defined as the time from randomization to the date of death from any cause. OS was censored on the last date a subject was known to be alive. Survival follow-up was to be conducted every 3 months after participants's off-treatment date.

Measure: Overall Survival (OS)

Time: From date of randomization to date of death (assessed up to October 2019, approximately 23 months)

Secondary Outcomes

Description: PFS (primary definition) was defined as the time from the randomization date to the date of the first documented tumor progression based on BICR assessment (per RECIST 1.1), or death from any cause, whichever occurred first. Participants who died without a reported prior progression were considered to have progressed on the date of their death. Participants who had not progressed or died were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the randomization date. Participants who started any palliative local therapy or subsequent anticancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to initiation of the palliative local therapy or subsequent anti-cancer therapy, whichever procedure occurred first.

Measure: Progression Free Survival (PFS) by BICR

Time: From date of randomization until date of documented tumor progression or death due to any cause, whichever occurs first (assessed up to October 2019, approximately 23 months)

Description: ORR was defined as the number of randomized participants with a best overall response (BOR) of confirmed CR or PR based on BICR assessments (using RECIST v1.1 criteria), divided by the number of all randomized participants. BOR was recorded between the date of randomization and the date of objectively documented progression per RECIST 1.1 or the date of initiation of palliative local therapy or the date of initiation of subsequent anti-cancer therapy, whichever occurred first. For participants without documented progression or palliative local therapy or subsequent anti-cancer therapy, all available response designations contributed to the BOR determination. For participants who continued treatment beyond progression, the BOR was determined based on response designations recorded up to the time of the initial RECIST 1.1 defined progression.

Measure: Objective Response Rate (ORR) by BICR

Time: From date of randomization until date of documented tumor progression or subsequent anti-cancer therapy, whichever occurs first (assessed up to October 2019, approximately 23 months)

Description: DoR was defined as the time between the date of first confirmed documented response (CR or PR) to the date of the first documented BICR-assessed tumor progression (per RECIST 1.1), or death from any cause, whichever occurred first. Participants who started subsequent therapy (including palliative local therapy) without a prior reported progression were censored at the last evaluable tumor assessments prior to initiation of the subsequent anticancer therapy (including palliative local therapy). Participants who died without a reported prior progression were considered to have progressed on the date of their death. For subjects who neither progressed nor died, DoR was censored on the date of their last evaluable tumor assessment. DoR was evaluated for responders (confirmed CR or PR) only.

Measure: Duration of Response (DoR)

Time: From date of first confirmed response to date of tumor progression (assessed up to October 2019, approximately 23 months)

Description: TTR was defined as the time from randomization to the date of the first confirmed documented response (CR or PR), as assessed by the BICR. TTR was evaluated for responders (confirmed CR or PR) only.

Measure: Time to Response (TTR)

Time: From date of randomization to date of first confirmed documented response (assessed up to October 2019, approximately 23 months)

Description: PD-L1 expression was defined as the percent of tumor cells with membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC 28-8 pharmDx test. PD-L1 expression was classified as PD-L1 ≥1% (≥1% tumor cells with membrane staining in a minimum of a hundred evaluable tumor cells), PD-L1 < 1% and PD-L1 not quantifiable (without quantifiable PD-L1 expression), PD-L1 expression ≥ 50%, PD-L1 expression 1 to 49%

Measure: Objective Response Rate (ORR) by BICR by PD-LI Tumor Cell Expression

Time: From date of randomization until date of documented tumor progression or subsequent anti-cancer therapy, whichever occurs first (assessed up to October 2019, approximately 23 months)

Description: PFS (primary definition) was defined as the time from the randomization date to the date of the first documented tumor progression based on BICR assessment (per RECIST 1.1), or death from any cause, whichever occurred first. Participants who died without a reported prior progression were considered to have progressed on the date of their death. Participants who had not progressed or died were censored on the date of their last evaluable tumor assessment. Participants who did not have any on-study tumor assessments and did not die were censored on the randomization date. Participants who started any palliative local therapy or subsequent anticancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to initiation of the palliative local therapy or subsequent anti-cancer therapy, whichever procedure occurred first.

Measure: PFS by BICR by PD-L1 Tumor Cell Expression

Time: From date of randomization until date of documented tumor progression or death due to any cause, whichever occurs first (assessed up to October 2019, approximately 23 months)

Description: OS was defined as the time from randomization to the date of death from any cause. OS was censored on the last date a subject was known to be alive. Survival follow-up was to be conducted every 3 months after participants's off-treatment date.

Measure: OS by PD-L1 Tumor Cell Expression

Time: From date of randomization to date of death (assessed up to October 2019, approximately 23 months)

188 A Randomized Phase I Trial to Evaluate Concurrent Or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV Non-Small Cell Lung Cancer (COSINR Study)

Trial Design - Patients with stage IV non-small cell lung cancer are randomized to nivolumab/ipilimumab plus either sequential or concurrent stereotactic body radiotherapy (SBRT). - The primary endpoint is the phase I safety endpoint of SBRT dose for each body site. - The same starting SBRT dose levels are used in each arm. If two or more patients experience a dose-limiting toxicity (DLT) at the starting dose level, then the reduced dose level will be used (Section 7.1-Page 72). - DLT is defined as any grade ≥3 toxicity possibly, likely, or definitely related to SBRT plus nivolumab/ipilimumab (the combination and not the individual components). - Irradiated metastases will be grouped into one of five locations, which have different SBRT doses, and the DLTs will be attributed to the relevant organ system. - The starting and decreased SBRT dose levels are found in Table 2 (Page 20). - SBRT will be delivered in 3-5 fractions over the course of 1-1.5 weeks. - Patients in the sequential arm will begin immunotherapy between 1-7 days after completion of SBRT - Given the accrual data for IRB15-1130, the investigators anticipate that approximately 1/3 of patients will contribute metastasis to 2 locations. Since there are 2 arms, and 5 metastasis locations with 6 patients per location for the starting dose level, this translates to 40 patients for the starting dose level, and another 40 patients should each of the 5 locations require de-escalation to the lower dose level. - Secondary endpoints include comparisons of efficacy and toxicity between the arms, as well as interrogation of changes in the immune microenvironment induced by the two approaches.

NCT03223155
Conditions
  1. Stage IV Small Cell Lung Cancer
Interventions
  1. Drug: Nivolumab
  2. Drug: Ipilimumab
  3. Radiation: Stereotactic body radiation therapy
MeSH:Lung Neoplasms Small Cell Lung Carcinoma
HPO:Neoplasm of the lung Small cell lung carcinoma

- 12. Patients whose tumors known to harbor an exon 19 deletion or exon 21 L858R EGFR mutation must have progressed on or had intolerance to an EGFR TKI. --- L858R ---

Primary Outcomes

Description: To determine the recommended SBRT dose to various metastatic locations in patients with stage IV NSCLC when delivered prior to or concurrently with nivolumab and ipilimumab.

Measure: Number of serious adverse events

Time: Up to 4 years

Secondary Outcomes

Description: To estimate and compare rates of ≥ grade 3-4 adverse events, by organ system, by CTCAEv4.0 that occur within 3 months from the start of SBRT when given prior to or concurrently with nivolumab/ipilimumab.

Measure: Number of adverse events of grade 3-4 or higher

Time: Up to 4 years

Description: To estimate and compare the rates of long-term adverse events (after 3 months) from the end of SBRT when given prior to or concurrently with nivolumab/ ipilimumab.

Measure: Rate of long term adverse events

Time: Up to 4 years

Description: Summarize and compare the response rate to determine the progression-free survival at 6 months with SBRT given either prior to or concurrently with nivolumab/ipilimumab.

Measure: Rate of response

Time: From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months

Description: To determine and compare the control of lesion(s) (SBRT treated and non-treated) when given either prior to or concurrently with nivolumab/ipilimumab.

Measure: Rate of lesion control

Time: Up to 4 years

Description: To evaluate and compare changes in the tumor microenvironment induced by radiation when given prior to or concurrently with nivolumab/ipilimumab.

Measure: Rate of change in tumor microenvironment

Time: Up to 4 years

Description: To evaluate whether response to therapy correlates with PD-L1 expression levels among patients treated with nivolumab/ipilimumab either concurrently or sequential to SBRT.

Measure: Rate of PD-L1 expression levels response

Time: Up to 4 years

Description: To explore whole PBMC by measuring peripheral blood cell T cell subset IFNγ ELISPOT levels throughout the study course and correlate with response to treatment.

Measure: Measure of peripheral blood cell T cell levels

Time: From the start of treatment, not to exceed 4 years

Description: To explore peripheral blood T cell receptor deep sequencing quantification of T cell receptor (TCR) repertoire changes throughout the study course and how TCR repertoire may correlate with progression free survival and/or overall survival.

Measure: Quantification of T cell receptor

Time: From the start of treatment until the date of first documented progression or date of death from any cause, whichever comes first, up to 100 months

189 Phase II, Multicenter, Single-arm, Open-label Study to Evaluate the Efficacy of Olmutinib(Olita®) in Patients With NSCLC Who Harboring T790M Mutation Confirmed Using DNA Extracted From Extracellular Vesicles in Bronchoalveolar Lavage Fluid

The purpose of this study is to evaluate the efficacy of Olmutinib(Olita®) in patients with T790M-positive non-small cell lung cancer (NSCLC) confirmed using DNA extracted from extracellular vesicles of bronchoalveolar lavage fluid.

NCT03228277
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Olmutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumor harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). 5. Eastern Cooperative Oncology Group performance status of 0 to 2 6. --- L858R ---

Primary Outcomes

Description: defined as the proportion of patients who achieved complete remission(CR) or partial remission(PR) based on RECIST version 1.1

Measure: Objective response rate (ORR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Secondary Outcomes

Description: defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Measure: Disease control rate (DCR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Description: defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Measure: Progression-free survival (PFS)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

190 Phase II Trial to Evaluate Trametinib in Patients With Advanced NF1-mutant Non-small Cell Lung Cancer

Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.

NCT03232892
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Trametinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

bevacizumab, ipilumimab) 4. Patients with a known activating mutation in epidermal growth factor receptor (EGFR) (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase inhibitor (TKI) (erlotinib, afatinib, or gefitinib). --- G719A --- --- S768I --- --- V769L --- --- T790M --- --- L833F --- --- L858R ---

Primary Outcomes

Description: For participants receiving at least one dose of study treatment, the ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% using the Fisher's exact test.

Measure: Objective Response Rate (ORR)

Time: Up to 1 year

Secondary Outcomes

Description: The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Duration of Response (DR)

Time: Up to 4 years

Description: DCR will be defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Disease Control Rate (DCR) According to RECIST Version 1.1 Criteria.

Time: Up to 4 years

Description: PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1 Criteria.

Time: Up to 1 year

Description: OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.

Measure: Overall Survival (OS)

Time: Up to 1 year

191 A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib

A multicentre, open-label, single-arm, molecular profiling study of patients with EGFR mutation-positive locally advanced or metastatic NSCLC treated with osimertinib.

NCT03239340
Conditions
  1. EGFR Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).. ORR in patient subgroups defined by molecular profile. --- T790M --- --- L858R ---

PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).. ORR in patient subgroups defined by molecular profile. --- T790M --- --- L858R --- --- L858R ---

ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. TTD in patient subgroups defined by molecular profile. --- T790M --- --- L858R ---

ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. TTD in patient subgroups defined by molecular profile. --- T790M --- --- L858R --- --- L858R ---

TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Tumour shrinkage/depth of response in patient subgroups defined by molecular profile. --- T790M --- --- L858R ---

TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Tumour shrinkage/depth of response in patient subgroups defined by molecular profile. --- T790M --- --- L858R --- --- L858R ---

Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Proportion of patients with pre-specified characteristics will be summarised by molecular profile. --- T790M --- --- L858R ---

Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Proportion of patients with pre-specified characteristics will be summarised by molecular profile. --- T790M --- --- L858R --- --- L858R ---

These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0. --- T790M --- --- L858R ---

These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0. --- T790M --- --- L858R --- --- L858R ---

Primary Outcomes

Description: To characterize the frequency of genetic and proteomic markers at disease progression regardless of their prevalence.

Measure: Proportion of patients with a given tumour genetic and proteomic marker at the point of disease progression as defined by the Investigator

Time: Tumour Genetic and Proteomic markers will be assessed from tissue samples collected prior to initiation of treatment and at the time of disease progression for max 4.2 years

Secondary Outcomes

Description: PFS is defined as the time from first dose of osimertinib until the date of Investigator assessed RECIST 1.1-defined progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression.

Measure: Progression-free survival (PFS)

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: ORR is defined as the number (%) of patients with at least one visit response of complete response or partial response that is confirmed at least 4 weeks later.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: DoR is defined as the time from the date of first documented response, (that is subsequently confirmed) until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint.

Measure: Duration of Response (DoR)

Time: From time of first documented response until date of documented progression or death in the absence of disease progression or end of study up to max 4.2 years

Description: TTD is defined as the time from the date of first dose of osimertinib to the earliest of treatment discontinuation or death.

Measure: Time toTreatment Discontinuation or Death (TTD)

Time: At every visit from enrolment to end of treatment or death or end of study for max 4.2 years

Description: TFST is defined as the time from the date of first dose of osimertinib to the earlier of the date of anticancer therapy start date following study treatment discontinuation, or death.

Measure: Time to first subsequent therapy or Death (TFST)

Time: At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years

Description: Percentage of patients who have a best overall response, complete response, partial response or stable disease.

Measure: Disease Control Rate

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).

Measure: PFS in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: ORR in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: TTD in patient subgroups defined by molecular profile

Time: At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years

Description: Tumour shrinkage is defined as the best change from baseline in the sum of diameters of target lesions. Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: Tumour shrinkage/depth of response in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: The patient characteristics will include: gender (male/female), age (<65yrs/>65yrs), race (Asian/non Asian), and WHO Performance Status (0/1). These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: Proportion of patients with pre-specified characteristics will be summarised by molecular profile

Time: At baseline

Other Outcomes

Description: To summarize the safety and tolerability profile of osimertinib as first-line EGFR tyrosine kinase inhibitor therapy for patients with EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer

Measure: Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0

Time: At every visit from signing informed consent until 28 days after last dose of study treatment

192 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03255083
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: DS-1205c
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response Evaluation Criteria in Solid Tumors [RECIST version 1.1] or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 4. Is currently receiving, and is able to discontinue erlotinib, gefinitib, or afatinib; or is currently receiving osimertinib at the prescribed 80 mg dose and is able to interrupt osimertinib. --- L858R ---

Primary Outcomes

Measure: Number of participants with dose-limiting toxicities (DLTs) when taking DS-1205c in combination with osimertinib during dose escalation

Time: within 28 days

Description: Categories: during dose escalation, during dose expansion

Measure: Number of participants with clinically significant safety measures when taking DS-1205c in combination with osimertinib

Time: within 36 months

Secondary Outcomes

Description: DS-1205a is the free form of DS-1205c when DS-1205c is administered alone

Measure: Area under the plasma concentration time curve (AUC) for DS-1205a

Time: during Cycle 0 of the dose escalation period (within 28 days)

Measure: Maximum observed analyte concentration (Cmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Actual sampling time to reach Cmax (Tmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: first dose to 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: baseline to objective disease progression or death from any cause (within 36 months)

Measure: Overall survival (OS)

Time: baseline to death from any cause (within 36 months)

193 A Phase II Study of Nivolumab in Combination With Carboplatin and Pemetrexed, or Nivolumab in Combination With Ipilimumab, in Patients With Advanced, EGFR-mutant or ALK-rearranged, Non-Small Cell Lung Cancer

This research study is studying a drug intervention as a possible treatment for lung cancer. The drugs involved in this study are: - Nivolumab - Carboplatin - Pemetrexed - Ipilimumab

NCT03256136
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Carboplatin
  2. Drug: Nivolumab
  3. Drug: pemetrexed
  4. Drug: Ipilimumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion) as well as a T790M mutation per local testing. --- L858R ---

Primary Outcomes

Description: Complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Objective Response Rate (ORR), Presented in Numbers of Participants

Time: Up to approximately 2 years

Secondary Outcomes

Description: The number of patients that achieved either complete response (CR), partial response (PR), or stable disease (SD) per RECIST version 1.1 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.

Measure: Disease Control Rate (DCR), Presented in Numbers of Participants

Time: Up to approximately 2 years

Description: Time from initiation of the study drugs to progression or death, whichever occurs first. Disease progression was assessed via RECIST 1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression). Confidence Intervals (CIs) were calculated using the Kaplan Meier (KM) method

Measure: Progression Free Survival (PFS)

Time: From the start of treatment until disease progression or death due to any cause, up to approximately 2 years

Description: Time from initiation of the study drugs to date of death due to any cause. CIs are the KM estimate CIs.

Measure: Overall Survival (OS)

Time: From the start of treatment until death due to any cause, up to approximately 2 years

Description: Time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).

Measure: Duration Of Response

Time: From the first documented response until disease progression or death, up to approximately 2 years

194 A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer

This study is designed to evaluate safety and antitumor activity of U3-1402 in two parts: Dose Escalation and Dose Expansion. In Dose Escalation, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy. In Dose Expansion, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without EGFR-activating mutations) with disease progression during/after systemic treatment for locally advanced or metastatic disease.

NCT03260491
Conditions
  1. Non-Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: U3-1402
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R ---

3. Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q. --- L858R ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. --- L858R --- --- L861Q --- --- L858R ---

Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q Non-Small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of U3-1402 in the study population and to determine the recommended dose for expansion (RDE) of U3-1402 in the study population - For Dose Expansion, to investigate the antitumor activity of U3-1402 The number of treatment cycles is not fixed in this study. --- L858R ---

Primary Outcomes

Measure: Dose-limiting toxicities (DLTs) in the dose escalation period

Time: 21 days of Cycle 1

Measure: Summary of adverse events in the dose escalation period

Time: By the global end of trial date, approximately within 36 months

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee in the dose expansion period

Time: Approximately within 36 months

Secondary Outcomes

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose escalation period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose escalation period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose escalation period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose escalation period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose escalation period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose escalation period

Time: Approximately within 36 months

Measure: Summary of adverse events in the dose expansion period

Time: By the global end of trial date, approximately within 36 months

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose expansion period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose expansion period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose expansion period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose expansion period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose expansion period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose expansion period

Time: Approximately within 36 months

195 Evaluation of the Efficacy of Domestic Gefitinib Tablets in the Treatment of Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients Using a Multicenter, Randomized, Positive Drug Gefitinib Pharmacodynamics and Pharmacodynamics

1. Gefitinib CTTQ production gefitinib and erlotinib sheet AstraZeneca imatinib sheet (trade name: Iressa ®) comparison, human pharmacokinetics and relative bioavailability of comparative studies which examine people in vivo pharmacokinetic behavior, provide the basis for clinical use. 2. Evaluation CTTQ gefitinib imatinib sheet production efficacy and safety of Chinese patients with locally advanced or metastatic non-small cell lung cancer.

NCT03264794
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib Tab (CTTQ),First medication;Gefitinib Tab (CTTQ),From the 8th day of trial
  2. Drug: Gefitinib tablets (Yi Ruisha),First medication
  3. Drug: Gefitinib Tab 250 MG(CTTQ),From the 8th day of trial.
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Patients volunteered to participate in this study, signed informed consent; 2. ≥18 years old; ECOG PS score: 0 ~ 1; expected survival period of more than 3 months; 3. patients with locally advanced or metastatic non-small cell lung cancer diagnosed by histology or cytology, who can not receive radical surgery or radiotherapy; patients with measurable lesions(according to RECIST criteria); 4. Detection of EGFR-positive exon 19 deletion or exon 21 (L858R) mutation was performed by providing a detectable specimen (tissue or cancerous pleural effusion) prior to enrollment; 5. --- L858R ---

Primary Outcomes

Description: After the use of gefitinib to reach the highest plasma concentration

Measure: Gefitinib plasma concentration

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: Taking the time required for the concentration of gefitinib to reach the peak

Measure: Tmax time

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: The area between the axis of the coordinate and the time drug concentration curve

Measure: AUC0-t

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: The time required for gefitinib to decrease by half the highest concentration in plasma

Measure: t 1/2

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

Description: Gefitinib absorbs the relative amount of blood into the cycle

Measure: F

Time: 0hour before administration and 1, 2, 3, 4, 5, 6, 7, 8,9,13,24,48,72,120,168 16 hour time points after administration

196 Gefitinib Versus Combination of Gefitinib With Chemotherapy or Anti-angiogenesis as 1st Line Treatment in Advanced NSCLC Patients Detected With Bim Deletion or Low EGFR Activating Mutation Abundance:A Randomized, Multicentre, Phase II Study

This is an open-label, multicenter, randomized, phase II clinical trial, which aims to evaluate the effectiveness and safety of gefitinib versus combination of gefitinib and doublet chemotherapy or apatinib in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutation (exon 19 deletion or exon 21 L858R point mutation), accompanied with Bim deletion or low activating EGFR mutation abundance.

NCT03267654
Conditions
  1. Non-small-cell Lung Cancer
Interventions
  1. Drug: gefitinib combined with chemotherapy
  2. Drug: gefitinib combined with apatinib
  3. Drug: gefitinib single agent
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Gefitinib With Chemotherapy or Anti-angiogenesis in NSCLC Patients With Bim Deletion or Low EGFR Mutation Abundance This is an open-label, multicenter, randomized, phase II clinical trial, which aims to evaluate the effectiveness and safety of gefitinib versus combination of gefitinib and doublet chemotherapy or apatinib in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutation (exon 19 deletion or exon 21 L858R point mutation), accompanied with Bim deletion or low activating EGFR mutation abundance. --- L858R ---

3. EGFR mutation (exon 19 deletion or exon 21 L858R) with Bim deletion or low abundance for EGFR mutation. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy until progression or death

Measure: Progression free survival

Time: 8 weeks

Secondary Outcomes

Description: evaluated in the 36th since treatment begain

Measure: overall survival

Time: 36 months

Description: Evaluated the rate of complete response and partial response in the 8 weeks since treatment began

Measure: objective response rate

Time: 8 weeks

Description: Evaluated the rate of complete response,partial response and stable disease in the 8 weeks since anti-cancer therapy

Measure: disease control rate

Time: 8 weeks

Description: interval between the time which complete response or partial response happened and progressive disease or death

Measure: duration of response

Time: 8 weeks

Description: Safety observation indexes were listed as following: adverse events and serious adverse events (according to CommonTerminology Criteria Adverse Events Version 4.03), physical exam, vital signs(blood pressure, heart rate, respiratory rate,body temperature), weight variation, laboratory examination(hematology, blood biochemistry, urinalysis and so on), electrocardiograph(ECG),ultrasonic cardiogram(UCG), ect.

Measure: safety evaluation

Time: 8 weeks

Description: Quality of Life Questionnaire(including QLQ-C30 and QLQ-LC13) evaluated since treatment began.At the end of the trial, the differences between the two indicators were compared with Mixed-effects model repeated measures (MMRM), where the baseline was scored as a covariant and the treatment group as a fixed variable. In addition, the baseline values of the two scores, the value of each visit, and the change value of the baseline were statistically described.

Measure: compare quality of life

Time: 24 months

197 Comprehensive Stereotactic Body Radiotherapy (SBRT) to All Sites of Oligometastatic Non-small Cell Lung Cancer (NSCLC) Combined With Durvalumab (MEDI4736) and Tremelimumab Dual Immune Checkpoint Inhibition.

This is a phase Ib study to evaluate safety and tolerability of dual checkpoint inhibition (DCI) of durvalumab (anti-PD-L1) and tremelimumab (anti-CTLA-4) with SBRT in the treatment of oligometastatic NSCLC. This study will examine the sequential delivery of SBRT to all disease sites followed by combination of durvalumab and tremelimumab for patients for whom the goal is ablating all known sites of disease. The investigators anticipate that for many participants this will be the first line-therapy. Participants who have received prior-platinum-based chemotherapy and/or any line of prior chemotherapy are eligible. Prior immunotherapy treatment is not allowed.

NCT03275597
Conditions
  1. Non-small Cell Lung Cancer
  2. Non-small Cell Lung Cancer Stage IV
Interventions
  1. Drug: Durvalumab
  2. Drug: Tremelimumab
  3. Radiation: Stereotactic Body Radiotherapy
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

exon 19 deletion or exon 21 L858R) or ALK rearrangement. --- L858R ---

Primary Outcomes

Description: Toxicities will be summarized by type and severity in tabular format. Toxicity rates (grade 2, grade 3, grade 4, grade ≥ 2, grade ≥ 3, etc.) will be calculated and reported along the corresponding 95% confidence intervals. The 95% confidence intervals will be constructed using the Wilson score method.

Measure: Safety and tolerability of SBRT followed by combined durvalumab and tremelimumab, assessed by CTCAE v4.03

Time: Up to 3 years

Secondary Outcomes

Description: Progression-free survival (PFS) will be defined as the difference (in months) between the date of study enrollment and the date of disease progression or death due to any cause. PFS will be analyzed using the Kaplan-Meier method, and the Brookmeyer-Crowley method will be used to construct the 95% confidence interval for the median PFS. PFS assessed with RECIST 1.1 tumor assessments. The effect of DCI with durvalumab and tremelimumab will be compared against historical controls for a 95% CI and p-value.

Measure: Progression Free Survival assessed with RECIST 1.1 tumor assessments

Time: Up to 4 years

Description: Overall survival (OS) will be defined as the difference (in months) between the date of study enrollment to the date death due to any cause. OS will be analyzed using the Kaplan-Meier method, and the Brookmeyer-Crowley method will be used to construct the 95% confidence interval for the median OS. The effect of DCI with durvalumab tremelimumab will be compared against historical controls for a 95% CI and p-value.

Measure: Overall Survival assessed with RECIST 1.1 tumor assessments

Time: Up to 4 years

Other Outcomes

Description: Determine whether immune response on biopsy sections or circulating tumor cells is increased following SBRT. The paired McNemar's test will be used to compare with subjects with an immune response between assessment time point.

Measure: Evaluate immune response

Time: Up to 4 years

Description: Determine whether PD-L1 expression on biopsy sections or circulating tumor cells is increased following SBRT. PD-L1 expression will be summarized in terms of means, standard deviation, median and range. Absolute and percentage changes in PD-L1 expression levels between the pre-SBRT versus post-SBRT assessment will be calculated and evaluated using a paired t-test.

Measure: Evaluate PD-L1 expression

Time: Up to 4 years

198 A Phase 2 Study of EGF816 and Gefitinib in TKI-naïve EGFR-mutant Non-Small Cell Lung Cancer

This research study is studying a combination of drugs as a possible treatment for EGFR mutation-positive lung cancer. The drugs involved in this study are: - EGF816 - Gefitinib

NCT03292133
Conditions
  1. Lung Cancer
Interventions
  1. Drug: EGF816
  2. Drug: Gefitinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Specifically, patients harboring the most common mutations, deletions in exon 19 or the L858R mutation in exon 21 are eligible. --- L858R ---

Primary Outcomes

Description: The number of participants that are free from objective disease progression or death at 9 months. Progression is evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Measure: Progression Free Survival at 9 months

Time: 9 months

Secondary Outcomes

Description: The number of participants that achieve either a complete response (CR) or a partial response (PR). Response is evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. All CRs and PRs must be confirmed by a second assessment not earlier than 4 weeks after the criteria for response are first met.

Measure: Response Rate

Time: 2 years

Description: Overall survival is defined as time from the start of treatment until death. Overall survival will be analyzed using the Kaplan-Meier method.

Measure: Overall Survival

Time: 2 years

Description: Summary of the adverse events experienced by study participants as evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v4.

Measure: Safety and Tolerability of the EGF816/gefitinib combination (Summary of the adverse events experienced by study participants as evaluated by CTCAE v4)

Time: 2 years

199 A Phase Ib, Open Label, Multi-center Study to Characterize the Safety, Tolerability and Preliminary Efficacy of EGF816 in Combination With Selected Targeted Agents in EGFR Mutant NSCLC

The study purpose is to evaluate the safety, tolerability, and preliminary efficacy of the addition of INC280, trametinib, ribociclib, gefitinib, or LXH254 to EGF816 in adult patients with advanced EGFR-mutant NSCLC.

NCT03333343
Conditions
  1. EGFR-mutant Non-small Cell Lung Cancer
Interventions
  1. Drug: EGF816
  2. Drug: trametinib
  3. Drug: ribociclib
  4. Drug: LXH254
  5. Drug: INC280
  6. Drug: gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Patients must have histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic (stage IV) EGFR mutant (ex19del, L858R) NSCLC. --- L858R ---

- Requirements of EGFR mutation status and prior lines of treatment: - Treatment naive patients, who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation (e.g., L858R and/or ex19del), have not received any systemic antineoplastic therapy for advanced NSCLC and are eligible to receive EGFR TKI treatment. --- L858R ---

- Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) following progression on prior treatment with a 1st-generation EGFR TKI or 2nd-generation EGFR TKI. --- T790M --- --- L858R ---

- Patients who have been treated with systemic anti-neoplastic therapy within: - 2 weeks for fluoropyrimidine monotherapy - 6 weeks for nitrosoureas and mitomycin - 4 weeks or ≤ 5 half-lives (whichever is shorter) for biological therapy (including monoclonal antibodies) and continuous or intermittent small molecule therapeutics or any other investigational agent Inclusion Criteria: - Patients must have histologically or cytologically confirmed locally advanced (stage IIIB) or metastatic (stage IV) EGFR mutant (ex19del, L858R) NSCLC. --- L858R ---

Primary Outcomes

Description: Assess safety and tolerability including incidence of dose limiting toxicities, adverse events, and serious adverse events.

Measure: Number of patients with adverse events and serious adverse events

Time: Every day until study end, approximately 4 years

Description: Modified objective response rate (ORR2) per RECIST v1.1 (taking as baseline the most recent assessment prior to initiating combination)

Measure: ORR2

Time: Every 8-12 weeks until study ends, approximately 4 years

Secondary Outcomes

Description: Overall response rate (ORR) per RECIST v1.1

Measure: ORR

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Time from the date of first dose of study treatment to the date of first documented disease progression (per RECIST v1.1) or death due to any cause

Measure: PFS

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Proportion of patients with best overall response of CR, PR, or SD

Measure: DCR

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause

Measure: DOR

Time: Every 8-12 weeks until study ends, approximately 4 years

Measure: Time to response

Time: Every 8-12 weeks until study ends, approximately 4 years

200 A Randomized Phase II Study of Gefitinib Alone Versus Gefitinib Plus Thalidomide for Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Activating Mutations

EGFR-TKIs are the standard first-line treatment option for EGFR-mutant NSCLC. After a randomized phase II trial, JO25567 was presented at 2014 ASCO, the synergistic effect of progression-free survival(PFS) could be expected when EGFR TKI, Gefitinib is combined with Antiangiogenesis agent thalidomide, Therefore Chinese data of treating EGFR mutation positive NSCLC patients with Gefitinib and thalidomide is significantly necessary for developing new standard treatment in first-line therapy in Chinese EGFR mutant NSCLC patients. In this study, The investigators will investigate the efficacy and safety of Gefitinib and thalidomide combination compare to Gefitinib alone in Chinese EGFR-mutant NSCLC patients.

NCT03341494
Conditions
  1. NSCLC Stage IV
  2. Chemotherapy Effect
Interventions
  1. Drug: Thalidomide

Inclusion Criteria: - Pathologically confirmed stage IIIB & IV non-small cell lung cancer other than squamous cell carcinoma - Patients with one or more measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Locally diagnosed sensitive EGFR mutation positive (Exon 19 deletion or L858R) - ECOG performance 0~1 - Age ≥ 19 years and - No previous treatment Adequate organ function by following: - ANC ≥1,500/uL, hemoglobin ≥9.0g/dL, platelet ≥100,000/uL - Serum bilirubin < 1 x UNL, AST (SGOT) and ALT (SGPT) < 2.5 x UNL, If Liver metastasis, Serum bilirubin < 3 x UNL, AST (SGOT) and ALT (SGPT) < 5 x UNL - Serum Cr ≤ 1 x UNL - Patients who have had undergone radiotherapy are acceptable if patients meet all of the following criteria: - No history of irradiation to pulmonary tumor lesions. --- L858R ---

- In case of irradiation to non-pulmonary sites: at least two weeks must have passed at the date of inclusion since the last irradiation of the sites - At the time of registration, at least the following period has passed since last date of the prior therapy or procedure: - Surgery(including exploratory/ examination thoracotomy): 4 weeks - Pleural cavity drainage: 1 weeks - Pleurodesis without anti-neoplastic agents (inclusive of BRM such as Picibanil): 2 week - Biopsy accompanied by incision (including thoracoscopic biopsy): 2 week - Procedure for trauma (exclusive of patients with unhealed wound): 2 weeks - Transfusion of blood, preparation of hematopoietic factor: 2 week - Puncture and aspiration cytology: 1 week - Other investigational product: 4 weeks - Written informed consent form Exclusion Criteria: - • Previous history of malignancy within 3 years from study entry except treated non-melanomatous skin cancer, uterine cervical cancer in situ, or thyroid cancer - Prior chemotherapy or systemic anti-cancer therapy for metastatic disease but postoperative adjuvant or neoadjuvant therapy of 6 months or more previously is allowed - Patients who received previous treatment for lung cancer with drugs - Symptomatic or uncontrolled central nervous system (CNS) metastases - Patients with increased risk of bleeding, clinically significant cardiovascular diseases, a history of thrombosis or thromboembolism in the 6 months prior to treatment, gastrointestinal problems, and neurologic problems - Any significant ophthalmologic abnormality - Pre-existing parenchymal lung disease such as pulmonary fibrosis - Known allergic history of Erlotinib or Bevacizumab - Interstitial lung disease or fibrosis on chest radiogram - Active infection, uncontrolled systemic disease (cardiopulmonary insufficiency, fatal arrhythmias, hepatitis) - Pregnant or nursing women Inclusion Criteria: - Pathologically confirmed stage IIIB & IV non-small cell lung cancer other than squamous cell carcinoma - Patients with one or more measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Locally diagnosed sensitive EGFR mutation positive (Exon 19 deletion or L858R) - ECOG performance 0~1 - Age ≥ 19 years and - No previous treatment Adequate organ function by following: - ANC ≥1,500/uL, hemoglobin ≥9.0g/dL, platelet ≥100,000/uL - Serum bilirubin < 1 x UNL, AST (SGOT) and ALT (SGPT) < 2.5 x UNL, If Liver metastasis, Serum bilirubin < 3 x UNL, AST (SGOT) and ALT (SGPT) < 5 x UNL - Serum Cr ≤ 1 x UNL - Patients who have had undergone radiotherapy are acceptable if patients meet all of the following criteria: - No history of irradiation to pulmonary tumor lesions. --- L858R ---

Primary Outcomes

Description: progression-free survival

Measure: PFS

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to at least 36 months

Secondary Outcomes

Description: Overall Response Rate

Measure: ORR

Time: through study completion, and average of 2 years

Description: Overall Survival

Measure: OS

Time: From date of randomization until the date of death or date of last visit/contact, whichever came first, assessed to at least 36 months

201 Randomized Phase III Study Testing Nivolumab and Ipilimumab Versus a Carboplatin Based Doublet in First Line Treatment of PS 2 or Elderly (More Than 70 Years Old) Patients With Advanced Non-small Cell Lung Cancer

Lung cancer is the most common cancer in the world and the leading cause of cancer-related deaths in Western countries. Unfortunately, at the time of diagnosis, the majority of patients already have metastatic disease and a systemic, palliative treatment is the primary therapeutic option. Guidelines for PS 2 patients or older than 75 years old patients at the time of diagnosis recommend for fit patients a carboplatin doublet chemotherapy. Nivolumab has proven efficacy in 3rd line squamous cell lung carcinoma and is superior to chemotherapy in 2nd line treatment of squamous and non-squamous lung cancer in term of overall survival. In 1st line, nivolumab failed to show superiority compared to a platin based doublet in terms of progression free survival and overall survival in tumors ≥ 5% PD-L1 expression. The association Nivolumab plus Ipilimumab showed encouraging results in first line setting in phase 1 study. The investigators think that with regard to the manageable toxicity of nivolumab in lung cancer population and the possibility to obtain long responses, this association could be a valid option for this population of elderly and/or PS2 patients in term of overall survival.

NCT03351361
Conditions
  1. Advanced Non Small Cell Lun
  2. Advanced Non Small Cell Lung Cancer
Interventions
  1. Drug: Nivolumab + Ipilimumab
  2. Drug: Chemotherapy
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Known activating mutation of EGFR (del LREA exon 19, mutation L858R or L861X of exon 21, mutation G719A/S in exon 18) or EML4-ALK or ROS-1 translocation - Superior at caval syndrome - Uncontrolled infectious status - All concurrent radiotherapy - Concurrent administration of one or several other anti-tumor therapies. --- L858R ---

Primary Outcomes

Measure: Overall survival

Time: From date of randomization until the date of date of death from any cause, whichever came first, assessed up to 3 years maximum

Secondary Outcomes

Measure: Survival rate

Time: 1 year

Description: according to RECIST 1.1

Measure: Objective response rate

Time: 2 years

Measure: Progression free survival

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years maximum

Description: Incidence of Treatment-Emergent Adverse Events according to CTCAE version 4.0

Measure: Safety rate

Time: 2 years

Description: Incidence of Treatment-Emergent Adverse Events according to CTCAE version 4.0

Measure: Tolerability rate

Time: 2 years

Description: according to EQ-5D questionnaire

Measure: Quality of life score

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years maximum

Description: according to EORTC QLQ-ELD14 questionnaire

Measure: Quality of life score

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years maximum

Description: testing by immunochemistry

Measure: PD-L1

Time: 2 years

Description: according to geriatric mini data set

Measure: Geriatric evaluation

Time: inclusion and 2 months

202 A Phase I/II, Open-label, Multi-center Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of AZD3759 in Chinese Patients With EGFRm+ NSCLC With Central Nervous System (CNS) Metastases

This is a multi-center, open-label, dose escalation and phase I/II study, consisting of dose escalation in Part A and phase II study in Part B.

NCT03360929
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD3759
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Histologically or cytologically confirmed non-small cell lung cancer with activating mutation in EGFR gene (including Exon19Del and/or L858R). --- L858R ---

Primary Outcomes

Description: AE.SAE,vital signs, physical examination,laboratory examinations etc.

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Time: 21 days after the first dose

Description: ORR, DCR, DOR, PFS and tumor size changing compared with baseline according to RECIST 1.1

Measure: anti-tumor activity

Time: every 6 weeks

Secondary Outcomes

Description: Peak Plasma Concentration (Cmax)

Measure: Peak Plasma Concentration (Cmax)

Time: Pre-dose and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h(C0D2) and 48h(C0D3) after the first single-dose(C0D1) ;Pre-dose of C1D1,C1D8, C1D15, C1D21 and C2D1 and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h post dose on C1D21 during multiple dosing.

Description: Area under the plasma concentration versus time curve (AUC)

Measure: Area under the plasma concentration versus time curve (AUC)

Time: Pre-dose and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 24h(C0D2) and 48h(C0D3) after the first single-dose(C0D1) ;Pre-dose of C1D1,C1D8, C1D15, C1D21 and C2D1 and 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h post dose on C1D21 during multiple dosing.

203 GioTag: Real-world Data Study on Sequential Therapy With Gi(l)Otrif®/ Afatinib as First-line Treatment Followed by Osimertinib in Patients With EGFR Mutation Positive Advanced Non-small Cell Lung Cancer

This is a non-interventional, multi-country, multi-centre cohort study based on existing data from medical records of patients with EGFR mutation-positive advanced NSCLC treated with afatinib (Gi(l)otrif®) as the first-line treatment followed by osimertinib in case the T790M resistance mutation was developed.

NCT03370770
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Afatinib
  2. Drug: Osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R ---

Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung null --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Measure: Time on treatment with afatinib (Gi(l)otrif®) followed by osimertinib

Time: 24 months

Secondary Outcomes

Measure: Type and proportion of acquired resistance mutations after osimertinib

Time: 24 months

204 A Phase III, Randomized, Multi-center Study to Determine the Efficacy of the Intercalating Combination Treatment of Chemotherapy and Gefitinib or Chemotherapy as Adjuvant Treatment in NSCLC With Common EGFR Mutations.

This study aims to compare the efficacy of intercalating chemotherapy (gefitinib and pemetrexed/cisplatin) and chemotherapy (navelbine/cisplatin) in completely resected NSCLC with common EGFR mutations.

NCT03381066
Conditions
  1. Completely Resected NSCLC With Common EGFR Mutations
Interventions
  1. Drug: gefitinib, pemetrexed,cisplatin
  2. Drug: Vinorelbine, cisplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Completely resected non-squamous cell NSCLC with stage IIa to IIIb (excluding N3) according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2. Tumors with common EGFR mutations (19del or L858R) 3. Adequate oran function Exclusion Criteria: 1. Patients who were exposed to the chemotherapy or EGFR TKIs for NSCLC. --- L858R ---

2. Patients with interstitial lung disease Inclusion Criteria: 1. Completely resected non-squamous cell NSCLC with stage IIa to IIIb (excluding N3) according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2. Tumors with common EGFR mutations (19del or L858R) 3. Adequate oran function Exclusion Criteria: 1. Patients who were exposed to the chemotherapy or EGFR TKIs for NSCLC. --- L858R ---

Primary Outcomes

Description: Time from the randomization to recurrence or any cause of death.

Measure: disease-free survival

Time: 5 years

Secondary Outcomes

Description: Time from the randomization to death of any cause

Measure: Overall survival

Time: 5 year

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE4.0

Time: 5 years

205 A Open-label, One-arm Trial of Gefitinib Combined With Radiotherapy as Adjuvant Therapy in Completely Resected Patients With Pathological Stage IIIA-N2 Non-small Cell Lung Cancer Harbouring Sensitive Mutations of EGFR

To explore the survival benefit of the gefitinib combined with radiotherapy as adjuvant therapy for completely resected patients with Pathological stage IIIA-N2 NSCLC harbouring sensitive mutations of EGFR.

NCT03381430
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Gefitinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- Target population is completely resected pathological stage IIIA-N2 NSCLC with EGFR exon 19 deletions and exon 21 L858R activating mutation. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy until progression or death. To evaluate the disease free survival of gefitinib combined with radiotherapy as adjuvant therapy in completely resected patients with Pathological stage IIIA-pN2 NSCLC harbouring sensitive mutations of EGFR.Disease free survival (DFS)- defined as the time from initial medication to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years.

Secondary Outcomes

Description: evaluated in the 6 years since treatment begain

Measure: Overall survival

Time: 6 years

Description: To compare the adjuvant treatment arm in terms of 3 yeas DFS rate.

Measure: 3 yeas DFS rate

Time: 3 years

Description: To compare the adjuvant treatment arm in terms of 5 years DFS rate.

Measure: 5 years DFS rate

Time: 5 years

Description: To compare the adjuvant treatment arm in terms of 5 years OS rate.

Measure: 5 years OS rate

Time: 5 years

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of radiotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Radiotherapy total dose 50-54Gy, divided dose 1.8-2Gy.

206 Retreatment With 1st Generation EGFR TKIs in Sensitizing EGFR Mutation Positive Non-Squamous Cell Carcinoma Patients Who Previously Treated With EGFR TKI and Cytotoxic Chemotherapy

In this trial, treatment efficacy and safety of retreatment with 1st generation epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI)s(Gefitinib/Erlotinib), will be assessed in patients with sensitizing EGFR mutation positive Non-Squamous Cell Carcinoma patients who previously treated with EGFR TKI and cytotoxic chemotherapy

NCT03382795
Conditions
  1. EGFR Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: EGFR
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Males or females ≥ 19 years of age 2. Non Small Cell Lung Cancer(Non-Squamous Cell Carcinoma) patients who had shown clinical benefits (Complete response(CR) or Partial response(PR) or Stable disease(SD) ≥6 months) from EGFR-TKIs as first line treatment and developed progressive disease, and then received cytotoxic chemotherapy more than 4 cycles and developed progressive disease, and then confirmed T790 negative and sensitizing EGFR mutation(E19Del, L858R, L861Q, G719X, E19insertion) positive in Histologic, cytologic specimen or blood. --- L858R ---

Patients who are difficult to include in this study in accordance with the investigator's judgment due to severe adverse effects during previous EGFR TKI treatment Inclusion Criteria: 1. Males or females ≥ 19 years of age 2. Non Small Cell Lung Cancer(Non-Squamous Cell Carcinoma) patients who had shown clinical benefits (Complete response(CR) or Partial response(PR) or Stable disease(SD) ≥6 months) from EGFR-TKIs as first line treatment and developed progressive disease, and then received cytotoxic chemotherapy more than 4 cycles and developed progressive disease, and then confirmed T790 negative and sensitizing EGFR mutation(E19Del, L858R, L861Q, G719X, E19insertion) positive in Histologic, cytologic specimen or blood. --- L858R ---

Primary Outcomes

Description: Assessed on based of RECIST 1.1.

Measure: Objective Response Rate(ORR) including rage of CR&PR

Time: Through study completion (5 years)

Secondary Outcomes

Description: Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause

Measure: Progression Free Survival, PFS

Time: Through study completion (5 years)

Description: Overall Survival (OR) the time from first dose of the study drug until the date of death by any cause

Measure: Overall Survival

Time: Through study completion (5 years)

Description: Assessment on the base of NCI-CTCAE (version 4.03)

Measure: The incidence of Adverse Events(including Serious Adverse Events and Adverse Drug Reactions)

Time: Through study completion (5 years)

207 An Open-label, Single Arm, Phase I/IIa Study to Evaluate Safety, Dose Escalation Tolerability, Pharmacokinetics and Antineoplastic Activity of the BPI-7711 Capsule in Patients With EGFR Mutation Advanced or Recurrent NSCLC

Lung cancer has the highest incidence rate in China and is also a very common cancer in the world. BPI-7711 is a new drug developed for patients with non-small cell lung cancer. The purpose of this study is to evaluate the safety, efficacy and PK profile of BPI-7711. The first part of the study will recruit 3~6 patients for different dose levels to evaluate safety. The dose will increase from the lowest level. The second part of the study is the dose expansion. Once efficacy is observed in the dose increasing process, additional 20~30 patients will be enrolled to further evaluate the anti-tumor efficacy. A recommended dose will be selected for Phase II study.

NCT03386955
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: BPI-7711 Capsule
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Prior to enrollment, a central laboratory testing report confirmed the tumor has EGFR positive gene mutation sensitive to EGFR-TKI treatment (including G719X, exon 19 loss, L858R, L861Q etc.). --- L858R ---

Primary Outcomes

Description: DLT to be evaluated according to NCI CTCAE V4.03

Measure: Number of patients with dose limiting toxicity ( DLT).

Time: From first dosing ( Day -7) to the last dosing of Cycle 1 ( Day 28).

Secondary Outcomes

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Maximum plasma concentration (Cmax) of BPI-7711 and its main metabolites.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Peak Plasma Time (tmax) of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Area under the plasma concentration versus time curve (AUC) of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Clearance of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Half life of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Cycle 1 Day1, Cycle Day 8, Cycle 1 Day 15 and Cycle 2 Day1 at designated time. points.

Measure: Blood concentration of BPI-7711 and its main metabolites after single dose under steady state.

Time: Pre-dose of Cycle1 Day1, 8, 15. Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h post dose on Cycle 2 Day1

Description: Objective response rate evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Objective response rate (ORR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Best objective response evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Best objective response (BOR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Disease control rate evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Disease control rate ( DCR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Duration of response evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Duration of response ( DoR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Progression free survival evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Progression free survival (PFS) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Other Outcomes

Description: To test EGFR mutation in plasma circulating tumor DNA (ctDNA).

Measure: EGFR mutation testing.

Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: To test T790M mutation in plasma circulating tumor DNA (ctDNA).

Measure: T790M mutation testing.

Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

208 A Phase 2 Study of Osimertinib in Combination With Selumetinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer

This research study is studying a combination of two targeted therapies as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The drugs involved in this study are: - Osimertinib (Tagrisso) - Selumetinib

NCT03392246
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Selumetinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.. Inclusion Criteria: - Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a CLIA-approved laboratory. --- L858R ---

Inclusion Criteria: - Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a CLIA-approved laboratory. --- L858R ---

Primary Outcomes

Description: RECIST1.1 measurements of CT scans will be measured during treatment to determine the objective response rate for patients being treated with combination osimertinib and selumetinib. A response rate and a 95% confidence interval will be calculated.

Measure: Best Objective Response

Time: 2 years

Secondary Outcomes

Description: Time from registration to documented disease progression or death from any cause, whichever occurs first. The Kaplan-Meier method will be used to determine the progression-free survival of patients enrolled on protocol and treated with combination osimertinib and selumetinib.

Measure: Progression Free Survival

Time: 2 years

Description: Survival follow-up with clinic visits or phone calls will be used to monitor for overall survival, from the time of study randomization to death from any cause. The Kaplan-Meier method will be used to calculate overall survival.

Measure: Overall Survival

Time: 2 years

Description: Fraction of patients continuing on study therapy at 6 months.

Measure: Tolerability

Time: 2 years

Description: Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.

Measure: Toxicity

Time: 2 years

209 A Phase II Study for Evaluating Anti-tumor Efficacy of TAGRISSO (Osimertinib) in NSCLC Patients in Whom T790 Mutations Are Detected by Liquid Biopsy Using Bronchoalveolar Lavage Fluid, Plasma or Pleural Effusion

In this trial, anti-tumor efficacy of TAGRISSO in NSCLC patients in whom T790 mutations are detected by liquid biopsy.

NCT03394118
Conditions
  1. NSCLC
Interventions
  1. Drug: Osimertinib
MeSH:Pleural Effusion
HPO:Pleural effusion

AE/SAE assessement on the base of NCI-CTCAE (version 4.03).. Inclusion Criteria: 1. Age ≥ 20, and patients who understand information about the trial and voluntarily agree to participate in the trial 2. Histological or cytological confirmation diagnosis of NSCLC and inoperable stage IIIB or IV at the time of study enrolment 3. Patients with EGFR sensitizing mutation (E19Del, L858R, L861Q, G719X) positive, who had shown clinical benefits (responders (CR or PR) and SD ≥6 months) from EGFR-TKIs and had developed progressive disease following those therapy - Patients who have histories of previous exposure to EGFR-TKIs or other systemic chemotherapies are permitted (regardless of the order of treatment) - Treated with at least one of KGFR-TKIs (regardless of treatment with or without systemic chemotherapies) - In case the patient previously received any of the treatments including systemic chemotherapy, radiation therapy, surgery, and hormonal therapy, there should be at least 2 weeks of time interval between the last day of the previous treatment and the start of TAGRISSO™, and the remaining toxicity should be ≤ CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2, prior platinum-therapy related neuropathy) 4. ECOG performance status 0-2 5. Patients in whom T790 mutations are detected in at least one of the samples including tumor tissues, BALF (cell-free DNA), plasma (cell-free DNA), and pleural effusion (cell-free DNA) 6. --- L858R ---

Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry Inclusion Criteria: 1. Age ≥ 20, and patients who understand information about the trial and voluntarily agree to participate in the trial 2. Histological or cytological confirmation diagnosis of NSCLC and inoperable stage IIIB or IV at the time of study enrolment 3. Patients with EGFR sensitizing mutation (E19Del, L858R, L861Q, G719X) positive, who had shown clinical benefits (responders (CR or PR) and SD ≥6 months) from EGFR-TKIs and had developed progressive disease following those therapy - Patients who have histories of previous exposure to EGFR-TKIs or other systemic chemotherapies are permitted (regardless of the order of treatment) - Treated with at least one of KGFR-TKIs (regardless of treatment with or without systemic chemotherapies) - In case the patient previously received any of the treatments including systemic chemotherapy, radiation therapy, surgery, and hormonal therapy, there should be at least 2 weeks of time interval between the last day of the previous treatment and the start of TAGRISSO™, and the remaining toxicity should be ≤ CTCAE grade 1 at the time of starting study treatment (except alopecia and grade 2, prior platinum-therapy related neuropathy) 4. ECOG performance status 0-2 5. Patients in whom T790 mutations are detected in at least one of the samples including tumor tissues, BALF (cell-free DNA), plasma (cell-free DNA), and pleural effusion (cell-free DNA) 6. --- L858R ---

Primary Outcomes

Description: Objective response rate (ORR) including rate of CR and PR on based of RECIST 1.1

Measure: ORR

Time: through study completion (43 months)

Secondary Outcomes

Description: Disease control rate (DCR) including rate of CR, PR and SD on based of RECIST 1.1

Measure: DCR

Time: through study completion (43 months)

Description: Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause.

Measure: PFS

Time: through study completion (43 months)

Measure: T790M postive rate in Plasma cell free DNA

Time: through study completion (43 months)

Measure: T790M postive rate in BALF free DNA

Time: through study completion (43 months)

Measure: T790M postive rate in tissue

Time: through study completion (43 months)

Measure: Concordance rate of T790M positivity between plasma & BALF

Time: through study completion (43 months)

Measure: T790M sensitivity & specificity in Plasma & BALF (gold standard: tissue biopsy)

Time: through study completion (43 months)

Description: AE/SAE assessement on the base of NCI-CTCAE (version 4.03).

Measure: The frequency of occurrence of grade 3 or higher AE/SAEs

Time: through study completion (43 months)

210 Icotinib as Consolidation Therapy After Synchronous or Sequential Chemoradiotherapy in Stage IIIA-IIIB Non-small Cell Lung Cancer With EGFR Sensitive Mutation: A Single Center, Single Arm, Open Label and Prospective Clinical Study

The main purpose of this study is to evaluate the relapse free survival of patients who have EGFR-mutant stage IIIA-IIIB Non-small Cell Lung Cancer and receive Icotinib as consolidation therapy after synchronous or sequential chemoradiotherapy.

NCT03396185
Conditions
  1. EGFR Gene Mutation
  2. Non Small Cell Lung Cancer Stage IIIA
  3. Non Small Cell Lung Cancer Stage IIIB
Interventions
  1. Drug: Icotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The number of participants with treatment-related adverse events as assessed by CTCAE v4.0 would be recorded and calculated after them participating into the study and taking the experimental drug.. Inclusion Criteria: - Unresectable stage IIIA-IIIB Non-small Cell Lung Cancer, histology or cytology confirmed lung adenocarcinoma, pathological specimens with EGFR 19 del and/or 21 L858R gene mutation detected by amplification refractory mutation system method - Before receiving synchronous or sequential chemoradiotherapy, no metastasis detected by head MRI, bone scan, chest enhanced CT scan and the abdominal (including dual adrenal) enhanced CT scan - Only received synchronous or sequential chemoradiotherapy as anti-tumor treatment; after that, chest enhanced CT showed no progressive disease (including Complete Response, Partial Response and Stable Disease ) - Platinum-based chemotherapy regimen, including: vinorelbine, docetaxel, paclitaxel, pemetrexed, etoposide, etc and combination of platinum (including but not limited to cisplatin and carboplatin) - 3DCRT or IMRT radiotherapy technology with a dose of 95% PTV 60-66gy, 2Gy once daily, 5 times weekly, up to 30-33 times - ECOG score 0-1 - Able to enter the group within 4-12 weeks after the completion of synchronous or sequential chemoradiotherapy - Expected survival more than 12 weeks Exclusion Criteria: - Other malignant tumors within five years, except for completely cured cervical carcinoma, basal or squamous cell carcinoma - In addition to synchronous or sequential chemoradiotherapy, ever received other systemic anti-tumor treatment, including chemotherapy or targeted therapy - Any unstable systemic disease, including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, liver, kidney or metabolic disease - Upper vena cava syndrome at baseline - Idiopathic pulmonary fibrosis detected by CT at baseline - Definite neurological or psychiatric disorders, including epilepsy or dementia - Pregnant or lactating women Inclusion Criteria: - Unresectable stage IIIA-IIIB Non-small Cell Lung Cancer, histology or cytology confirmed lung adenocarcinoma, pathological specimens with EGFR 19 del and/or 21 L858R gene mutation detected by amplification refractory mutation system method - Before receiving synchronous or sequential chemoradiotherapy, no metastasis detected by head MRI, bone scan, chest enhanced CT scan and the abdominal (including dual adrenal) enhanced CT scan - Only received synchronous or sequential chemoradiotherapy as anti-tumor treatment; after that, chest enhanced CT showed no progressive disease (including Complete Response, Partial Response and Stable Disease ) - Platinum-based chemotherapy regimen, including: vinorelbine, docetaxel, paclitaxel, pemetrexed, etoposide, etc and combination of platinum (including but not limited to cisplatin and carboplatin) - 3DCRT or IMRT radiotherapy technology with a dose of 95% PTV 60-66gy, 2Gy once daily, 5 times weekly, up to 30-33 times - ECOG score 0-1 - Able to enter the group within 4-12 weeks after the completion of synchronous or sequential chemoradiotherapy - Expected survival more than 12 weeks Exclusion Criteria: - Other malignant tumors within five years, except for completely cured cervical carcinoma, basal or squamous cell carcinoma - In addition to synchronous or sequential chemoradiotherapy, ever received other systemic anti-tumor treatment, including chemotherapy or targeted therapy - Any unstable systemic disease, including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, liver, kidney or metabolic disease - Upper vena cava syndrome at baseline - Idiopathic pulmonary fibrosis detected by CT at baseline - Definite neurological or psychiatric disorders, including epilepsy or dementia - Pregnant or lactating women EGFR Gene Mutation Non Small Cell Lung Cancer Stage IIIA Non Small Cell Lung Cancer Stage IIIB Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single center, single arm, open label and prospective clinical study. --- L858R ---

The number of participants with treatment-related adverse events as assessed by CTCAE v4.0 would be recorded and calculated after them participating into the study and taking the experimental drug.. Inclusion Criteria: - Unresectable stage IIIA-IIIB Non-small Cell Lung Cancer, histology or cytology confirmed lung adenocarcinoma, pathological specimens with EGFR 19 del and/or 21 L858R gene mutation detected by amplification refractory mutation system method - Before receiving synchronous or sequential chemoradiotherapy, no metastasis detected by head MRI, bone scan, chest enhanced CT scan and the abdominal (including dual adrenal) enhanced CT scan - Only received synchronous or sequential chemoradiotherapy as anti-tumor treatment; after that, chest enhanced CT showed no progressive disease (including Complete Response, Partial Response and Stable Disease ) - Platinum-based chemotherapy regimen, including: vinorelbine, docetaxel, paclitaxel, pemetrexed, etoposide, etc and combination of platinum (including but not limited to cisplatin and carboplatin) - 3DCRT or IMRT radiotherapy technology with a dose of 95% PTV 60-66gy, 2Gy once daily, 5 times weekly, up to 30-33 times - ECOG score 0-1 - Able to enter the group within 4-12 weeks after the completion of synchronous or sequential chemoradiotherapy - Expected survival more than 12 weeks Exclusion Criteria: - Other malignant tumors within five years, except for completely cured cervical carcinoma, basal or squamous cell carcinoma - In addition to synchronous or sequential chemoradiotherapy, ever received other systemic anti-tumor treatment, including chemotherapy or targeted therapy - Any unstable systemic disease, including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, liver, kidney or metabolic disease - Upper vena cava syndrome at baseline - Idiopathic pulmonary fibrosis detected by CT at baseline - Definite neurological or psychiatric disorders, including epilepsy or dementia - Pregnant or lactating women Inclusion Criteria: - Unresectable stage IIIA-IIIB Non-small Cell Lung Cancer, histology or cytology confirmed lung adenocarcinoma, pathological specimens with EGFR 19 del and/or 21 L858R gene mutation detected by amplification refractory mutation system method - Before receiving synchronous or sequential chemoradiotherapy, no metastasis detected by head MRI, bone scan, chest enhanced CT scan and the abdominal (including dual adrenal) enhanced CT scan - Only received synchronous or sequential chemoradiotherapy as anti-tumor treatment; after that, chest enhanced CT showed no progressive disease (including Complete Response, Partial Response and Stable Disease ) - Platinum-based chemotherapy regimen, including: vinorelbine, docetaxel, paclitaxel, pemetrexed, etoposide, etc and combination of platinum (including but not limited to cisplatin and carboplatin) - 3DCRT or IMRT radiotherapy technology with a dose of 95% PTV 60-66gy, 2Gy once daily, 5 times weekly, up to 30-33 times - ECOG score 0-1 - Able to enter the group within 4-12 weeks after the completion of synchronous or sequential chemoradiotherapy - Expected survival more than 12 weeks Exclusion Criteria: - Other malignant tumors within five years, except for completely cured cervical carcinoma, basal or squamous cell carcinoma - In addition to synchronous or sequential chemoradiotherapy, ever received other systemic anti-tumor treatment, including chemotherapy or targeted therapy - Any unstable systemic disease, including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, liver, kidney or metabolic disease - Upper vena cava syndrome at baseline - Idiopathic pulmonary fibrosis detected by CT at baseline - Definite neurological or psychiatric disorders, including epilepsy or dementia - Pregnant or lactating women EGFR Gene Mutation Non Small Cell Lung Cancer Stage IIIA Non Small Cell Lung Cancer Stage IIIB Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single center, single arm, open label and prospective clinical study. --- L858R --- --- L858R ---

Primary Outcomes

Description: Relapse Free Survival was defined as the time from randomization to relapse of disease or death from any cause.

Measure: Relapse Free Survival of participants

Time: three years

Secondary Outcomes

Description: Overall survival was defined as the time from participants' randomization to their death due to any cause.

Measure: Overall survival of participants

Time: three years

Description: The number of participants with treatment-related adverse events as assessed by CTCAE v4.0 would be recorded and calculated after them participating into the study and taking the experimental drug.

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: three years

211 Randomized Phase II Trial of Local Consolidation Therapy (LCT) After Osimertinib for Patients With EGFR Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC)

This phase II trial studies how well osimertinib, surgery, and radiation therapy work in treating patients with stage IIIB or IV non-small cell lung cancer with EGFR mutations. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving osimertinib, surgery, and radiation therapy may work better at treating non-small cell lung cancer with EGFR mutations.

NCT03410043
Conditions
  1. EGFR Exon 19 Deletion Mutation
  2. EGFR NP_005219.2:p.L858R
  3. EGFR NP_005219.2:p.T790M
  4. Lung Non-Small Cell Carcinoma
  5. Recurrent Lung Non-Small Cell Carcinoma
  6. Stage IIIB Lung Cancer AJCC v8
  7. Stage IV Lung Cancer AJCC v8
  8. Stage IVA Lung Cancer AJCC v8
  9. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Osimertinib
  2. Radiation: Radiation Therapy
  3. Procedure: Therapeutic Conventional Surgery
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

The association between the types and severity of toxicity and the treatment groups will be evaluated.. Inclusion Criteria: - Histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - Patients must have one of the following: - NSCLC which harbors EGFR exon 19 deletion or L858R mutation. --- L858R ---

In addition, these lesions will be counted towards the total number of metastases, and will also be counted as target lesions Inclusion Criteria: - Histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - Patients must have one of the following: - NSCLC which harbors EGFR exon 19 deletion or L858R mutation. --- L858R ---

Primary Outcomes

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Progression free survival (PFS)

Time: From the start date of osimertinib assessed up to 4 years

Secondary Outcomes

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Overall survival

Time: From the treatment start date assessed up to 4 years

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Time to progression of target lesions

Time: Up to 4 years

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Time to appearance of new metastases

Time: Up to 4 years

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: PFS in oligometastatic subgroup

Time: Up to 4 years

Description: Toxicity data related to the treatments will be summarized by frequency tables. The association between the types and severity of toxicity and the treatment groups will be evaluated.

Measure: Incidence of adverse events

Time: Up to 30 days post treatment

212 An Open Label, Multicenter, Phase II Single-arm Trial of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients With Uncommon Epidermal Growth Factor Receptor Mutations

EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in NSCLC, approximately 10% of EGFR mutation-positive tumors harbor uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18-21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M [11]. In preclinical data, the potency of AZD9291 against uncommon EGFR mutants other than exon 20 insertion mutation was fairly good. Based on the result, in this study, we try to evaluate the efficacy of AZD9291, the potent irreversible inhibitor, in NSCLC patients with harboring uncommon EGFR mutations.

NCT03424759
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in NSCLC, approximately 10% of EGFR mutation-positive tumors harbor uncommon mutations. --- L858R ---

Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M [11]. --- L858R ---

Inclusion Criteria: - Histologically confirmed metastatic or recurrent stage IV NSCLC with activating EGFR mutation other than deletion in exon 19, L858R, T790M and insertion in exon 20 - metastatic or recurrent NSCLC - Be 19years of age on day of signing informed consent - ECOG performance status of 0 to 2 - At least one measurable lesion by RECIST 1.1(The part of radiation treatment in the palliative setting is excluded.) --- L858R ---

- Untreated asymptomatic brain metastasis or symptomatic brain metastasis treated with local treatment such as operation, whole brain radiotherapy, or gamma-knife surgery - At least 2 weeks later after whole brain radiotherapy or at least 4 weeks later after palliative thoracic radiotherapy - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; Hb > 9.0g/dL; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 2.5 ULN if no demonstrable liver metastases or < 5 UNL in the presence of liver metastases, CCr ≥ 50mL/min - Written informed consent form Exclusion Criteria: - Prior treatment with EGFR TKI - Major surgery undertaken less than 4 weeks before the study - Localized palliative radiotherapy unless completed more than 2 weeks before the study - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Pregnant or nursing women (Women of reproductive potential have to agree to use an adequate contraceptive method) - Uncontrolled symptomatic brain metastasis - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, or well-treated thyroid cancer - Concomitant use of CYP3A4 inducers/inhibitors - Prolonged QT interval in ECG (QTc >450 msec) - Prior history of interstitial lung disease Inclusion Criteria: - Histologically confirmed metastatic or recurrent stage IV NSCLC with activating EGFR mutation other than deletion in exon 19, L858R, T790M and insertion in exon 20 - metastatic or recurrent NSCLC - Be 19years of age on day of signing informed consent - ECOG performance status of 0 to 2 - At least one measurable lesion by RECIST 1.1(The part of radiation treatment in the palliative setting is excluded.) --- L858R ---

Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M (9). --- L858R ---

Primary Outcomes

Description: 30%

Measure: Objective response rate

Time: through study completion, an average of 2 years

213 A Phase II Study to Evaluate Neoadjuvant Osimertinib Therapy in Patients With Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer

This phase II trial studies how well osimertinib works in treating participants with stage I-IIIA Epithelial Growth Factor Receptor (EGFR) -mutant non-small cell lung cancer before surgery. Osimertinib may stop the growth of tumor cells by blocking mutant EGFR signaling in cancer cells.

NCT03433469
Conditions
  1. Stage I Non-Small Cell Lung Cancer
  2. Stage IA Non-Small Cell Lung Cancer
  3. Stage IB Non-Small Cell Lung Cancer
  4. Stage II Non-Small Cell Lung Cancer
  5. Stage IIA Non-Small Cell Lung Cancer
  6. Stage IIB Non-Small Cell Lung Cancer
  7. Stage IIIA Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Procedure: Therapeutic Conventional Surgery
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Males and females >=18 years of age - Histologically or cytologically confirmed non-small cell lung cancer (NSCLC), performed on a biopsy that occurred within the last 90 days - Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Clinical Laboratory Clinical Laboratory Improvement Amendments (CLIA)-approved test - Positron emission tomography (PET)-computed tomography (CT) within the last 60 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required) - Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 60 days showing no evidence of metastatic disease - Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery certified surgeon - The patient must have a tumor size >=1 centimeter (cm) in its longest diameter. --- T790M --- --- L858R ---

malabsorption syndrome, history of biliary tract disease), including refractory nausea or vomiting, or chronic GI disease which may affect absorption or tolerance to oral medications - History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - Participation in another clinical study with an investigational product during the last 2 months or within five half-lives of the compound, whichever is longer - Uncontrolled medical, psychological, familial, sociological, or geographical conditions that interfere with the patient?s safety, ability to provide informed consent, or ability to comply with the protocol Inclusion Criteria: - Males and females >=18 years of age - Histologically or cytologically confirmed non-small cell lung cancer (NSCLC), performed on a biopsy that occurred within the last 90 days - Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Clinical Laboratory Clinical Laboratory Improvement Amendments (CLIA)-approved test - Positron emission tomography (PET)-computed tomography (CT) within the last 60 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required) - Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 60 days showing no evidence of metastatic disease - Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery certified surgeon - The patient must have a tumor size >=1 centimeter (cm) in its longest diameter. --- T790M --- --- L858R ---

Primary Outcomes

Description: Tumors that exhibit =< 10% viable tumor will meet the criteria for a major pathological response. MPR rate will be determined in patients who receive at least one dose of study drug and become ineligible for surgery either because of disease progression or adverse event will be deemed not to have achieved MPR. The major pathological response rate will be reported with 95% confidence intervals.

Measure: Major pathological response rate (MPR)

Time: Up to 1 year

Secondary Outcomes

Description: The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and by investigator's assessment will be determined from the time of treatment until surgery. The frequency and percentages of patients with a best ORR of CR, PR, SD, or PD will be determined. The ORR will be reported with 95% confidence intervals.

Measure: Objective Response Rate (ORR)

Time: Up to 70 days

Description: DFS will be calculated as 1+ the number of days from date of surgical resection to documented radiographic relapse/progression or death due to any cause over a period of 60 months. The Kaplan-Meier analysis will be used to calculate the median DFS with 95% confidence interval.

Measure: Mean Disease-free survival (DFS)

Time: Up to 5 years

Description: DFS will be calculated as 1+ the number of days from date of surgical resection to documented radiographic relapse/progression or death due to any cause over a period of 60 months. The 5-year DFS rate will be calculated as the percentage of patients who are disease free at 5 years. This will be calculated using the Kaplan-Meier method

Measure: Disease-free survival rate (DFS)

Time: Up to 5 years

Description: 5-year OS rate will be calculated using the Kaplan-Meier method . OS will be defined as the 1+ the number of days from surgical resection to death due to any cause over a period of 60 months. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.

Measure: Overall survival (OS)

Time: Up to 5 years

Description: DpR will be defined as the percentage change in tumor burden by RECIST criteria at best response versus baseline imaging. DpR will be summarized using descriptive statistics and correlated with patient outcomes using hazard ratios via the Cox proportional hazards model.

Measure: Depth of response (DpR)

Time: Up to 1 year

Description: The pCR is defined as absence of (0%) viable tumor present histologically in the resected tumor specimen

Measure: Pathologic complete response rate (pCR)

Time: Up to 1 year

Description: Treatment-emergent adverse events will be classified according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Measure: Number of Treatment-emergent adverse events (AEs)

Time: Up to 1 year

Description: Rate of conversion from operable to non-operative will be recorded as rate of patients initially assessed as surgically resectable, who are subsequently unable to undergo surgical resection due to either treatment-related adverse events (AEs) or disease progression.

Measure: Percentage of participants unable to undergo surgical resection

Time: Up to 70 days

Description: Rate of surgical complications occurring prior to the end of treatment visit will be reported

Measure: Percentage of surgical complications

Time: Up to 1 year

214 A Single Arm Phase II Study Osimertinib in Patients With Stage 4 Non-small Cell Lung Cancer With Uncommon EGFR Mutations

This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. Patients on the study will not have had previous tyrosine kinase inhibitor (TKI) treatment.

NCT03434418
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Malabsorption syndrome, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib - Detection of concurrent EGFR mutation with exon 20 T790M, exon 19 deletion, exon 21 L858R mutation or exon 20 insertion. --- T790M --- --- L858R ---

Primary Outcomes

Description: RECIST 1.1 will be used to measure confirmed partial or complete responses to the study drug.

Measure: Objective response rate as assessed by the investigator using Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name)

Time: Up to 3 years

Secondary Outcomes

Description: Progression will be defined as time from starting study therapy to disease progression or death (whichever occurs first)

Measure: Progression free survival as measured by Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name) as assessed by the investigator.

Time: Up to 5 years

Description: Evaluation of safety using the National Cancer Institute (NCI) CTCAE version 4.03

Measure: AEs as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Time: Up to 3 years

Description: Overall survival as defined as time from starting study therapy until death from any causes.

Measure: Overall survival as noted by follow-up via composite of telephone or medical record review.

Time: Up to 5 years

215 A Phase 1/2 Open Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of ZN-e4 (KP-673) in Patients With Advanced Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor (EGFR) Mutations

This is a Phase 1/2, open-label, multicenter, sequential dose-escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ZN-e4 administered orally in subjects with advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations who have progressed while on treatment with an EGFR tyrosine kinase inhibitor (TKI) agent (other lines of treatment are allowed, except for other epidermal growth factor receptor inhibitors [EGFRis]) for Phase 1; and for Phase 2, subjects who have T790M+ and are osimertinib naïve (Cohort 1), and also those who have not been treated with an EGFR Inhibitor (EGFRi) (Cohort2).

NCT03446417
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: ZN-e4
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Phase 1 only: Confirmation that the tumor harbors an EGFR mutation known to be associated with aberrations that are amenable to EGFRi therapy including but not limited to: G719X, exon 19 deletion, exon 21 L858R, and L861Q. --- L858R ---

- Measurable disease meeting the criteria specified by RECIST v1.1 - Phase 2, Cohort 1 only: Subjects must have confirmation of tumor T790M mutation status (confirmed positive) and are osimertinib naïve - Phase 2, Cohort 2 only: EGFR aberrations that are amenable to EGFRi therapy, including but not limited to: G719X, exon 19 deletion, exon 21 L858R, and L861Q, and be EGFRi naïve EXCLUSION CRITERIA - Subjects who have received only neoadjuvant or adjuvant therapy for NSCLC. --- T790M --- --- L858R ---

Primary Outcomes

Measure: Observed dose limiting toxicities

Time: 1 Cycle (21 days)

Secondary Outcomes

Measure: Safety and tolerability as measured by incidence of treatment emergent adverse events

Time: Through study completion, approximately 2 years

216 A Randomized, Controlled, Open-label, Prospective Trial of S-1 Plus Gefitinib Versus Gefitinib Monotherapy for First-line Treatment of Advanced Non-squamous Non-small Cell Lung Cancer With EGFR-sensitive Mutation

To investigate the survival benefit of first-line therapy for patients with EGFR-sensitive mutation-positive advanced non-squamous non-small cell lung cancer treated with S-1plus gefitinib versus gefitinib monotherapy

NCT03457337
Conditions
  1. Advanced NSCLC With EGFR Mutation
Interventions
  1. Drug: S-1 plus Gefitinib
  2. Drug: Gefitinib
MeSH:Hypersensitivity
HPO:Allergy

4. exon 19 deletion or exon 21 L858R for EGFR mutation. --- L858R ---

Primary Outcomes

Description: From start of anti-cancer therapy until progression or death.To evaluate the disease free survival of gefitinib combined with S-1 and gefitinib in patients with Pathological stage IIIc-IV NSCLC harbouring sensitive mutations of EGFR. Progression free survival (PFS)- defined as the time from initial medication to the first documented disease progression or death, whichever occurs first.

Measure: Progression free survival(PFS)

Time: 2 years

Secondary Outcomes

Description: To evaluate the overall survivalof gefitinib combined with S-1 and gefitinib in patients with Pathological stage IIIc-IV NSCLC harbouring sensitive mutations of EGFR in the 3 years since treatment begain

Measure: Overall survival(OS)

Time: 3 years

Description: To compare disease control rate of the two arms from start of anti-cancer therapy until progression

Measure: Disease control rate

Time: 2 years

Description: To compare objective response rate of the two arms from start of anti-cancer therapy until progression

Measure: Objective response rate(ORR)

Time: 2 years

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of radiotherapy.

Measure: Number of Participants with Adverse Events

Time: 3 years

Other Outcomes

Description: Quality of Life Questionnaire(such as QLQ-C30 and QLQ-LC13) evaluated since treatment began.At the end of the trial, the differences between the two indicators were compared with Mixed-effects model repeated measures (MMRM), where the baseline was scored as a covariant and the treatment group as a fixed variable. In addition, the baseline values of the two scores, the value of each visit, and the change value of the baseline were statistically described.

Measure: Assessment of Health-related quality of life

Time: 3 years

217 An Open-label PET Study to Determine Brain Exposure of Osimertinib After IV Microdose Administration of [11C]Osimertinib and Therapeutic Oral Doses of Osimertinib to Patients With EGFR Mutated NSCLC With Brain Metastases

This is an open-label, single centre, Phase I study to determine the brain exposure of [11C]osimertinib in patients with EGFRm NSCLC with brain metastases.

NCT03463525
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: [11C]osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or T790M EGFR resistance mutation as assessed by local laboratory/or central laboratory via tissue/cytology or in plasma. --- L858R ---

Primary Outcomes

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 1

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 2

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 29

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Secondary Outcomes

Description: Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax)

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.

Measure: Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Other Outcomes

Description: Collection and assessment of adverse events graded using CTCAE (version 4.03).

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with IV [11C]osimertinib administration

Time: From study Day 1 and until 30 days after the study drug is discontinued.

Description: Collection and assessment of adverse events using CTCAE (version 4.03)

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with continuous oral osimertinib

Time: From study Day 1 and until 30 days after the study drug is discontinued.

218 A Randomized Phase II Trial of Nivolumab, Cabozantinib Plus Nivolumab, and Cabozantinib Plus Nivolumab Plus Ipilimumab in Patients With Previously Treated Non-Squamous NSCLC

This partially randomized phase II trial studies how well nivolumab, cabozantinib s-malate, and ipilimumab work in treating patients with stage IV non-small cell lung cancer that has come back. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving nivolumab, cabozantinib s-malate, and ipilimumab may work better than cabozantinib s-malate alone in treating patients with stage IV non-small cell lung cancer.

NCT03468985
Conditions
  1. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  3. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Cabozantinib
  2. Drug: Cabozantinib S-malate
  3. Biological: Ipilimumab
  4. Other: Laboratory Biomarker Analysis
  5. Biological: Nivolumab
  6. Other: Questionnaire Administration
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.. Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R ---

- Serious non-healing wound/ulcer/bone fracture within 28 days prior to registration - History of organ transplant - Concurrent symptomatic untreated hypothyroidism within 7 days prior to registration - History of surgery as follows: - Major surgery (as an example, surgery requiring anesthesia and a > 24 hour hospital stay) within 3 months prior to registration, with wound healing at least 28 days prior to registration - Minor surgery within 28 days prior to registration with complete wound healing at least 10 days prior to registration - Minor procedures within 7 days prior to registration such as thoracentesis, paracentesis, or 18 g or smaller needle biopsy of tumor - Patients with clinically relevant ongoing complications from prior surgery are not eligible - Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration - Patients must be able to swallow tablets - No currently active other malignancies which require systemic treatment - No patients that have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - No patients with known active autoimmune disease or known history of autoimmune disease for which recurrence may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, autoimmune hepatitis; patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including type I diabetes mellitus or thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - No ongoing major illness or psychosocial issues that would limit compliance with the protocol - Women must not be pregnant or breast-feeding due to contraindications with the study agents - All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy - A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) - Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use an accepted and effective method of contraception or abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP - Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral therapy are excluded because there are no safety data with the combination of antiretroviral therapy and cabozantinib or ipilimumab or nivolumab with ipilimumab - Patients with known chronic active hepatitis B (defined as a positive hepatitis B surface antigen and/or hepatitis B viral load in the last Inclusion Criteria: - ELIGIBILITY CRITERIA FOR STEP 0 - Patients with tumors with the following molecular alterations must submit testing results via Medidata Rave to determine eligibility to Arm T; the study chair, co-chair, biology co-chair, or a delegate must review the molecular testing and agree that the testing meets one of the molecular eligibility criteria below: - ROS1 gene rearrangement by fluorescence in situ hybridization (FISH) or deoxyribonucleic acid (DNA) analysis (may have progressed on prior crizotinib therapy) - MET exon 14 splice mutations on DNA analysis (may have progressed on prior crizotinib therapy) - MET high amplification by FISH or DNA analysis or other MET mutations predicted to be sensitive to MET inhibitor (no prior targeted therapy allowed) - RET gene rearrangement by FISH or DNA analysis (no prior targeted therapy allowed) - Institutions will be notified of the patient's eligibility status for Arm T within two (2) business days of submission of the molecular testing reports - If patients do not have tumors with the above molecular alterations noted proceed directly to step 1 - ELIGIBILITY CRITERIA FOR STEP 1 - For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports - Pathologically confirmed non-squamous non-small cell lung carcinoma (NSCLC) - Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th edition of the lung cancer tumor, node, and metastasis (TNM) classification system - Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS] are eligible); mixed tumors will be categorized by the predominant cell type; if small cell elements are present the patient is ineligible - Tumors must be tested and known negative for EGFR tyrosine kinase inhibitor (TKI) sensitizing mutations (EGFR exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods; negative circulating tumor DNA results alone are not acceptable; prior testing for tumor PD-L1 status is not required - Patients must have progressed radiographically following first line platinum-based chemotherapy, no additional lines of therapy are permitted - NOTE: Prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy - Exception for targeted therapy sub-study (Arm T): At least one line of prior chemotherapy or targeted therapy is required, but there is no limit on number of prior treatments - Patients must have measurable disease as defined by RECIST v. 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - No prior anti-MET therapy such as crizotinib or cabozantinib, or PD-1/PD-L1 immune checkpoint inhibitor therapy (such as nivolumab, pembrolizumab, atezolizumab) or CTLA4 inhibitor therapy (such as ipilimumab); no prior allergic reaction to small molecule tyrosine kinase inhibitors or monoclonal antibodies - Exception for targeted therapy sub-study (Arm T): Prior crizotinib may be allowed depending on the gene alteration - Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the following times prior to registration: - Chemotherapy/ targeted oral therapy administered in a daily or weekly schedule must be completed >= 1 week prior to registration; - Any chemotherapy administered in an every 2 week or greater schedule must be completed >= 2 weeks prior to registration - Additionally, patients should be recovered to equal to or less than grade 1 toxicities related to any prior treatment, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy - No prior radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks prior to registration - Patients with no known brain metastasis must have baseline brain imaging within 12 weeks prior to study registration not demonstrating brain metastases OR - Patients with known brain metastases must have baseline brain imaging within 4 weeks prior to study registration and meet all of the following criteria: - Have completed treatment to all symptomatic brain metastases (with whole brain radiation or radiosurgery) >= 4 weeks prior to registration, or have undergone complete neurosurgical resection >= 3 months prior to registration - Be clinically stable from brain metastases at time of screening, if no treatment was administered - Known leptomeningeal disease is not allowed - Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - NOTE: Participants with impaired decision-making capacity (IDMC) should not be allowed to participate in this study due to its complexity - Patients must have anticipated life expectancy greater than 3 months - Absolute neutrophil count >= 1,500/mm^3 (within 2 weeks prior to registration) - Platelets >= 100,000/mm^3 (within 2 weeks prior to registration) - Hemoglobin >= 9 g/dL (within 2 weeks prior to registration) - Subject has prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) test =< 1.3 x the laboratory upper limit of normal (ULN) (within 2 weeks prior to registration) - Total bilirubin =< 1.5 x ULN (within 2 weeks prior to registration) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN (within 2 weeks prior to registration) - Serum albumin >= 2.8 g/dL (within 2 weeks prior to registration) - Serum calcium (absolute or albumin corrected), magnesium and potassium >= lower limit of normal (LLN) (within 2 weeks prior to registration) - NOTE: serum calcium, magnesium and potassium can be replaced if values are below LLN - Creatinine =< 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 --- L858R ---

Primary Outcomes

Description: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparison of PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Other comparisons of groups will be made using the logrank test and Cox modeling.

Measure: Progression-free survival (PFS)

Time: From randomization to documented disease progression or death from any cause, whichever occurs first, assessed up to 5 years

Secondary Outcomes

Description: Will be estimated using the Kaplan-Meier method and Cox proportional hazards models will be used to estimate the treatment hazard ratios.

Measure: Overall survival

Time: From randomization to death from any cause, assessed up to 5 years

Description: According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response and partial response) will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Best objective response evaluated

Time: Up to 5 years

Description: Evaluated according to Common Terminology Criteria for Adverse Events version 5 criteria. Toxicity will be compared using Fischer's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Incidence of toxicity

Time: Up to 5 years

Other Outcomes

Description: As measured by RECIST 1.1 criteria.

Measure: Time to tumor response

Time: Up to 5 years

Measure: Comparison of RECIST 1.1 imaging response assessment measurements

Time: Up to 5 years

Description: A combined analysis of the data from the selected Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN) trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco on provider-reported cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose modifications

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco on patient-reported physical symptoms and psychological symptoms

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Assessment of quitting behaviors, behavioral counseling/support and cessation medication utilization

Time: Up to 5 years

Description: A combined analysis of the data from the selected ECOG-ACRIN trials is planned. Data collected from the tobacco use assessment in each parent study will not be analyzed and reported in the clinical study report.

Measure: Effects of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit

Time: Up to 5 years

219 A Randomized Phase 3 Trial Comparing Continuation Nivolumab-Ipilimumab Doublet Immunotherapy Until Progression Versus Observation in Treatment-naive Patients With PDL1-positive Stage IV Non-Small Cell Lung Cancer (NSCLC) After Nivolumab-Ipilimumab Induction Treatment

Non Small Cell lung cancer (NSCLC) remains the first cause of death by cancer in the World. For the patients presenting a NSCLC stage IV, the median of survival is about 15 months today. The chemotherapy with platinum is the standard treatment for these patients but immunotherapy showed these efficacy in 1st line for patients PD-L1 positive. On the other hand, the duration of treatment by immunotherapy is not clear. Indeed, prolonged responses and long survivals have been described in patients having interrupted the treatment. In the melanoma, a treatment of 6 months of ipilimumab demonstrated its efficacy. The objective of the study is to demonstrate that a treatment of 6 months followed by an observation (stop and go) is not less effective than a treatment given until progression or toxicity. This strategy would allow to decrease the accumulated toxicities, to improve the quality of life of the patients and to decrease the costs.

NCT03469960
Conditions
  1. Non-Small Cell Lung Cancer Metastatic
Interventions
  1. Drug: Ipilimumab
  2. Drug: Nivolumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: 1. Small cell lung cancer or tumors with mixt histology including a SCLC component 2. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18) or HER exon 20 insertion (either tissue or plasma cfDNA mutation). --- L858R ---

Primary Outcomes

Description: Time between the date of randomization and the first date of documented progression, as determined by BICR (Blinded Independent Central Review), or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS1)

Time: 24 months after randomization of the last subject

Secondary Outcomes

Description: Time between the start date of the second line and the second date of documented progression, as determined by BICR, or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS2)

Time: 24 months after randomization of the last subject

Description: Time until definitive deterioration (TUDD) from the randomization time in the experimental arm B.

Measure: Quality of life (QoL)

Time: 24 months after randomization of the last subject

Measure: Overall survival (OS)

Time: 6, 12 and 18 months after randomization

Description: PD-L1-stained % of tumor cells will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (PD-L1)

Time: 6 months

Description: PD-L1 H-score will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (PD-L1 H score)

Time: 6 months

Description: CD3/CD8 tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (CD3/CD8)

Time: 6 months

Description: neutrophil tumor infiltration will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (neutrophil)

Time: 6 months

Description: plasma concentration of different cytokines at baseline or at the randomization point, will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (cytokines)

Time: 6 months

Description: plasma concentration of different chemokines at baseline or at the randomization point, will be associated to the rate of disease control patients at 6 months, PFS1, PFS2 and OS

Measure: Biological correlative exploratory studies (chemokines)

Time: 6 months

220 An Open-label Phase II Trial of Gefitinib and Berberine in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 11 months when treated with gefitinib. Combination of gefitinib and berberine could improve efficacy in lung cancer with EGFR mutation in vivo and vitro. The investigators hypothesize that progression-free survival could be improved by combination of gefitinib and berberine.

NCT03486496
Conditions
  1. Lung Adenocarcinoma
  2. EGFR Mutation
Interventions
  1. Drug: gefitinib
  2. Drug: Berberine
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Gefitinib and Berberine in the First-line Treatment of Lung Adenocarcinoma With EGFR Mutation Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 11 months when treated with gefitinib. --- L858R ---

- Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R) Exclusion Criteria: - Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. --- L858R ---

Primary Outcomes

Description: Time from the date of enrolment to discontinuation of treatment for any reason (including progression of disease, treatment toxicity, refusal and death)

Measure: Progression free survival

Time: Within 6 months of the last visit of last patient, approximately 30 months after inclusion of first patient

Secondary Outcomes

Description: Best overall response (complete remission or partial remission) across all assessment time-points according to RECIST Criteria 1.1, during the period from enrolment to termination of trial treatment.

Measure: Objective response

Time: through study completion,an average of three years

Description: Adverse events graded according to NCI CTCAE V4.

Measure: safety

Time: Within 6 months of the last visit of last patient, approximately 30 months after inclusion of first patient

221 A Randomised Phase II Trial of Osimertinib With or Without Stereotactic Radiosurgery for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases

20-40% of patients with NSCLC will develop brain metastases at some point during their course of disease. Osimertinib has demonstrated intracranial activity in EFGR mutated NSCLC with leptomeningeal disease in the phase 1 BLOOM study. Stereotactic radiosurgery (SRS) is one of the standard local treatment for patients with limited number of brain metastases. Currently, it is unclear whether adding SRS to Osimertinib will result in superior intracranial disease control in patients with EGFR mutated NSCLC with brain metastases diagnosed de novo or developed while on first line EGFR tyrosine kinase inhibitors (TKIs) such as Erlotinib and Gefinitib. The aim of this study is to compare the effects of Osimertinib alone versus SRS plus Osimertinib on intra-cranial disease control in EGFR mutated NSCLC with brain metastases diagnosed or developed while on first line EGFR tyrosine kinase inhibitors.

NCT03497767
Conditions
  1. Metastatic Non Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Radiation: Stereotactic Radiosurgery (SRS)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice. --- L858R ---

Primary Outcomes

Description: To assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib by assessment of intracranial progression free survival at 12 months.

Measure: Intracranial progression free survival at 12 months

Time: 12 months post randomisation

Secondary Outcomes

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on use of salvage whole-brain radiotherapy (WBRT) +/- neurosurgery.

Measure: Use of salvage whole-brain radiotherapy (WBRT)

Time: 18 months post randomisation

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on local brain failure.

Measure: Local brain failure

Time: 18 months post randomisation

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on distant brain failure.

Measure: Distant brain failure

Time: 18 months post randomisation

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on extra-cranial progression.

Measure: Extra-cranial progression

Time: 18 months post randomisation

Description: To further assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib in terms of overall survival.

Measure: Overall Survival

Time: 18 months post randomisation

222 A Phase I/II Study to Assess the Safety,Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Patients With Locally Advanced or Metastatic T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed Following Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

ASK120067 Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT03502850
Conditions
  1. Locally Advanced or Metastatic NSCLC
Interventions
  1. Drug: ASK120067
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R ---

- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: - Patients of either gender, aged from 18 years older to 70. - Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC - Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including at least one of G719X, exon 19 deletion, L858R, L861Q mutation) - Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI e.g. --- L858R ---

Primary Outcomes

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Secondary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Evaluation of Disease control rate assessed by RECIST 1.1

Measure: Disease control rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: defined as the time from date of first dose until date of death due to any cause

Measure: Overall survival

Time: Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Collect plasma concentrations of ASK120067 and 1 metabolites following single dose at designated time points of Day 1 to figure out Cmax

Measure: Maximum Plasma Concentration [Cmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out tmax

Measure: Peak Plasma Time [tmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day1 to figure out AUC

Measure: Area under the plasma concentration versus time curve (AUC) of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out terminal rate constant

Measure: Terminal rate constant of single dose single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out clearance

Measure: Clearance of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out half life

Measure: Half life of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of f ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out volume of distribution

Measure: Volume of distribution of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out mean resistance time

Measure: Mean resistance time of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Cmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Tmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state tmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Cmin of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: AUC of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state AUC of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Clearance of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state clearance of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Accumulation ratio of ASK120067 and 1 metabolite following multiple doses

Measure: Accumulation ratio of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Time dependency of ASK120067 and 1 metabolite following multiple doses

Measure: Time dependency of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

223 Toripalimab Combined With Pemetrexed Plus Carboplatin for Treatment of Recurrent or Advanced Non-small-cell Lung Cancer With EGFR-mutation Positive and T790M Negative After Progression on EGFR-TKI Treatment:a Multi-center, Single Arm Phase II Study

JS001 combined with pemetrexed plus carboplatin for treatment of recurrent or advanced non-small-cell lung cancer with EGFR-mutation positive and T790M negative after progression on EGFR-TKI treatment:a multi-center, single arm phase II study

NCT03513666
Conditions
  1. NSCLC
Interventions
  1. Combination Product: Drug intervention
MeSH:Disease Progression

Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; NSCLC Disease Progression null --- L858R ---

Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; NSCLC Disease Progression null --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Description: The primary endpoint is the antitumor activities in this study

Measure: Objective response rate (ORR)

Time: 12 weeks

Secondary Outcomes

Description: Progression free survival (PFS)

Measure: PFS

Time: 18 months

Description: Overall survival (OS)

Measure: OS

Time: 18 months

Description: Duration of response (DOR)

Measure: DOR

Time: 18 months

224 A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)

The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has superior efficacy compared to saline placebo plus chemotherapy in terms of: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This study will be considered to have met its success criteria if the combination of pembrolizumab plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS.

NCT03515837
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Biological: pembrolizumab
  2. Drug: pemetrexed
  3. Drug: carboplatin
  4. Drug: cisplatin
  5. Drug: saline solution
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PFS will be assessed by blinded independent central review (BICR) using RECIST 1.1. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions is also considered PD. The PFS for participants will be presented.

Measure: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Time: Up to approximately 32 months

Description: OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis will be censored at the date of the last follow-up. The OS of participants will be presented.

Measure: Overall Survival (OS)

Time: Up to approximately 59 months

Secondary Outcomes

Description: ORR is defined as the percentage of participants in the analysis population who experience a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR for participants will be presented.

Measure: Objective Response Rate (ORR) Per RECIST 1.1

Time: Up to approximately 32 months

Description: For participants who experience a response of CR or PR, DOR is defined as the time from the earliest date of qualifying response until earliest date of PD or death from any cause, whichever comes first. DOR will be assessed per RECIST 1.1 based on BICR. The DOR of participants who experience a CR or PR will be presented.

Measure: Duration of Response (DOR) Per RECIST 1.1

Time: Up to approximately 32 months

Description: The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Global Health Status, participants are asked "How would you rate your overall health during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Global Health Status will be presented.

Measure: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Item (QLQ-C30) Global Health Status (Item 29) Scale Score

Time: Baseline and Week 12, Week 27

Description: TTD is the time from baseline to first onset of 10 points or more decrease from baseline with confirmation by the subsequent visit of 10 points or more deterioration from baseline in the composite endpoint of cough [EORTC QLQ-Lung Cancer Module 13 (LC13) Item 1; How much did you cough?], chest pain [EORTC QLQ-LC13 Item 10; Have you had pain in your chest?], or dyspnea [EORTC QLQ-C30 Item 8; Were you short of breath?]. Individual responses are given on a 4-point scale (1=Not at all; 4=Very much), with a lower score indicating a better outcome. The time to true deterioration in the composite endpoint of cough, chest pain or dyspnea will be presented.

Measure: Time to True Deterioration (TTD) in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea

Time: Up to approximately 32 months

Description: An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experience an AE will be presented.

Measure: Adverse Events (AEs)

Time: Up to 90 days after last dose of study treatment (Up to approximately 42 months)

Description: The number of participants who discontinue study treatment due to an AE will be presented.

Measure: Study Treatment Discontinuations Due to AEs

Time: Up to approximately 39 months

Description: The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Quality of Life, participants are asked "How would you rate your overall quality of life during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Quality of Life will be presented.

Measure: Change from Baseline in EORTC-QLQ-C30 Quality of Life (Item 30) Scale Score

Time: Baseline and Week 12, Week 27

225 An Observational, Multi-centre Study on EGFR T790M Mutation Testing Practices and Outcomes Conducted Among Locally Advanced/Metastatic NSCLC Patients Who Progressed on Previous EGFR Tyrosine-kinase Inhibitor (TKI) Therapy in Hong Kong

To describe the T790M mutation status of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment in a real-world setting.

NCT03519958
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Diagnostic Test: Plasma-tissue testing
MeSH:Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R ---

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R --- --- T790M --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Based on the plasma-tissue testing algorithm in NSCLC patients who progressed on previous EGFR TKI therapy

Measure: EGFR T790M mutation prevalance

Time: 3 years

Secondary Outcomes

Description: Proportion of study subjects who have a valid tissue/cytology T790M testing result after receiving a negative plasma test result for the T790M mutation

Measure: Proportion of Valid Tissue T790M Testing Result

Time: 3 years

Description: Proportions of study subjects who are T790M plasma-negative

Measure: T790M Plasma Outcome

Time: 3 years

Description: Proportion of study subjects who are T790M plasma-negative but T790M tissue/cytology-positive

Measure: False Negative Proportation

Time: 3 years

Description: reasons given for not performing re-biopsy and tissue/cytology testing after obtaining a negative plasma test result

Measure: Reasons for not performing re-biopsy

Time: 3 years

Description: Demographics of T790M-positive subjects and T790M-negative subjects

Measure: Demographics

Time: Baseline

Description: Disease characteristics of T790M-positive subjects and T790M-negative subjects

Measure: Disease Characteristics

Time: 3 years

Description: Number of particapants with complications assoicated with tissue/cytology re-biopsy

Measure: Number of particapants with complications assoicated with re-biopsy

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are T790M plasma-positive

Measure: Clinical Outcomes in T790M plasma-positive subejects

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are urine-positive

Measure: Clinical Outcomes in urine-positive

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are tissue/cytology-positive

Measure: Clinical Outcomes in tissue/cytology-positive

Time: 3 years

Other Outcomes

Description: To analyze the concordance of T790M mutation status as determined by urine, plasma, and tissue/cytology T790M testing

Measure: Concordance

Time: 3 years

226 A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study of Osimertinib as Maintenance Therapy in Patients With Locally Advanced, Unresectable EGFR Mutation-positive Non-Small Cell Lung Cancer (Stage III) Whose Disease Has Not Progressed Following Definitive Platinum-based Chemoradiation Therapy (LAURA).

A global study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable Epidermal Growth Factor Receptor Mutation Positive non-small cell lung cancer

NCT03521154
Conditions
  1. Non Small Cell Lung Cancer (Stage III)
Interventions
  1. Drug: Osimertinib 80mg/40mg
  2. Drug: Placebo Osimertinib 80mg/40mg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PFS in patients with EGFR Ex19del or L858R mutation. --- L858R ---

PFS in patients with EGFR mutations Ex19del or L858R detectable in plasma-derived ctDNA. --- L858R ---

3. The tumor harbours one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by cobas® EGFR Mutation Test v2 (Roche Diagnostics) in a CLIA certified (USA sites) or an accredited local laboratory (sites outside of the USA) or by central testing. --- L858R ---

Contraindication to MRI, including but not limited to, claustrophobia, pace makers, metal implants, intracranial surgical clips and metal foreign bodies Non Small Cell Lung Cancer (Stage III) Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase 3 double-blind, randomized, placebo-controlled, study to assess the efficacy and safety of osimertinib following chemoradiation in patients with stage III unresectable EGFR mutation-positive NSCLC, including the most common EGFR sensitising mutations (Ex19Del and L858R), either alone or in combination with other EGFR mutations. --- L858R ---

Primary Outcomes

Description: Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression, based on blinded independent central review assessment according to RECIST 1.1

Measure: Progression-free survival (PFS)

Time: Approximately 13 months

Secondary Outcomes

Description: Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.' based on blinded independent central review assessment according to RECIST 1.1

Measure: PFS in patients with EGFR Ex19del or L858R mutation

Time: Approximately 13 months

Description: Defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.' based on blinded independent central review assessment according to RECIST 1.1

Measure: PFS in patients with EGFR mutations Ex19del or L858R detectable in plasma-derived ctDNA

Time: Approximately 13 months

Description: Defined as earlier event of CNS progression or death based on blinded independent central review assessment according to RECIST 1.1

Measure: Time to CNS PFS

Time: Approximately 13 months

Description: Defined as the time from randomization until death from any cause

Measure: Overall survival (OS)

Time: Approximately 45 months

Description: Defined as the number (%) of patients with measurable disease with at least 1 visit response of CR (Complete response) or PR (Partial response) based on blinded independent central review assessment according to RECIST 1.1

Measure: Objective response rate (ORR)

Time: Approximately 13 months

Description: Defined as the time from the date of first documented response (i.e., subsequently confirmed) until the date of documented progression or death in the absence of disease progression based on blinded independent central review assessment according to RECIST 1.1

Measure: Duration of response (DoR)

Time: Approximately 13 months

Description: Defined as Disease control rate is defined as the percentage of subjects who have a best overall response of CR or PR or SD based on blinded independent central review assessment according to RECIST 1.1

Measure: Disease control rate (DCR)

Time: Approximately 13 months

Description: Defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions or progression of non-target lesions compared to baseline based on blinded independent central review assessment according to RECIST 1.1

Measure: Tumor shrinkage

Time: Approximately 13 months

Description: Defined as the time from the date of randomization until the first date of distant metastasis or date of death in the absence of distant metastasis based on blinded independent central review assessment according to RECIST 1.1

Measure: Time to death or distant metastases (TTDM)

Time: Approximately 13 months

Description: Defined as the time from randomization to the earlier of the date of study treatment discontinuation (regardless of the reason for study treatment discontinuation) or death

Measure: Time to treatment discontinuation

Time: Approximately 13 months

Description: Time from randomisation to second progression (PFS2) is defined as the time from the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PFS or date of death after starting subsequent anti-cancer treatment.

Measure: Second progression free survival on a subsequent treatment (PFS2)

Time: Assessed by investigator in accordance with clinical practice-approximately 21 months

Description: Defined as the time from the date of randomization to the earlier of the date of anti-cancer therapy start date following study drug discontinuation or death

Measure: Time to first subsequent therapy (TFST)

Time: Approximately 13 months

Description: Defined as the time from the date of randomization to the earlier of the date of second subsequent anti-cancer therapy start date following study drug discontinuation or death.

Measure: Time to second subsequent therapy (TSST)

Time: Approximately 21 months

Description: Change in symptoms from baseline

Measure: Patients reported disease-related symptoms and HRQoL by EORTC QLQ-LC13 and EORTC QLQ-30 questionnaires

Time: Approximately 21 months

Description: AEs graded by CTCAE version 5.0

Measure: Incidence of Adverse Events (AEs)

Time: Approximately 14 months

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of osimertinib and AZD5104

Measure: Plasma concentrations of osimertinib and AZD5104

Time: Trough concentrations at Week 4,12 and 24

227 A Randomized, Open-label, Phase III Study of Single Agent Nazartinib Versus Investigator's Choice (Erlotinib or Gefitinib) as First-Line Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring EGFR Activating Mutations

This is a phase III, open label, randomized controlled multi-center global study designed to evaluate the safety and efficacy of single agent nazartinib (EGF816) compared with investigator's choice (erlotinib or gefitinib) in patients with locally advanced or metastatic NSCLC who are treatment naïve and whose tumors harbor EGFR activating mutations (L858R or ex19del).

NCT03529084
Conditions
  1. Carcinoma, Non-small Cell Lung
Interventions
  1. Drug: EFG816
  2. Drug: erlotinib or gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Phase III Study of Nazartinib (EGF816) Versus Erlotinib/Gefitinib in First-line Locally Advanced / Metastatic NSCLC With EGFR Activating Mutations This is a phase III, open label, randomized controlled multi-center global study designed to evaluate the safety and efficacy of single agent nazartinib (EGF816) compared with investigator's choice (erlotinib or gefitinib) in patients with locally advanced or metastatic NSCLC who are treatment naïve and whose tumors harbor EGFR activating mutations (L858R or ex19del). --- L858R ---

- Histologically documented locally advanced or metastatic, stage IIIB/ IIIC or stage IV NSCLC with documented EGFR activating mutation (L858R or ex19del) - Provision of a tumor tissue sample to allow for retrospective analysis of EGFR mutation status - No prior treatment with any systemic antineoplastic therapy in the advanced setting - Recovered from all toxicities related to prior treatment - Presence of at least one measurable lesion according to RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance ≤1 - Meet the following laboratory values at the screening visit: - Absolute Neutrophil Count ≥1.5 x 109/L - Platelets ≥75 x 109/L - Hemoglobin (Hgb) ≥9 g/dL - Creatinine Clearance ≥ 45 mL/min using Cockcroft-Gault formula - Total bilirubin ≤1.5 x ULN - Aspartate transaminase (AST) ≤ 3.0 x ULN, except for patients with liver metastasis, who may only be included if AST ≤5.0 x ULN - Alanine transaminase (ALT) ≤ 3.0 x ULN, except for patients with liver metastasis, who may only be included if ALT ≤5.0 x ULN Exclusion Criteria: - Prior treatment with EGFR-TKI. --- L858R ---

Any other known EGFR activating mutations other than L858R or ex19del. --- L858R ---

Patients whose tumors harbor other EGFR mutations concurrent with L858R or ex19del EGFR mutations are eligible. --- L858R ---

Primary Outcomes

Description: PFS using central BIRC assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by BIRC per RECIST 1.1) or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS) by Blinded independent review committee (BIRC)

Time: Approximately 3 years

Secondary Outcomes

Description: Overall survival is defined as the time from date of randomization to date of death due to any cause.

Measure: Overall Survival

Time: Approximately 6 years

Description: PFS by Investigator assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by Investigator per RECIST 1.1) or death due to any cause, whichever occurs first.

Measure: PFS by investigator

Time: Approximately 3 years

Description: PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1 is defined as time from date of randomization to the first documented disease progression (clinical or radiologic) as per investigator assessment on next-line therapy or death from any cause, whichever occurs first.

Measure: PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1

Time: Approximately 4 years

Description: Time to progression in CNS, defined as time from date of randomization to the date of first documented progression of brain metastases as assessed by central neuro-radiologist BIRC per modified RECIST 1.1 for patients with at least one non-measurable and/or measurable lesion in the brain at baseline.

Measure: Time to progression in Central Nervous System (CNS) per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: ORR in accordance with RECIST 1.1. ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR)

Measure: Overall response rate (ORR) by central BIRC

Time: Approximately 3 years

Description: DOR is defined as the time from date of first documented response (CR and PR) to the date of the first documented progression or death due to underlying cancer, whichever occurs first.

Measure: Duration of response (DOR) by central BIRC

Time: Approximately 3 years

Description: DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD).

Measure: Disease control rate (DCR) by central BIRC

Time: Approximately 3 years

Description: TTR is defined as the time from the date of randomization to the first documented response CR or PR.

Measure: Time to response (TTR) by central BIRC

Time: Approximately 3 years

Description: CNS ORR in patients with brain metastases who have measurable disease in the brain at baseline review per modified RECIST 1.1

Measure: CNS ORR per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: CNS DoR in patients with brain metastases who have measurable disease in the brain at baseline per modified RECIST 1.1

Measure: CNS DoR per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: Peak plasma concentration (Cmax) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (Cmax) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: Area under the plasma concentration versus time curve (AUC) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (AUC) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: Elimination half life (t1/2) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (t1/2) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life score

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-C30 Questionnaire

Time: Approximately 4 years

Description: HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 quality of life score

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-LC13 Questionnaire

Time: Approximately 4 years

Description: Global health status/quality of life score of the EQ-5D-5L

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by EuroQoL-5 Dimension-5 (EQ-5D-5L) Questionnaire

Time: Approximately 4 years

228 EGFR Tyrosine Kinase Inhibitor Combined With Concurrent or Sequential Chemotherapy for Advanced Lung Cancer Patients of Gradual Progression After First-line EGFR-TKI Therapy: a Randomized Controlled Study

To compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients gradually progressed from first-line EGFR-TKI treatment. Patients who had gradual progression and EGFR-T790M mutation-negative were randomly divided into two groups: in concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI; in sequential group, patients continued with EGFR-TKI until the disease progressed again according to the RECIST criteria, and then switched to chemotherapy. We evaluated progression-free survival (PFS) and overall survival (OS) time of patients. For sequential group, PFS was PFS1 (gradual progression to discontinue EGFR-TKI) plus PFS2 (chemotherapy alone).

NCT03544814
Conditions
  1. Lung Adenocarcinoma
  2. EGFR Activating Mutation
Interventions
  1. Drug: icotinib combined with pemetrexed plus cisplatin
  2. Drug: first icotinib and then pemetrexed plus cisplatin
MeSH:Adenocarcinoma of Lung

3. A cytologic diagnosis is acceptable (i.e., FNA or pleural fluid cytology) 4. Sensitive EGFR mutations (exon 19 deletion or L858R mutation in exon 21) 5. --- L858R ---

Primary Outcomes

Description: Radiographic assessments were performed when enrolled and every 8 weeks until disease progression after chemotherapy according to RECIST version 1.1. After PD, collect the survival information every 16 weeks until death or withdrawal of study consent.

Measure: Progression-free survival (PFS)

Time: 16 months

Secondary Outcomes

Description: Radiographic assessments were performed when enrolled and every 8 weeks until disease progression after chemotherapy according to RECIST version 1.1. After PD, collect the survival information every 16 weeks until death or withdrawal of study consent.

Measure: overall survival (OS)

Time: 32 months

229 A Phase II Study of Osimertinib With On-study and Post-progression Biopsy in the First Line Treatment of EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer

This research study is studying a targeted therapy as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The names of the study drug involved in this study is: - Osimertinib (Tagrisso)

NCT03586453
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The Kaplan-Meier method will be used to calculate overall survival.. Inclusion Criteria: - Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a CLIA-approved laboratory from tumor tissue. --- L858R ---

Inclusion Criteria: - Participants must have histologically confirmed stage IV NSCLC (per AJCC 7th edition) with either the L858R or exon 19 deletion activating EGFR mutation as identified in a CLIA-approved laboratory from tumor tissue. --- L858R ---

Primary Outcomes

Description: Evaluated by comparing the genomic changes using targeted next generation sequencing in the post-osimertinib tumor to the pre-treatment tumor specimen.

Measure: Mechanisms of resistance to Osimertinib

Time: 4 Months

Secondary Outcomes

Description: Best objective response will be evaluated via RECIST 1.1 criteria. RECIST1.1 measurements of CT scans will be measured every 2 cycles on treatment to determine the objective response rate for patients being treated with osimertinib.

Measure: Best objective response

Time: 6 months

Description: Defined as the proportion of patients with best response of CR or PR per investigator assessment using RECIST 1.1. start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started.

Measure: Overall Response Rate

Time: 3 years

Description: Time from registration to documented disease progression or death from any cause, whichever occurs first. The Kaplan-Meier method will be used to determine the progression-free survival of patients enrolled on protocol and treated with combination osimertinib and selumetinib.

Measure: Progression-free survival (PFS)

Time: 2 years

Description: Survival follow-up with clinic visits or phone calls will be used to monitor for overall survival from time of study randomization to death from any cause. The Kaplan-Meier method will be used to calculate overall survival.

Measure: Overall survival

Time: 2 years

230 Maintenance Targeted Therapy With or Without Stereotactic Body Radiation Therapy for Stage IV Non-small Cell Lung Cancer: a Prospective, Multicenter, Randomized Controlled Clinical Trial.

This is a Prospective, Multicenter, Randomized Controlled study to evaluate Stereotactic Body Radiation Therapy (SBRT) as a potential treatment for stage IV non-small cell lung cancer (NSCLC) that has a mutated epidermal growth factor receptor (EGFR) and has been receiving treatment with a targeted agent such as gefitinib, erlotinib and icotinib.

NCT03595644
Conditions
  1. Stage IV Non-small Cell Lung Cancer
Interventions
  1. Radiation: SBRT+TKI
  2. Drug: TKI
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

exon 19 deletion or exon 21 L858R) 10. --- L858R ---

Primary Outcomes

Description: progression-free survival

Measure: PFS

Time: 2 years

Secondary Outcomes

Description: overall survival

Measure: OS

Time: 3 year

231 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Gefitinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with gefitinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population. In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03599518
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: DS-1205c
  2. Drug: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 3. Has acquired resistance to EGFR tyrosine kinase inhibitor (TKI) according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression [Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 4. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib 5. Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day 6. Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib 7. Has at least one measurable lesion per RECIST version 1.1 8. --- L858R ---

Has history of pancreatitis within the past 6 months Inclusion Criteria: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 3. Has acquired resistance to EGFR tyrosine kinase inhibitor (TKI) according to the Jackman criteria (PMID: 19949011): 1. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) OR 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression [Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 4. Is currently receiving and able to interrupt gefitinib or discontinue erlotinib, afatinib, or osimertinib 5. Has been receiving gefitinib, erlotinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of screening period; participants who have been receiving gefitinib must be taking gefitinib at a dose of 250 mg/day 6. Has radiological documentation of disease progression while receiving continuous treatment with gefitinib, erlotinib, afatinib, or osimertinib 7. Has at least one measurable lesion per RECIST version 1.1 8. --- L858R ---

Primary Outcomes

Measure: Number pf participants with dose-limiting toxicities during the Dose Escalation period

Time: within 28 days

Description: An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

Measure: Number of participants with adverse events (AEs)

Time: within 36 months

Secondary Outcomes

Measure: Plasma concentration of DS-1205a versus time

Time: during the 7 day run-in period

Measure: Maximum observed analyte concentration (Cmax)

Time: during the 7 day run-in period

Measure: Actual sampling time to reach Cmax (Tmax)

Time: during the 7 day run-in period

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau)

Time: during the 7 day run-in period

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough)

Time: during the 7 day run-in period

Description: Categories: DS-1205a, gefitinib

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: within 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: within 36 months

Measure: Overall survival (OS)

Time: within 36 months

232 Dose Climbing Trial of Anlotinib Plus Gefitinib in the First-line Treatment of Advanced Gene Positive Non-squamous Non-small Cell Lung Cancer

The purpose of this clinical study is to evaluate the tolerability and toxicity of different dose of Anlotinib puls Gefitinib in First-line Treatment of Advanced Gene Positive Non-squamous Non-small Cell Lung Cancer , to provide a reference of dosage for Phase II clinical trials

NCT03602027
Conditions
  1. Non-squamous Non-small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib
  2. Drug: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

recurrent patients, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant were assessed for eligibility, and the last treatment time must be more than 6 months before enrollment) - Epidermal Growth Factor Receptor(EGFR)mutations confirmed by molecular detection (including, but not limited to, 20 exon, 19 exon deletion and L858R) external pathological examination was accepted (including pathological or blood test results) - Patients have not been received systematic treatment,including chemotherapy and EGFR -TKIs(Tyrosine kinase inhibitors) - There were at least one target lesions in the past three months has not yet accepted radiotherapy, and could be recorded by magnetic resonance imaging (MRI) or computer tomography (CT) measuring accurately at least in one direction(The maximum diameter needs to be recorded), including conventional CT ≥20 mm or spiral CT ≥10 mm. - Life expectancy ≥3 months. --- L858R ---

Primary Outcomes

Description: Dose Limiting Toxicity (DLT) is referred to grade 3 non-hematological toxicity or grade 4 hematological toxicity according to NCI CTCAE 4.03 criteria

Measure: Dose limiting toxicity

Time: From enrollment to completion of study. Estimated about 4 months.

Description: Maximum Tolerance Dose (MTD) is the dose of treatment in the cohort where there are 2 cases of DLT reported.

Measure: Maximum tolerance dose

Time: From enrollment to completion of study. Estimated about 4 months

Secondary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (DCR, disease control rate)

Measure: disease control rate

Time: From enrollment to 2 months after treatment

Description: The length of time from enrollment until the time of progression of disease (TTP, time to progression).

Measure: time to progression

Time: From enrollment to progression of disease. Estimated about 6 months

233 A Phase I, Open-label Study to Assess the Safety, Tolerability and Pharmacokinetics of Ascending Doses of SH-1028 Tablets in Patients With Advanced Non-small Cell Lung Cancer

This is a Phase 1, open-label study of SH-1028 with dose escalation and dose expansion cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent.

NCT03603262
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: SH-1028
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or must have experienced clinical benefit from EGFR TKI, according to the Jackman criteria while on continuous treatment with an EGFR TKI(PR/CR, or SD continued ≥6 months). --- L858R ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD)

Time: Within the first 28 days of treatment

Measure: Incidence of Dose Limiting Toxicity (DLT)

Time: Within the first 28 days of treatment

Measure: Area under the plasma concentration versus time curve (AUC) of SH-1028

Time: 4 weeks

Measure: Elimination half-life(T1/2) of SH-1028

Time: 4 weeks

Measure: Maximum (or peak) concentration of SH-1028

Time: 4 weeks

Secondary Outcomes

Measure: Overall Response Rate (ORR)

Time: 12 months

Measure: Progression-free survival (PFS)

Time: 12 months

Measure: Disease control rates(DCR)

Time: 12 months

Measure: Overall survival(OS)

Time: 12 months

234 First Line Durvalumab in Patients With PD-L1 Positive, Advanced NSCLC With Performance Status 2 Unsuitable for Combination Chemotherapy. A Multicenter, Single-arm Phase II Trial

The aim of the trial is to assess efficacy and safety of the treatment with durvalumab in PS 2 patients with treatment-naïve, locally advanced or metastatic, PD-L1 positive NSCLC who are considered unsuitable for combination platinum-containing therapy.

NCT03620669
Conditions
  1. NSCLC Stage IV
  2. NSCLC Stage IIIB
Interventions
  1. Drug: Durvalumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Cytology could be accepted if histology is not possible - PD-L1 expression of ≥ 25% of the tumor cells by local testing (Ventana SP142 excluded) - No sensitizing EGFR mutation (L858R or exon 19 deletions), ALK fusion oncogene or rearrangements of the ROS1 gene detected in patients with a non-squamous cell NSCLC - Patient unsuitable for platinum-containing combination chemotherapy according to investigator or due to patient preference - WHO PS of 2. Confirmation of PS2 by a second medical doctor is mandatory. --- L858R ---

Primary Outcomes

Description: OS at 6 months is defined as being alive at 6 months after registration.

Measure: Overall survival (OS) at 6 months

Time: At 6 months after registration

Secondary Outcomes

Description: OR is defined as any complete response (CR) or partial response (PR) according to RECIST 1.1 criteria achieved during trial treatment.

Measure: Objective response (OR) according to RECIST 1.1

Time: At trial treatment discontinuation or the latest 5 years after last patient discontinued trial treatment

Description: iOR is defined as any complete response (CR/iCR) or partial response (PR/iPR) according to RECIST1.1 or iRECIST criteria achieved during trial treatment.

Measure: Objective response according to iRECIST (iOR)

Time: At trial treatment discontinuation or the latest 5 years after last patient discontinued trial treatment

Description: DoR is defined as the time from the first documentation of OR until disease progression according to RECIST 1.1 criteria or death due to disease progression, whichever occurs first.

Measure: Duration of response (DoR) according to RECIST 1.1

Time: At disease progression according to RECIST 1.1 criteria or death due to disease progression or the latest 5 years after last patient discontinued trial treatment

Description: iDoR is defined as the time from the first documentation of iOR until disease progression according to iRECIST criteria (iPD) or death due to disease progression.

Measure: Duration of response according to iRECIST (iDoR)

Time: At disease progression according to iRECIST criteria (iPD) or death due to disease progression or the latest 5 years after last patient discontinued trial treatment

Description: PFS is defined as the time from registration until disease progression according to RECIST v1.1 criteria or death due to any cause, whichever occurs first.

Measure: Progression-free survival (PFS) according to RECIST 1.1

Time: At disease progression according to RECIST v1.1 criteria or death due to any cause or the latest 5 years after last patient discontinued trial treatment

Description: iPFS is defined as the time from registration until disease progression according to iRECIST criteria (iPD) or death due to any reason, whichever occurs first. iPD is defined as the time point of first iUPD without subsequent iSD, iPR or iCR before trial treatment discontinuation. Patients not experiencing an event at the time of the analysis, as well as patients starting a subsequent anticancer treatment in the absence of an event, will be censored at the date of their last available tumor assessment showing no evidence of iPD before starting a subsequent anticancer treatment, if any.

Measure: Progression-free survival according to iRECIST (iPFS)

Time: At disease progression according to iRECIST criteria (iPD) or death due to any reason or the latest 5 years after last patient discontinued trial treatment

Description: OS is defined as the time from registration until death due to any cause

Measure: Overall survival (OS)

Time: At death of the patient or the latest 5 years after last patient discontinued trial treatment

Description: All AEs will be assessed according to NCI CTCAE v5.0

Measure: Adverse events (AEs)

Time: From registration until 28 days after last trial treatment dose

Description: QoL is measured by the Questionnaire Core 30 (QLQ-C30) including the complementary Lung Cancer Module (QLQ-LC13)

Measure: Quality of life (QoL): Core 30 (QLQ-C30)

Time: From registration until trial treatment discontinuation or the latest 1 year after registration

Description: Screening instrument (G8)

Measure: Geriatric assessment (GA) - Screening instrument (G8)

Time: At baseline

Description: Assessment with IADL

Measure: Geriatric assessment (GA) - Assessment with IADL

Time: At baseline

Description: Comorbidities assessment with CCI

Measure: Geriatric assessment (GA)

Time: At baseline

235 A Multicentre, Open-Label, Exploratory Phase Ib Clinical Study to Assess Safety and Efficacy of an EGFR Tyrosine Kinase Inhibitor in Combination With EGF Pathway Targeting Immunisation (EGF-PTI) in Treatment-Naïve Patients With EGFR Mutant NSCLC. The EPICAL Study

This is a multicentre, open-label, uncontrolled, Phase Ib clinical study. Patients who give informed consent will be screened for the study, including genotyping of the tumour and baseline characteristics. Eligible patients will receive a single pre-treatment of low dose of intravenous cyclophosphamide 200 mg/m2 (Day -3). Patients will commence daily oral therapy with the EGFR TKI afatinib as soon as possible, preferably on the same day as low dose cyclophosphamide. Afatinib will be prescribed according to the Summary of Product Characteristics (SmPC) of the product, and will continue in nominal 21-day cycles for as long as clinically indicated. The first day of dosing with EGF-PTI will be designated Day 1. Immunisation with EGF-PTI will commence 3 days after low dose cyclophosphamide and commencement of EGFR TKI, and will be repeated on Day 14, Day 28, Day 43, and Day 92. After the 5 th vaccination, patients will be followed up every 6 weeks for basic safety data and every 3 months for complete efficacy data, safety data, and maintenance (reduced) doses of EGF-PTI. Patients will continue in the study until disease progression, death, safety concerns (in the opinion of the investigator), non-compliance with the protocol, the patient withdraws from the study, 1 year after randomisation of the last patient, or the study is stopped the sponsor, whichever occurs sooner

NCT03623750
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: EGFR-TK Inhibitor
  2. Biological: EGF-PTI
  3. Drug: Cyclophosphamide
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Centrally confirmed EGFR exon 19 deletion, exon 21 (L858R, L861Q) or exon 18 (G719X) mutation before treatment (concomitant T790M pre-treatment mutation is permitted). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. --- L858R ---

Primary Outcomes

Description: Evaluate the safety and tolerability of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in newly diagnosed patients with advanced or metastatic non-squamous NSCLC with EGFR mutations who are not candidates for local curative treatment throughout the patient's participation in the study.

Measure: Frequency and severity of Adverse Events

Time: 36 months

Secondary Outcomes

Description: Evaluate the anti-tumor activity of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in terms of clinical response. Every 3 months after the first dose of EGF-PTI and throughout the patient's participation in the study.

Measure: Clinical response efficacy assessments

Time: 36 months

236 A Study of Apatinib Plus EGFR-TKI as First Line Treatment in Patients With Non-squamous NSCLC Harboring EGFR Mutations

The purpose of this study is to evaluate the efficacy and safety of apatinib plus EGFR-TKI as first line treatment in patients with non-squamous NSCLC harboring EGFR mutation.

NCT03634059
Conditions
  1. NSCLC
Interventions
  1. Drug: Apatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Age:18 to 75 years old (man or female); 2. Pathologically diagnosed with non-squamous NSCLC; 3. Imageology diagnosed with locally advanced/metastatic or recurrent (stage ⅢB - IV); 4. Histologically or cytologic confirmed,harboring an activating EGFR mutation (19del or 21 L858R); 5. None previous chemotherapy or targeted therapy.(NOTE: --- L858R ---

Primary Outcomes

Description: Baseline to measured date of progression or death from any cause

Measure: Progression free survival

Time: evaluated in two years since the treatment began

Secondary Outcomes

Description: Baseline to measured stable disease

Measure: Objective response rate

Time: tumor assessment every 8 weeks,up to two years

Description: Baseline to measured progressive disease

Measure: Disease control rate (DCR)

Time: tumor assessment every 8 weeks,up to two years

Description: Baseline to measured date of death from any cause

Measure: Overall survival (OS)

Time: the first day of treatment to death or last survival confirm date,up to two years

Description: throughout study

Measure: Adverse events

Time: evaluated in the two years since the treatment began according to the Common Terminology Criteria for Adverse Events Version 4.0

237 Real World Study to Evaluate the Efficacy and Resistant Mechanism of Erlotinib/Gefitinib Combined With Bevacizumab in First Line EGFR Mutation Positive Advanced Non-aquamous Non-small Cell Lung Cancer

This study aims to explore the efficacy and safety of Erlotinib/Gefitinib combined with bevacizumab in the real world for advanced non-squamous cell lung cancer with EGFR mutation, explore new drug resistance mechanisms under the A+T regimen and consistency between plasma and tissue detection driving genes, and finally assess the predictive value of plasma dynamic detection driving gene mutation profiles in predicting disease. The role of disease progression risk.

NCT03647592
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib/Gefitinib combined with Bevacizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - EGFR mutation(19del/L858R) - advanced non-saquamous non-small cell lung cancer - primary treatment of first diagnosis - performance status(0-1) Exclusion Criteria: - other genes mutation - saquamous Inclusion Criteria: - EGFR mutation(19del/L858R) - advanced non-saquamous non-small cell lung cancer - primary treatment of first diagnosis - performance status(0-1) Exclusion Criteria: - other genes mutation - saquamous Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung A retrospective study of 30 cases of advanced non-squamous non-small cell lung cancer (NSCLC) with EGFR mutation positive treated with A+T was conducted to observe the efficacy and safety of A+T regimen in the real world. --- L858R ---

Inclusion Criteria: - EGFR mutation(19del/L858R) - advanced non-saquamous non-small cell lung cancer - primary treatment of first diagnosis - performance status(0-1) Exclusion Criteria: - other genes mutation - saquamous Inclusion Criteria: - EGFR mutation(19del/L858R) - advanced non-saquamous non-small cell lung cancer - primary treatment of first diagnosis - performance status(0-1) Exclusion Criteria: - other genes mutation - saquamous Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung A retrospective study of 30 cases of advanced non-squamous non-small cell lung cancer (NSCLC) with EGFR mutation positive treated with A+T was conducted to observe the efficacy and safety of A+T regimen in the real world. --- L858R --- --- L858R ---

Primary Outcomes

Description: Progression free survival

Measure: PFS

Time: Approximately 1 years

Secondary Outcomes

Description: Overall survival

Measure: OS

Time: Approximately 1 years

Description: Disease control rate

Measure: DCR

Time: Approximately 1 years

238 A Randomized, Open-label, Controlled, Multi-Center Phase II/III Study to Assess the Efficacy and Safety of AZD3759 vs. a Standard of Care EGFR TKI, as First Line Treatment to EGFR Mutation Positive Advanced NSCLC With CNS Metastases

Primary Hypothesis The first-line treatment with single agent AZD3759 results in superior Progression Free Survival (PFS) compared to Standard of Care (SoC) Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKI), in patients with advanced Non-Small Cell Lung Cancer (NSCLC) with Central Nervous System (CNS) metastasis Secondary Hypothesis The safety profile of AZD3759 is comparable to EGFR TKI first-line treatment in patients with advanced NSCLC with CNS metastasis.

NCT03653546
Conditions
  1. Non-small Cell Lung Cancer
  2. EGFR Gene Mutation
  3. Brain Metastases
Interventions
  1. Drug: AZD3759
  2. Drug: Erlotinib
  3. Drug: Gefitinib
MeSH:Neoplasm Metastasis Neoplasms, Second Primary

Blinded Independent Central Radiological (BICR) assessment of PFS using modified RECIST 1.1.. Inclusion Criteria: 1. Properly completed patient informed consent 2. Male or female aged at least 18 years 3. Histologically or cytologically confirmed diagnosis of NSCLC with activating EGFR mutations including L858R and/or Exon19Del. --- L858R ---

Inclusion Criteria: 1. Properly completed patient informed consent 2. Male or female aged at least 18 years 3. Histologically or cytologically confirmed diagnosis of NSCLC with activating EGFR mutations including L858R and/or Exon19Del. --- L858R ---

Eligible patients with documented EGFR mutation+ (L858R and/or Exon 19Del) TKI-naïve advanced NSCLC and documented intracranial disease will be enrolled. --- L858R ---

Primary Outcomes

Description: To assess if first line treatment with AZD3759 results in significant PFS efficacy compared to Gefitinib or Erlotinib as determined by Blinded Independent Central Radiological (BICR) review using RECIST 1.1.

Measure: PFS assessed by Blinded Independent Central Radiological

Time: 36 months

Secondary Outcomes

Description: Investigator assessment of PFS using RECIST 1.1

Measure: PFS assess by investigator

Time: 36 months

Description: Intracranial PFS (iPFS) assessed by investigator using RECIST 1.1

Measure: Intracranial PFS (iPFS) assessed by investigator

Time: 36 months

Description: Intracranial PFS (iPFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1

Measure: Intracranial PFS (iPFS) assessed by BICR

Time: 36 months

Description: Extracranial PFS (ePFS) assessed by investigator using RECIST 1.1

Measure: Extracranial PFS (ePFS) assessed by investigator

Time: 36 months

Description: Extracranial PFS (ePFS) assessed by Blinded Independent Central Radiological (BICR) using RECIST 1.1

Measure: Extracranial PFS (ePFS) assessed by BICR

Time: 36 months

Description: Objective Response Rate (ORR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1

Measure: Objective Response Rate (ORR) assessed by investigator using RECIST 1.1

Time: 36 months

Description: Disease Control Rate (DCR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1

Measure: Disease Control Rate (DCR) assessed by investigator using RECIST 1.1

Time: 36 months

Description: Duration of Response (DoR) for Intracranial lesions and Extracranial lesions assessed separately by investigator using RECIST 1.1

Measure: Duration of Response (DoR) assessed by investigator using RECIST 1.1

Time: 36 months

Description: Overall ORR assessed by investigator using RECIST 1.1

Measure: Overall ORR assessed by investigator using RECIST 1.1

Time: 36 months

Description: Overall DCR assessed by investigator using RECIST 1.1

Measure: Overall DCR assessed by investigator using RECIST 1.1

Time: 36 months

Description: Overall DoR assessed by investigator using RECIST 1.1

Measure: Overall DoR assessed by investigator using RECIST 1.1

Time: 36 months

Description: ORR for Intracranial lesions assessed by investigator using RANO-BM

Measure: ORR for Intracranial lesions assessed by investigator using RANO-BM

Time: 36 months

Description: DCR for Intracranial lesions assessed by investigator using RANO-BM

Measure: DCR for Intracranial lesions assessed by investigator using RANO-BM

Time: 36 months

Description: DoR for Intracranial lesions assessed by investigator using RANO-BM

Measure: DoR for Intracranial lesions assessed by investigator using RANO-BM

Time: 36 months

Description: Overall Survival

Measure: Overall Survival

Time: 36 months

Description: The 30-items questionnaire measures cancer patients' functioning and symptoms. The scale range of EORTC QLQ-C30 is 30-126. Lower values represent a better outcome.

Measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).

Time: 36 months

Description: The 20-items questionnaire was used among brain cancer patients. The scale range of EORTC BN20 is 20-80. Lower values represent a better outcome.

Measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire BN20 (EORTC QLQ-BN20).

Time: 36 months

Description: Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)

Measure: Neurological function improvement rate assessed by Mini-Mental Status Examination (MMSE)

Time: 36 months

Description: Neurological function improvement rate assessed by RANO-BM criteria

Measure: Neurological function improvement rate assessed by RANO-BM criteria

Time: 36 months

Description: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Measure: Number of participants with treatment-related Adverse Events as assessed by CTCAE v5.0

Time: 36 months

Description: Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0

Measure: Number of participants with treatment-related Serious Adverse Events as assessed by CTCAE v5.0

Time: 36 months

Description: Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0

Measure: Incidence of laboratory abnormalities collected by hematology tests during the study as assessed by CTCAE v5.0

Time: 36 months

Description: Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0

Measure: Incidence of laboratory abnormalities collected by biochemistry tests during the study as assessed by CTCAE v5.0

Time: 36 months

Description: Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0

Measure: Incidence of laboratory abnormalities collected byurinalysis tests during the study as assessed by CTCAE v5.0

Time: 36 months

Description: Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.

Measure: Rhythm, PR, R-R, QRS and QT intervals and an overall evaluation of ECG assessed during the study period.

Time: 36 months

Description: Systolic and Diastolic Blood Pressure assessed during the study period.

Measure: Systolic and Diastolic Blood Pressure assessed during the study period.

Time: 36 months

Description: Pulse rate to assessed during the study period.

Measure: Pulse rate assessed during the study period.

Time: 36 months

Description: Body temperature assessed during the study period.

Measure: Body temperature assessed during the study period.

Time: 36 months

Description: Blinded Independent Central Radiological (BICR) assessment of PFS using modified RECIST 1.1.

Measure: PFS assess by BICR

Time: 36 months

239 A Randomized Phase II Study of Anlotinib Combined With Pemetrexed and Cisplatin in First Treatment for Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Negative Mutations

Chemotherapy is still the standard first-line treatment option for EGFR unmutated patients. After a randomized phase Ⅲ trial, BEYOND was presented the synergistic effect of progression-free survival(PFS) could be expected when chemotherapy is combined with Antiangiogenesis agent bevacizumab in China;Therefore,in this study, The investigators will investigate the efficacy and safety of Anlotinb combined With Pemetrexed and Cisplatin as first-line therapy in patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations.

NCT03671538
Conditions
  1. Non-squamous Non-small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib
  2. Drug: pemetrexed
  3. Drug: Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

recurrent patients, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant were assessed for eligibility, and the last treatment time must be more than 6 months before enrollment) - Patients have not been received systematic treatment,including chemotherapy and EGFR-TKIs - EGFR mutations confirmed by molecular detection (including, but not limited to, T790M, 19 exon deletion and L858R) external pathological examination was accepted (including pathological or blood test results) - There were at least one target lesions in the past three months has not yet accepted radiotherapy, and could be recorded by magnetic resonance imaging (MRI) or computer tomography (CT) measuring accurately at least in one direction(The maximum diameter needs to be recorded), including conventional CT ≥20 mm or spiral CT ≥10 mm. - Life expectancy ≥3 months. --- T790M --- --- L858R ---

Primary Outcomes

Description: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first

Measure: progression-free survival

Time: From enrollment to completion of study. Estimated about 24 months.

Secondary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (ORR, Overall Response Rate)

Measure: Overall Response Rate

Time: From enrollment to progression of disease. Estimated about 24 months

Description: Clinical response of treatment according to RESIST v1.1 criteria (DCR, disease control rate)

Measure: disease control rate

Time: From enrollment to progression of disease. Estimated about 24 months

Description: From date of randomization until the date of death or date of last visit/contact, whichever came first

Measure: Overall Survival

Time: From enrollment to completion of study. Estimated about 24 months.

Description: Proportion of people who first documented disease progression or death from any cause, whichever came first ,during 6 months

Measure: 6-month PFS rate

Time: From enrollment to analysis, Estimated about 6 months

Description: Proportion of people who first documented disease progression or death from any cause, whichever came first ,during 12 months

Measure: 12-month PFS rate

Time: From enrollment to analysis. Estimated about 12 months.

240 Efficacy and Safety of Anlotinib Combined With Platinum Plus Pemetrexed in T790M Mutation Negative Metastastic Non-squamous Non-small-cell Lung Cancer After Progression on First-line EGFR TKI: a Phase II, Muti-center, Single Arm Study

This study is conducted to explore the safety and efficacy of anlotinib, a tyrosine kinase inhibitors of vascular endothelial growth factor receptor 2(VEGFR)、FGFR(fibroblast growth factor receptor), platelet-derived growth factor receptor(PDGFR) and tumor cell proliferation related kinase c-Kit, combined with platinum plus pemetrexed in T790M mutation negative metastatic non-squamous non-small cell lung cancer(NSCLC) after the failure of EGFR-TKI.

NCT03706287
Conditions
  1. Lung Cancer Metastatic
Interventions
  1. Drug: anlotinib 8mg + AP/PC
  2. Drug: anlotinib 10mg + AP/PC
  3. Drug: anlotinib 12mg + AP/PC
  4. Drug: anlotinib + AP/PC
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- Epidermal Growth Factor Receptor(EGFR)mutations confirmed by molecular detection (including, but not limited to 19 exon deletion and L858R) external pathological examination was accepted (including pathological or blood test results) - Patients have only be treated with EGFR -TKIs(Tyrosine kinase inhibitors)including gefitinib, elotinib or icotinib, and received a best response of PR for ≥4months or SD for 6 months; disease has progressed recently according to RECIST 1.1 and negative for T790M detection(detection methods including ddPCR, ARMS or NGS) (For recurrent patients, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant were assessed for eligibility, and the last treatment time must be more than 6 months before enrollment) - Must have at least one measurable lesion as per RECIST 1.1 defined as a lesion that is 10mm in longest diameter imaged by CT scan or MRI;prior topical treatment, such as radiotherapy cryosurgery to the lesions is not allowed in less than 3 months; - Life expectancy ≥3 months. --- L858R ---

Primary Outcomes

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: Progression-free survival (PFS)

Time: Up to 24 months

Description: Dose Limiting Toxicity (DLT) is referred to grade 3 non-hematological toxicity or grade 4 hematological toxicity according to NCI CTCAE 4.03 criteria

Measure: Dose limiting toxicity (DLT)

Time: Estimated about 6 months

Description: Maximum Tolerance Dose (MTD) is the dose of treatment in the cohort where there are 2 cases of DLT reported.

Measure: Maximum tolerance dose (MTD)

Time: Estimated about 6 months

Secondary Outcomes

Description: To determine ORR of Anlotinib Anlotinib combined with Platinum-based Pemetrexed in T790M mutation negative Advanced NSCLC. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.

Measure: Objective response rate(ORR)

Time: Up to 24months

Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate (DCR)

Time: Up to 24months

Description: Defined as the the time from first confirmed CR or PR until the first date of either objective disease progression or death due to any cause.

Measure: Duration of Response (DOR)

Time: Up to 24months

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety (Number of Participants with Adverse Events as a Measure of Safety and Tolerability)

Time: Until 21 day safety follow-up visit

241 An Multicenter,Phase II Trial of EGFR-TKIs Combine With Anlotinib as First-line Treatment for Patients With Advanced EGFR Mutation-positive NSCLC

A single arm study: EGFR-TKIs Combine With Anlotinib as First-line Treatment in patients with EGFR-mutant non-small-cell lung cancer (NSCLC).

NCT03720873
Conditions
  1. EGFR Gene Mutation
Interventions
  1. Drug: erlotinib or gefitinib or icotinib
  2. Drug: Anlotinib

- Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R) Exclusion Criteria: - - Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. --- L858R ---

Primary Outcomes

Description: Time from the date of enrolment to discontinuation of treatment for any reason (including progression of disease, treatment toxicity, refusal and death)

Measure: Progression free survival

Time: within 6 months of the last visit of last patient, approximately 30 months after inclusion of first patient

Secondary Outcomes

Description: Best overall response (complete remission or partial remission) across all assessment time-points according to RECIST Criteria 1.1, during the period from enrolment to termination of trial treatment.

Measure: Objective response

Time: through study completion,an average of three years

Description: Adverse events graded according to NCI CTCAE V4.03

Measure: Safety - Adverse events graded according to NCI CTCAE V4.03

Time: within 6 months of the last visit of last patient, approximately 30 months after inclusion of first patient

Description: Defined as the time in month from diagnosis of recurrent NPC to the date of death is observed or to last follow-up visit.

Measure: Overall survival

Time: Three years

242 A Randomized Ⅲ Phase Trial of Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combined With Early Stereotactic Body Radiation Therapy to the Primary Tumor in Advanced Non-small Cell Lung Cancer Patients Harboring Epidermal Growth Factor Receptor Mutation

Non-small cell lung cancer (NSCLC) is a prevalent disease with high mortality and morbidity, particularly of adenocarcinoma in Asians. Fortunately, with the development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), treatment of lung cancer usher in a new era, resulting in a hit of precise therapy and molecule sequencing. However, it is inevitable for patients to gain acquired resistance of EGFR TKI. Several studies have been demonstrated that there were approximately 30% heterogeneous cells in primary tumors. And emerging studies illuminated that main pattern of treatment failure was the recurrence of primary site. Moreover, it was proved that despite of the drug-resistance cells in progressive site, continual prescription of EGFR TKI in oligometastasis lung cancer could make a difference for patients in progression free survival (PFS) and overall survival (OS), owing to the residual responsive cells in another sites. Therefore, to explore an unique method to control heterogeneous cells in primary site so as to delay or prevent acquired resistance when taking EGFR TKI orally may be of great benefit and therapy. It is known to all that stereotactic body radiation therapy (SBRT), with the advantage of hypofractionation and rapid release, succeed in several cancers, such as early lung cancer, prostatic, liver cancer and so on, for local control. Numerous reports explained SBRT played an irreplaceable role in progressive NSCLC patients after oral targeted medicine, regardless of EGFR or anaplastic lymphoma kinase (ALK) mutation. And the radiosensitivity of EGFR TKI in vitro and vivo may account for these inspiring results. What's more, it has reported that SBRT could induce inflammatory cell death, activate dendritic cell as well as accelerate antigen presentation in the draining lymph node, leading to antigen-specific adaptive immune response. Nevertheless, although the potential effects of SBRT on advanced NSCLC are obviously, few studies explore the preventive benefits of early SBRT combined with oral EGFR TKI on advanced lung cancer by eliminating the heterogeneous cells in primary site. In addition, the investigators' previous phase II study of SBRT combined with oral EGFR TKI had revealed its safety and potentially improvement of PFS for 6 months. In this trial, the investigators put sight into assessing the efficacy of early application of SBRT to primary site in the advanced NSCLC patients and provide a hypothesis that early SBRT could strengthen the anti-tumor effect of EGFR TKI through eradicating the heterogenity of initial tumor cells.

NCT03727867
Conditions
  1. Advanced Non-small Cell Lung Cancer
Interventions
  1. Drug: Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
  2. Device: Stereotactic Body Radiation Therapy
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

exon 19 deletion or exon 21 L858R); 4. Estimated life expectancy >8 weeks; 5. Patients should have adequate bone marrow function defined as absolute peripheral granulocyte count (AGC) of >/= 1500 cells/mm3, platelet count of >/= 100000 cells/mm3; adequate hepatic function with bilirubin /= 50 ml/min and international normalized ration (INR) 0.8-1.2; --- L858R ---

Primary Outcomes

Description: Evaluate the effect of EGFR TKI with or without SBRT on progression free survival.

Measure: Progression free survival

Time: Duration of time from the start of EGFR TKI therapy to the time of disease progression, assessed up to 3 years.

Secondary Outcomes

Description: To describe the rate of local control and out-of-field disease progression, irrespectively.

Measure: Local control rate (LCR)

Time: Up to 3 years.

Description: To evaluate overall survival in EGFR TKI therapy with SBRT in comparison to EGFR TKI therapy alone.

Measure: Overall survival

Time: Duration of time from the start of EGFR TKI therapy to 3 years or until time of death, whichever occurs first.

Description: The acute and chronic profile associated with the study regimen using CTCAE v5.0.

Measure: Adverse events

Time: Up to 3 years.

243 A Multi-center, One-arm Clinical Study of Anlotinib Combined With Icotinib as the First-line Treatment in Patients With EGFR Mutation-positive Advanced NSCLC. The Trial Aims to Evaluate the Efficacy and Safety of This Treatment.

Evaluate the efficacy and safety of Anlotinib plus Icotinib as the first-line treatment in patients with sensitive EGFR mutations advanced non-small cell lung cancer.

NCT03736837
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib Plus Icotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Signed and dated informed consent 2. 18-75years,ECOG PS:0-2,Life expectancy of more than 3 months,with measurable lesion ( RECIST1.1) 3. Histologically or cytologically confirmed, locally advanced and/or metastatic IIIB, IIIC or IV non-squamous NSCLC or recurrent non-squamous NSCLC(according to the 8th Edition of the AJCC Staging system)with EGFR 19 del and/or 21 L858R gene mutation 4. Has not received chemotherapy or other targeted therapies;For recurrent disease, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant chemotherapy may be accepted, but recurrence occurs after ≥6 months from stopping treatment. --- L858R ---

HIV test positive history or AIDS; untreated active hepatitis; combined with hepatitis B and hepatitis C co-infection Inclusion Criteria: 1. Signed and dated informed consent 2. 18-75years,ECOG PS:0-2,Life expectancy of more than 3 months,with measurable lesion ( RECIST1.1) 3. Histologically or cytologically confirmed, locally advanced and/or metastatic IIIB, IIIC or IV non-squamous NSCLC or recurrent non-squamous NSCLC(according to the 8th Edition of the AJCC Staging system)with EGFR 19 del and/or 21 L858R gene mutation 4. Has not received chemotherapy or other targeted therapies;For recurrent disease, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant chemotherapy may be accepted, but recurrence occurs after ≥6 months from stopping treatment. --- L858R ---

Primary Outcomes

Description: The PFS time is defined as time from enrollment to locoregional or systemic recurrence, second malignancy or death due to any cause; censored observations will be the last date of : "death", "last tumor assessment", "last follow up date" or "last date in drug log"

Measure: PFS(Progress free survival)

Time: each 42 days up to PD or death (up to 24 months)

Secondary Outcomes

Description: OS was defined as time from date of enrollment to date of death due to any cause. For participants still alive at the time of analysis, OS time was censored on last date that participants were known to be alive.

Measure: OS(Overall Survival)

Time: From enrollment until death (up to 24 months)

Description: To evaluate the effectiveness of Anlotinib Hydrochloric Capsule Plus Icotinib Hydrochloric Tablet by enhanced CT/MRI scan every two cycles. Objective Response Rate (ORR) is defined as participants who had complete response (CR) or partial response(PR) divided by the total number of patients.

Measure: ORR(Objective Response Rate)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: To evaluate the effectiveness of Anlotinib Hydrochloric Capsule Plus Icotinib Hydrochloric Tablet by enhanced CT/MRI scan every two cycles. Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease).

Measure: DCR(Disease Control Rate)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Adverse Events

Time: Until 30 day safety follow-up visit

244 A Prospective, Single-arm, Multicenter Study of Anlotinib Hydrochloride Combined With First-generation EGFR TKIs as Second-line Treatment in Acquired (Non-T790M Mutation) Resistance Advanced Non-small Cell Lung Cancer

After the second-line treatment of patients with non-T790M mutations, chemotherapy with platinum-containing drugs was used, and chemotherapy-related toxicity was high. Studies have shown that bevacizumab combined with EGFR TKI have a good trend of benefit. This study is aimed to evaluate the efficacy and safety of Anlotinib Hydrochloride combined with first-generation EGFR TKIs as second-line treatment in advanced non-small cell lung cancer . The patients with IV non-small lung cancer have acquired resistance to prior first-generation EGFR TKIs and have non-T790M mutation.

NCT03766490
Conditions
  1. Non-Small-Cell Lung
Interventions
  1. Drug: Anlotinib Hydrochloride
  2. Drug: Gefitinib
  3. Drug: Icotinib
MeSH:Carcinoma, Non-Sma Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. - Previously, EGFR gene test showed EGFR exon 19 deletion or exon 21 (L858R) mutation, and the gene test showed no T790M mutation before enrollment. --- L858R ---

Primary Outcomes

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: PFS(Progress free survival)

Time: each 42 days up to PD or death(up to 24 months)

Secondary Outcomes

Description: OS is defined as the time until death due to any cause.

Measure: Overall Survival (OS)

Time: From randomization until death (up to 24 months)

Description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.

Measure: Objective Response Rate (ORR)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: use EORTC QLQ-C30(version 3) questionnaire to evaluate the quality of life.

Measure: Quality of Life(QoL)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate (DCR)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

245 Open Label, Multicenter, Phase II Study of Patients With Treatment Naïve Metastatic Epidermal Growth Factor Receptor (EGFR) Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases Randomized to Stereotactic Radiosurgery (SRS) and Osimertinib or Osimertinib Alone

This open-label, multicenter, randomized phase II study will evaluate the usage of osimertinib alone for brain metastases compared to SRS and osimertinib in patients with newly diagnosed, treatment naiive EGFR positive lung cancer.

NCT03769103
Conditions
  1. Lung Cancer Non-small Cell Stage IV
  2. Brain Metastases
Interventions
  1. Drug: Osimertinib
  2. Radiation: Stereotactic radiotherapy
MeSH:Lung Neoplasms Neoplasm Metastasis Brain Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Able to provide written informed consent by patient or legally acceptable representative - Meets the criteria in the approved regulatory indication for first line treatment with osimertinib and agree to the restrictions, monitoring, and dose-adjustment criteria stipulated in the associated product label - Epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations) - No prior systemic therapy except neoadjuvant, adjuvant or concurrent chemotherapy given greater than 3 months prior to enrollment on study - Asymptomatic or minimally symptomatic brain metastases (ie. --- L858R ---

Headache, nausea, or seizure responsive to dexamethasone/analgesic/antiepileptic on stable doses of medications for a minimum of 3 days) - Brain metastases must meet the following criteria on a diagnostic MRI: at least one lesion can be classified as measurable disease per RANO-BM, ≤ 10 brain or brainstem metastases, ≤ 30 mm and brainstem metastases must be ≤ 5 mm, metastases > 5 mm from the optic nerve or chiasm - ECOG performance status 0-2 - Life expectancy > 6 months - Willing to abstain from sexual activity or willing to use double-barrier method during sexual intercourse Exclusion Criteria: - Previous treatment with osimertinib, or any other EGFR TKI - Patient with symptomatic brain metastases causing any neurologic deficit (not including headache, nausea, or medically controlled seizure) - Multiple sclerosis - Pacemaker or MRI-incompatible metal in the body - Allergy to gadolinium MRI contrast - Brain metastasis requiring surgery for decompression - Leptomeningeal disease - Previous cranial RT, or surgery for brain metastases - Uncontrolled systemic lupus erythematosis, scleroderma or other connective tissue disorders considered a contraindication for radiotherapy - Active cancer from another anatomical site within 5 years (non-melanomatous skin and cervical cancers permitted) - Any medical or non-medical issue that would render patient unable to reliably complete regular QOL and neurocognitive assessments - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements - Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater - Patients with symptomatic CNS metastases who are neurologically unstable - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of cytochrome P450 (CYP) 3A4 - Patients taking any drugs that are known to prolong QT interval that can't be withdrawn prior to Osimertinib - Pregnant or breastfeeding Inclusion Criteria: - Able to provide written informed consent by patient or legally acceptable representative - Meets the criteria in the approved regulatory indication for first line treatment with osimertinib and agree to the restrictions, monitoring, and dose-adjustment criteria stipulated in the associated product label - Epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations (either alone or in combination with other EGFR mutations) - No prior systemic therapy except neoadjuvant, adjuvant or concurrent chemotherapy given greater than 3 months prior to enrollment on study - Asymptomatic or minimally symptomatic brain metastases (ie. --- L858R ---

Primary Outcomes

Description: Absence of progressive brain metastases according to the Response Assessment in Neuro-Oncology Brain Metastasis (RANO-BM criteria)

Measure: Intracranial progression free survival

Time: 1 year

Secondary Outcomes

Description: partial or complete response to therapy based on RANO-BM criteria

Measure: Intracranial overall response rate

Time: 2 years

Description: time from randomization to WBRT

Measure: Time to whole brain radiotherapy (WBRT)

Time: 2 years

Description: time from randomization to SRS (not including initial SRS in the SRS + osimertinib treatment arm)

Measure: Time to stereotactic radiosurgery (SRS)

Time: 2 years

Description: according to institutional standards based on radiologic findings with or without pathologic confirmation and multidisciplinary review when required

Measure: Rate of radionecrosis

Time: 2 years

Description: defined as time from randomization to death by any cause

Measure: Overall survival

Time: 2 years

Description: time from randomization to progression of extracranial metastases or development of new sites of disease per RECIST 1.1

Measure: Time to distant progression

Time: 2 years

Description: Assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30. Subscales for: general presence of symptoms in patients with cancer question 1-28 (1=Not at all; 4=very much); overall health/quality of life question 29-30 (1=very poor; 7=excellent) & EORTC-QLQ Brain Neoplasm (BN)20: Subscales for presence of symptoms in patients with brain tumours question 31-50 (1=Not at all; 4=very much)

Measure: Quality of life

Time: 2 years

Description: Assessed by Montreal Cognitive Assessment. Total score:30. 1=poor function; 30=good function

Measure: Neurocognitive function

Time: 2 years

Description: Osimertinib dose (40mg or 80mg) for x number of days (max=730 days)

Measure: Exposure to osimertinib

Time: 2 years

246 A Phase II, Single Arm Study Assessing Efficacy of Osimertinib With Savolitinib in Patients With EGFRm+ MET+, Locally Advanced or Metastatic Non Small Cell Lung Cancer Who Have Progressed Following Osimertinib Treatment (SAVANNAH Study)

This study (the SAVANNAH study) will investigate the efficacy of osimertinib in combination with savolitinib in patients with EGFRm+ and MET+, locally advanced or metastatic NSCLC who have progressed following treatment with osimertinib

NCT03778229
Conditions
  1. Carcinoma
Interventions
  1. Drug: osimertinib
  2. Drug: savolitinib

- Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity (including either exon 19 deletion and/or L858R) which is not amenable to curative therapy. --- L858R ---

Primary Outcomes

Description: To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. The primary analysis of ORR will occur when all patients have had the opportunity to be treated for 6 months.

Measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1

Time: Up to approximately 36 months after 1st patient dosed (117 centrally confirmed MET+ FISH patients).

Secondary Outcomes

Description: To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+ (centrally confirmed by FISH, and centrally confirmed by IHC) locally advanced or metastatic NSCLC who have progressed on osimertinib.

Measure: Objective response rate (ORR) by investigator assessment in accordance with RECIST 1.1.

Time: Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).

Description: To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: PFS by investigator assessment in accordance with RECIST 1.1.

Time: Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).

Description: To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality-of-life questionnaire (QLQ-C30), version 3 (QLQ-C30 v3).

Time: Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).

Description: To evaluate the pharmacokinetics of osimertinib and savolitinib in this patient population.

Measure: Plasma concentrations of osimertinib, savolitinib and their metabolites.

Time: Blood sampling on Cycles 1 and 2 on Day 1 pre-dose, 1 hour and 3 hours post-dose; Day 1 of Cycles 3, 6, and 11; discontinuation visit (if discontinued due to liver toxicity) (One cycle = 28 days)

Description: To determine the prevalence of ctDNA clearance after osimertinib and savolitinib treatment in patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: Prevalence of EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).

Time: From date of first dose until the date of first documented progression, up to approximately 36 months.

Description: To evaluate the safety and tolerability of savolitinib in combination with osimertinib.

Measure: AEs, SAEs and discontinuation rate due to AEs, as characterized and graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event [CTCAE] v5.

Time: Continuously from first dose to 28 (+/-7) days after discontinuation of study drug, or up to approximately 36 months.

Description: To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: Overall Survival by investigator assessment in accordance with RECIST 1.1.

Time: Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).

Description: To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: Duration of Response by investigator assessment in accordance with RECIST 1.1.

Time: Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).

Description: To determine the efficacy of savolitinib in combination with osimertinib in patients with EGFRm+, MET+, locally advanced or metastatic NSCLC who have progressed on osimertinib. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: Percentage change in tumour size by investigator assessment in accordance with RECIST 1.1.

Time: Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).

Description: To assess the impact of savolitinib and osimertinib on disease related symptoms and health related quality of life (HRQoL) in patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: Mean change from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) complementary 13-item quality-of-life questionnaire - lung cancer symptoms questionnaire (QLQ-LC13).

Time: Up to approximately 36 months after 1st patient dosed (at the time of the primary outcome measure assessment).

Other Outcomes

Description: To assess the impact of savolitinib in combination with osimertinib on patient reported treatment-related symptoms.

Measure: PRO CTCAE symptoms

Time: From date of consent until the date of first documented progression, up to approximately 36 months.

Description: To assess patients' overall impression of severity of cancer symptoms. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: Patient's Global Impression of Severity (PGIS)

Time: From date of consent until the date of first documented progression, up to approximately 36 months.

Description: To explore the impact of treatment and disease on health state utility. In patients centrally confirmed as MET positive by FISH, by IHC and in all patients.

Measure: EQ-5D-5L

Time: From date of consent until the date of first documented progression, up to approximately 36 months.

Description: To assess the predictive value of changes in circulating biomarkers on clinical efficacy endpoints.

Measure: Longitudinal changes in circulating DNA and/or RNA compared with PFS, OS and ORR.

Time: Blood samples collected at Screening within 28 days before the first dose of study treatment; on day of first dose of study treatment; at discontinuation 7 days after last dose of study treatment. (One cycle = 28 days)

Description: To collect and store DNA (according to each country's local and ethical procedures) for future exploratory research into genes/genetic variation that may influence response (ie, distribution, safety, tolerability and efficacy) to study treatments and or susceptibility to disease (optional).

Measure: Pharmacogenetic analyses on blood samples.

Time: Screening within 28 days before first dose; at first dose; 7 days after last dose. (One cycle = 28 days)

Description: To collect and store tissue and plasma samples for companion diagnostic development and exploratory analyses.

Measure: Disease relevant or response markers in tumour tissue and circulating tumour DNA/RNA including but not limited to EGFR mutations and MET amplifications.

Time: Screening within 28 days before first dose; at first dose; 7 days after last dose. Tumour tissue collected during Pre-screening and at treatment discontinuation 7 days after last dose. (One cycle = 28 days)

Description: To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.

Measure: HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity).

Time: On first day of study treatment at Cycle 1 Day 1. (One cycle = 28 days)

247 Phase II, Open Label, Single Arm Trial of Alectinib in Combination With Bevacizumab in Untreated and Previously Treated Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) With Positive ALK Driver Mutation

Lung cancer remains the most lethal malignancy in both sexes around the world. It is estimated that lung cancer caused 234,030 deaths in the United States in 2016, accounting for 28% of all cancer-related deaths. In 2012 alone, a total of 6,697 deaths from lung cancer were registered in Mexico; this number exceeds the death toll from other common solid neoplasms (i.e., stomach, prostate, breast, and liver). In addition to its high incidence, lung cancer patients face a dismal prognosis, with an overall 5-year survival ranging from 5-16%. In the last two decades, the outlook for a subset of Non-small cell lung cancer (NSCLC) patients has shifted. Novel approaches have been able to identify that a significant number of patients present tumors with actionable mutations, opening the possibility of treatment with targeted therapies, which have increased survival outcomes in these patients. A number of specific therapies have been developed over the past decade, such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors. Additionally, treatment options for patients with NSCLC with actionable mutations has increased in the last two decades, with several third generation inhibitors available, which have different efficacy and tolerability profiles, nonetheless, global 5-year survival rates remain below 20%, which highlights the need to explore therapeutic combinations which might derive in greater long-term survival for this patient subgroup. Although encouraging data has been reported in terms of adding Bevacizumab to EGFR-TKIs, this scheme has not been explored for patients who have ALK-rearranged NSCLC and who are candidates for ALK-inhibitors. Currently, Alectinib has been shown to offer several advantages compared to first-generation ALK-TKIs, including a stronger ALK-inhibition, better outcomes in patients with Central Nervous System (CNS) involvement and longer duration of response. However, the addition of Bevacizumab to therapy with Alectinib in treatment naïve or previously treated NSCLC patients remains unexplored. Based on this data and the need to continue searching for safe and effective therapeutic options, a phase II, single arm trial assessing Alectinib in combination with Bevacizumab in untreated and previously treated patients with Advanced or Metastatic Non-Squamous ALK-rearranged NSCLC has been designed.

NCT03779191
Conditions
  1. ALK Gene Rearrangement Positive
  2. Non-Squamous Non-Small Cell Neoplasm of Lung
Interventions
  1. Drug: Alectinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Men who are sexually active with WOCBP, follow the instructions of birth control for a period of 90 days, plus the time required for the investigational drug is subject to five half-lives Exclusion Criteria: 1. Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded. --- L858R ---

All patients´ tumors contained either an exon 19 deletion or the amino acid substitution at position 858 in EGFR, from a leucine (L) to an arginine (R) (L858R) mutation. --- L858R ---

Primary Outcomes

Description: PFS based on response criteria according to RECIST 1.1 in untreated and previously treated patients with Advanced or metastatic ALK-rearranged Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab

Measure: Progression-free survival

Time: Through study completion, an average of 18 months

Secondary Outcomes

Description: To assess the ORR, based on response criteria according to RECIST 1.1, in untreated and previously treated patients with Advanced or Metastatic ALK-rearranged Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab.

Measure: Objective response rate

Time: 8 weeks

Description: To assess the brain ORR, based on response criteria according RECIST 1.1, in untreated and previously treated patients with Advanced or metastatic Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab.

Measure: Brain- ORR

Time: 8 weeks

Description: To assess the OS in untreated and previously treated patients with Advanced or metastatic Non-Squamous ALK-rearranged NSCLC who receive treatment with Alectinib plus Bevacizumab.

Measure: Overall survival

Time: Through study completion, an average of 18 months

Description: To assess the time since inclusion until developing brain metastases in untreated and previously treated patients with Advanced or metastatic Non-Squamous ALK-rearranged NSCLC who receive treatment with Alectinib plus Bevacizumab.

Measure: Time to developing brain metastases

Time: Through study completion, an average of 18 months

Description: To measure disease-related symptoms we will apply the Lung Cancer Symptom Scale (LCSS). The LCSS is designed as a disease-specific measure of quality of life particularly for use in clinical trials. It evaluates six major symptoms associated with lung mallignancies and their effect on overal symptomatic distress, functional activities, and global quality of life. The scale consists of two segments, one completed by the patient (9 items) and one completed by the health care professional (6 items). Scoring is assigned as follows: The patient scale consists of 9 visual analogue scales (100 mm horizontal line). Patient puts a mark on line to indicate intensity of response to the items in question (0 = lowest rating). The observer scale consists of a 5-point categorical scale (100=none; 75=mild; 50=moderate; 25=marked; 0=severe). The score is equal to the length of line marked by patient. An average of the aggregate score of all 9 items is the total score (0-100, 0= least symptom burden).

Measure: Disease-related symptom improvement

Time: 12 weeks since treatment start

248 A Randomized, Double-blind, Positive-controlled, Multi-center Phase III Clinical Study of Evaluating Alflutinib Mesylate Versus Gefitinib as First-line Therapy in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC) With EGFR-sensitive Mutations(FlAG)

To assess the efficacy and safety of Alflutinib Mesylate versus Gefitinib in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

NCT03787992
Conditions
  1. Locally Advanced or Metastatic EGFR Sensitising Mutation Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: Alflutinib Mesylate (AST2818) 80mg//40 mg+ placebo
  2. Drug: Placebo Gefitinib 250 mg
  3. Drug: Gefitinib 250 mg
  4. Drug: Placebo AST2818 80mg//40 mg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent alflutinib compared with SoC EGFR-TKI therapy as measured by PFS.

Measure: Median Progression Free Survival (PFS) (Months)

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression ( (approximately 12 months)

Secondary Outcomes

Description: Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy

Measure: Overall Survival (OS)- Number of Participants With an Event

Time: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 29 months)

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy or received another anti-cancer therapy prior to progression and was used to assess the efficacy of single agent alflutinib compared with SoC EGFR-TKI therapy as measured by PFS.

Measure: Progression Free Survival (PFS) evaluated by investigator

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: ORR was defined as the number (%) of patients with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy.

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of alflutinib compared with SoC EGFR-TKI therapy

Measure: Depth of Response

Time: At baseline and every 6 weeks for the first 17 months and then every 12 weeks relative to randomisation until progression (approximately 12 months)

Description: The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain [pain in chest, pain in arm or shoulder, and pain in other parts); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. Except for a multi-item scale for dyspnoea, all were single items. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and better function. Higher scores on the symptoms scales indicated greater symptom burden. The results of the analyses were presented in terms of a least squares mean together with its associated 95% profile likelihood CI

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)

Time: Questionnaires completed at week 1, 4, 7, 9, 12, 15 , 18,21,27,33,39,45and51

Description: he EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, which were combined to produce 5 functional scales (Physical, Role, Cognitive, Emotional, Social); 3 symptom scales (Fatigue, Pain, Nausea/Vomiting); 6 individual items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties); and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The results of the analyses were presented in terms of a least squares mean together with its associated 95% profile likelihood CI.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items

Time: Questionnaires completed at week 1, 4, 7, 9, 12, 15 , 18,21,27,33,39,45and51

249 Anlotinib Combined With Pemetrexed And Carboplatin Followed by Maintenance Therapy With Anlotinib Plus Pemetrexed as the First-line Treatment in Patients With Advanced Nonsquamous NSCLC

In recent years, with the progress in the treatment field, Non-Small Cell Lung Cancer(NSCLC) has become the most successful cancer species in precision medicine. Patients with positive driving genes such as EGFR, ALK, ROS1, BRAF and so on have clearly targeted drugs, which bring survival benefits to patients.However, about 50% of patients still lack a clear driving gene target, which has become the focus of current research.In the field of wild-type NSCLC with negative driver genes, the classic first-line treatment regimen is the two-drug regimen containing platinum.The study by Kimura T in the first-line treatment of 54 wild-type advanced NSCLC patients with carboplatin and pemetrexed showed that the ORR, mPFS and mOS of patients with wild-type non-squamous NSCLC treated with carboplatin permetrexine were 35.8%, 5.4 months and 12.7 months respectively. Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and development.In the phase Ⅲ study, patients who failed at least two kinds of systemic chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib or placebo, the anlotinib group PFS and OS were 5.37 months and 9.46 months, the placebo group PFS and OS were 1.4 months and 6.37 months. The efficacy and safety of Anlotinib combined with Pemetrexed and Carboplatin followed by maintenance therapy with Anlotinib plus Pemetrexed as the first-line treatment in patients with advanced nonsquamous NSCLC deserve further exploration.

NCT03790228
Conditions
  1. Non-squamous Cell Non-Small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib Combined With Pemetrexed And Carboplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer),Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis of non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; - Medical history and combined history: 1. Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); 2. The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; 3. Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with cervical carcinoma in situ , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); 4. Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy;Note: Under the premise of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; 5. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; 6. --- S768I --- --- L858R ---

Primary Outcomes

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: Progression free survival,PFS

Time: each 42 days up to PD or death(up to 24 months)

Secondary Outcomes

Description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.

Measure: Objective Response Rate,ORR

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate,DCR

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).

Description: Defined as the time until death due to any cause.

Measure: Overall Survival,OS

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months) .

Description: Number of Participants with Adverse Events.

Measure: Safety(Number of Participants with Adverse Events )

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months).

250 to Evaluate SCT510 Compared to Avasitin Respectively Combined Paclitaxel and Carboplatin First-line Treatment of Locally Advanced and Metastatic or Recurrent Squamous Cell Non-small Cell Lung Cancer Efficacy and Safety

To evaluate the safety, efficacy and immunogenicity of SCT510 combined with paclitaxel and carboplatin compared with bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of locally advanced metastatic or recurrent squamous cell non-small cell lung cancer.

NCT03792074
Conditions
  1. Non-squamous Cell Non-small Cell Lung Cancer
Interventions
  1. Drug: SCT510
  2. Drug: Bevacizumab
  3. Drug: Paclitaxel
  4. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

21 (L858R, L861Q)) and ALK fusion.Subjects who have not previously undergone EGFR and ALK gene testing will need to undergo genetic testing during the screening period.Among them, subjects whose EGFR or ALK gene status cannot be determined for various reasons can be enrolled;Subjects who are known to have EGFR sensitive mutations and/or ALK fusion may also be enrolled if they are currently unable to obtain the corresponding targeted drugs (including the rejection of the subjects) and chemotherapy is standard treatment at the research center; 5. --- L858R ---

Primary Outcomes

Description: the proportion of subjects whose CR(complete response) and PR(partial response)combined , according to RECIST 1.1 criteria

Measure: Objective response rate

Time: 12 weeks

Secondary Outcomes

Description: the proportion of subjects whose CR(complete response) and PR(partial response)combined , according to RECIST 1.1 criteria

Measure: Objective response rate

Time: 18 week

Description: the proportion of subjects with CR(complete response), PR(partial response) and SD(Stable disease) combined,according to RECIST 1.1 criteria

Measure: Disease control rate

Time: 12 weeks and 18 weeks

Description: The time from the first assessment of CR(complete response) or PR(partial response) to the first assessment of PD(progressive disease) or any cause of death,according to RECIST 1.1 criteria

Measure: Duration of Response

Time: 3 years

Description: The time from randomization to PD(progressive disease) or any cause of death,according to RECIST 1.1 criteria

Measure: Progression free survival

Time: 3 years

Description: The proportion of subjects who survived longer than 1 year after randomization

Measure: 1-year overall survival rate

Time: 1 year

Description: Defined as the time from randomization of subjects to death from any cause

Measure: Overall survival

Time: 3 years

251 A Single Arm, Multi-center Study to Assess the Efficacy and Safety of Docetaxel Combined With Carboplatin Plus Anlotinib as First Line Treatment in Non-squamous Non-small-cell Lung Cancer (NSCLC)

Anlotinib which has shown an affirmatory efficacy in ALTER0303 controlled trial as a 3rd-line treatment on advanced NSCLC is a tyrosine kinase inhibitor with a favorable safety profile in phase I trial which mainly targets VEGFR1/2/3, FGFR, PDGFR and c-kit. The purpose of this trail is to establish whether advanced non-squamous NSCLC patients could benefit from the combination treatment of docetaxel, carboplatin and anlotinib as the first-line and maintenance treatment.

NCT03799601
Conditions
  1. NSCLC
Interventions
  1. Drug: Anlotinib
  2. Drug: Docetaxel
  3. Drug: Carboplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Exclusion Criteria: - Small cell lung cancer (including lung cancer mixed with small cell lung cancer and non-small cell lung cancer), Lung sarcomatoid carcinoma; - Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma; - Patients with pathological fracture in bone metastasis induced by non-small-cell lung cancer; - Tumor histology or cytology confirmed EGFR mutagenesis [EGFR sensitive mutations include 18 exon point mutations (G719X), 19 exon deletions, 20 exon S768I mutations and 21 exon point mutations (L858R and L861Q)] and ALK gene rearrangement positivity, include EGFR/ALK status cannot be determined for various reasons; - Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood vessel; or there is a significant pulmonary cavity or necrotizing tumor; Medical history and combined history: - Active brain metastases, cancerous meningitis, spinal cord compression, or imaging CT or MRI screening for brain or pia mater disease (a patient with brain metastases who have completed treatment and stable symptoms in 28 days before enrollment may be enrolled, but should be confirmed by brain MRI, CT or venography evaluation as no cerebral hemorrhage symptoms and metastases in midbrain, pons, cerebellum, medulla oblongata, or spinal cord, brain metastases and local radiotherapy after two weeks to allow group); - The patient is participating in other clinical studies or completing the previous clinical study in less than 4 weeks; - Had malignant tumors except NSCLC within 5 years before enrollment(except for patients with carcinoma in situ of the cervix , basal cell or squamous cell skin cancer who have undergone a curative treatment, local prostate cancer after radical resection, ductal carcinoma in situ or papillary thyroid cancer after radical resection); - Abnormal blood coagulation (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or APTT > 1.5 ULN), with bleeding tendency or undergoing thrombolytic or anticoagulant therapy; Note: Under the condition of prothrombin time international normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for preventive purposes; - Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed 24-hour urine protein ≥ 1.0g; - The effects of surgery or trauma have been eliminated for less than 14 days before enrollment in subjects who have undergone major surgery or have severe trauma; - Severe acute or chronic infections requiring systemic treatment; Suffering from severe cardiovascular disease: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including men with QTc interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV Insufficient function, or cardiac color Doppler ultrasound examination indicates left ventricular ejection fraction (LVEF) <50%; - There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for trauma; - Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including pleural effusion, ascites, pericardial effusion) requiring surgical treatment; Long-term unhealed wounds or fractures; - Decompensated diabetes or other ailments treated with high doses of glucocorticoids; - Factors that have a significant impact on oral drug absorption, such as inability to swallow, chronic diarrhea, and intestinal obstruction; - Clinically significant hemoptysis (daily hemoptysis greater than 50ml) within 3 months prior to enrollment; or significant clinically significant bleeding symptoms or defined bleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, baseline fecal occult blood ++ and above, or suffering from vasculitis; - Events of venous/venous thrombosis occurring within the first 12 months prior to enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism; - Physical examination and laboratory findings: 1. --- S768I --- --- L858R ---

Primary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (PFS, progression-free survival)

Measure: progression-free survival

Time: Estimated about 24 months.

Secondary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (OS, overall survival)

Measure: Overall Survival

Time: Estimated about 24 months.

Description: Clinical response of treatment according to RESIST v1.1 criteria (DCR, disease control rate)

Measure: Disease Control Rate

Time: Estimated about 24 months.

Description: Clinical response of treatment according to RESIST v1.1 criteria (ORR, Overall Response Rate)

Measure: Overall Response Rate

Time: Estimated about 24 months.

252 A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-788 in Japanese Non-Small Cell Lung Cancer Patients

The purpose of this study is to evaluate the safety, efficacy, tolerability and pharmacokinetics (PK) of TAK-788. At first, Phase 1 part of this study is designed to determine a recommended phase 2 dose (RP2D) of TAK-788 in Japanese participants with locally advanced or metastatic non-small cell lung cancer (NSCLC). After phase 1 study, the phase 2 part of this study will be conducted to evaluate the efficacy and safety of TAK-788 in treatment naive Japanese NSCLC patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation.

NCT03807778
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: TAK-788
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR common mutations (exon 19 del or L858R). --- L858R ---

Primary Outcomes

Description: The RP2D is the maximum tolerated dose (MTD) or less. An RP2D less than the MTD may be chosen if aspects of tolerability or efficacy not encompassed by the MTD determination suggest utilizing a lower dose.

Measure: Phase 1 Part: Recommended Phase 2 Dose (RP2D) of Orally Administered TAK-788

Time: Up to approximately 28 days

Description: IRC assessed objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in participants with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) mutations. ORR is defined as the percentage of participants achieving complete response (CR) and partial response (PR) per RECIST version 1.1. CR: Disappearance of all extranodal target lesions; PR: At least a 30% decrease in Sum of the Longest Diameters (SLD) of target lesions, taking as a reference the baseline SLD.

Measure: Phase 2 Part: Overall Response Rate (ORR) as Assessed by the Independent Review Committee (IRC)

Time: Up to approximately 1.5 years

Secondary Outcomes

Description: An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant who has signed informed consent to participate in a study; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Measure: Phase 1 Part: Number of Participants with Treatment-Emergent Adverse Events (TEAEs)

Time: Up to approximately 1.5 years

Description: Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.00. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications.

Measure: Phase 1 Part: Number of Participants with First Cycle Dose-Limiting Toxicities (DLTs)

Time: Up to approximately 1.5 years

Description: Toxicity will be evaluated according to the NCI CTCAE, Version 5.00. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications.

Measure: Phase 1 Part: DLTs of Orally Administered TAK-788

Time: Up to approximately 28 days

Description: The MTD is the highest dose level at which the participant tolerates treatment without dose-limiting toxicities.

Measure: Phase 1 Part: Maximum Tolerated Dose (MTD) of Orally Administered TAK-788

Time: Up to approximately 28 days

Measure: Phase 1 Part: Cmax: Maximum Plasma Concentration for TAK-788 and its Active Metabolites after a Single Oral Dose

Time: Up to 24 hours; Pre-dose and multiple time points post-dose on Cycle 1 Day 1 (C1D1)

Measure: Phase 1 Part: Tmax: Time to Cmax for TAK-788 and its Active Metabolites after a Single Oral Dose

Time: Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1

Measure: Phase 1 Part: AUC24: Area Under the Plasma Concentration-Time Curve from Time 0 to 24 hours for TAK-788 and its Active Metabolites after a Single Oral Dose

Time: Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1

Measure: Phase 1 Part: AUClast: Area Under the Plasma Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for TAK-788 and its Active Metabolites after a Single Oral Dose

Time: Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1

Measure: Phase 1 Part: Cmax, ss: Maximum Plasma Concentration for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses

Time: Up to approximately 57 days; Pre-dose and multiple time points post-dose

Measure: Phase 1 Part: Tmax, ss: Time to Cmax for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses

Time: Up to approximately 57 days; Pre-dose and multiple time points post-dose

Measure: Phase 1 Part: AUC24, ss: Area Under the Plasma Concentration-Time Curve from Time 0 to 24 hours for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses

Time: Up to approximately 57 days; Pre-dose and multiple time points post-dose

Measure: Phase 1 Part: Rac: Extent of Accumulation Ratio on Multiple Dosing for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses

Time: Up to approximately 57 days; Pre-dose and multiple time points post-dose

Description: IRC assessed objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in participants with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) mutations. ORR is defined as the percentage of participants achieving complete response (CR) and partial response (PR) per RECIST version 1.1. CR: Disappearance of all target lesions; PR: At least a 30% decrease in SLD of target lesions, taking as a reference the baseline SLD.

Measure: Phase 2 Part: Overall Response Rate (ORR) as Assessed by the Independent Review Committee (IRC)

Time: Up to approximately 4 years

Description: Duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that PD is objectively documented.

Measure: Phase 2 Part: Duration of Response (DOR)

Time: Up to approximately 4 years

Description: Time to response is defined as the time interval from the date of randomization until the initial observation of CR or PR.

Measure: Phase 2 Part: Time to Response

Time: Up to approximately 4 years

Description: DCR is defined as the percentage of participants who have achieved CR, PR, or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 42 days) after the initiation of study drug.

Measure: Phase 2 Part: Disease Control Rate (DCR)

Time: Up to approximately 4 years

Description: PFS is defined as the time interval from the date of randomization until the first date at which the criteria for progressive disease (PD) according to RECIST version 1.1 are met or death, whichever occurs first.

Measure: Phase 2 Part: Progression Free Survival (PFS)

Time: Up to approximately 4 years

Description: OS is defined as the interval from the date of randomization until death.

Measure: Phase 2 Part: Overall Survival (OS)

Time: Up to approximately 4 years

Description: EORTC QLQ-C30 is a cancer-specific questionnaire which comprises of 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and a global health status/quality-of-life (QoL) scale. Six single-item scales are also included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores will be converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QoL scale, higher scores represent better HRQoL, whereas for the symptom scales lower scores represent better HRQoL (i.e., a low level of symptomatology/problems).

Measure: Phase 2 Part: Patient-reported Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30

Time: Up to approximately 4 years

Description: EORTC QLQ-LC13 contains 13 questions to assess for: dyspnea, and a series of single items including pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Score of each item will range from 0 to 100, where 0 indicates no symptoms and 100 indicates worst possible symptoms.

Measure: Phase 2 Part: Patient-reported Symptoms (particular core symptoms of lung cancer), Functioning, and HRQoL as Assessed by the EORTC lung cancer module QLQ-LC13

Time: Up to approximately 4 years

253 A Phase IIb, Open-label, Single-arm Study to Assess the Safety and Efficacy of BPI-7711 Capsule in Patients With Metastatic or Recurrent Non-small Cell Lung Cancer With EGFR Mutation and T790M Mutation Positive.

A phase IIb, open-label, single-arm study to assess the safety and efficacy of BPI-7711 capsule in patients with metastatic or recurrent non-small cell lung cancer with EGFR mutation and T790M mutation positive.

NCT03812809
Conditions
  1. NSCLC
Interventions
  1. Drug: BPI-7711
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q). --- L858R ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by an Independent Central Review (ICR)

Time: up to 52 weeks

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by investigators

Time: up to 52 weeks

Description: DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease control rate (DCR) according to RECIST 1.1

Time: up to 104 weeks

Description: PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from BPI-7711 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression free survival(PFS) according to RECIST 1.1

Time: up to 104 weeks

254 A Multicenter, Open-label, Phase II Study to Evaluate the Safety and Efficacy of SH-1028 in Locally Advanced or Metastatic NSCLC

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of SH-1028 with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene.

NCT03823807
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: SH-1028
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR-TKI sensitivity (including exon 19 deletion, L858R, L861Q, G719X or dual mutation) for treatment-naive NSCLC patients (without systemic therapy or with relapse after previous surgery; patients with locally treatment for non-target lesions are accepted ).(This criteria applies to treatment-naïve NSCLC patients in Part B). - Patients must have confirmation of T790M+ mutation status, which have experienced disease progression while on a previous continuous treatment with an EGFR-TKI or clinical benefit from EGFR-TKI according to the Jackman criteria while on continuous treatment with an EGFR-TKI (PR/CR, or SD continued ≥6 months); Patients can receive more than one line of systemic therapy. --- L858R ---

Primary Outcomes

Measure: Objective Response Rate (ORR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Secondary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time: From Baseline up to 30 days after the last dose, an average of 1 year.

Measure: Maximum Plasma Concentration (Cmax)

Time: Part A: Day 1 of Cycle 1 and 2 (21 days for 1 cycle).

Measure: Area Under the Curve [AUC]

Time: Part A: Day 1 of Cycle 1 and 2 (21 days for 1 cycle).

Measure: Progression-free survival (PFS)

Time: Every 2 cycles (21 days for 1 cycle) until end of follow-up, an average of 1 year.

Measure: Duration of Response(DOR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Measure: Disease Control Rates(DCR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Measure: Overall survival(OS)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment; Every 12 weeks until end of follow-up, an average of 2 years.

Other Outcomes

Description: optional,use NGS to analyse the gene associated with NSCLC and to determine the reason of SH-1028-resistance.

Measure: Biomakers (eg. AF value of KRAS,MET mutation or other gene mutations ) of drug-resistance measured by next-generation sequencing (NGS).

Time: at end of treatment,an average of 1 years.

Measure: Minimum Plasma Concentration (Cmin)

Time: Before administration in Day 1 of cycle 2, 3 and 5 (21 days for 1 cycle).

255 A Phase I/II Study of AZD9291 (Osimertinib) and CB-839 HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of telaglenastat hydrochloride, and to see how well it works when given together with osimertinib in treating patients with stage IV non-small cell lung cancer and a mutation in the EGFR gene. Telaglenastat hydrochloride and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03831932
Conditions
  1. Advanced Lung Non-Small Cell Carcinoma
  2. Metastatic Lung Non-Small Cell Carcinoma
  3. Stage IV Lung Cancer AJCC v8
  4. Stage IVA Lung Cancer AJCC v8
  5. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Osimertinib
  2. Drug: Telaglenastat Hydrochloride
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.. Inclusion Criteria: - Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease - Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in combination with other EGFR mutations) as per local assessment of a tissue biopsy/cytology specimen. --- L858R ---

Screening for chronic conditions is not required - Patients with symptomatic CNS metastases who are neurologically unstable - Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of CB-839 HCl (telaglenastat) and AZD9291 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - PHASE 2: Prior chemotherapy for NSCLC is not permitted - PHASE 2: Must be T790M mutation negative as determined by local Clinical Laboratory Improvement Amendments (CLIA)-certified assessment of a tissue biopsy obtained after progression on front-line therapy Inclusion Criteria: - Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease - Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in combination with other EGFR mutations) as per local assessment of a tissue biopsy/cytology specimen. --- T790M --- --- L858R ---

Primary Outcomes

Measure: Recommended phase II dose (RP2D) (Phase I)

Time: Up to 28 days

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least one dose of therapy. All evaluable patients will be included in calculating the ORR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed).

Measure: Objective response rate (ORR) (Phase II)

Time: Up to 30 days after completion of therapy

Secondary Outcomes

Description: Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Measure: Dose limiting toxicities (DLT) (Phase I)

Time: Up to 28 days

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Progression-free survival (PFS) (Phase II)

Time: From initiation of therapy to documented progression or death without progression, assessed up to 30 days after completion of therapy

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Overall survival (OS) (Phase II)

Time: From initiation of therapy to death from any cause, assessed up to 30 days after completion of therapy

Other Outcomes

Description: Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and osimertinib (AZD9291). Will explore PK endpoints such as concentration steady state (Css), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to assess the PK and pharmacodynamics (PD) markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-glutaminase inhibitor CB-839 hydrochloride pharmacokinetics (PK) (CB-839 HCl) (Phase I)

Time: Day 15 of cycle 1, day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)

Description: Will be assessed by AZD9291 drug levels following combination therapy with CB-839 HCl and AZD9291. Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and AZD9291. Will explore PK endpoints such as Css, AUC, CL, Vd, and t1/2 computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, GEE) to assess the PK and PD markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-AZD9291 PK (Phase I)

Time: Day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)

Description: Will be assessed by cell-free deoxyribonucleic acid (cfDNA). All continuous measurements will be summarized using mean +/- standard error of mean (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in EGFR mutational status (Phase II)

Time: Baseline up to disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by plasma concentrations of these compounds. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in circulating levels of glutamine, glutamate, aspartate, and asparagine (Phase II)

Time: Baseline up to time of disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by static (standard uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters. Will be summarized using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.

Measure: Change in 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) imaging (Phase II)

Time: Baseline up to 2 cycles of treatment (each cycle = 28 days)

256 A Randomized, Open-Label, Multi Center, Phase III Study to Assess the Efficacy and Safety of HS-10296 Versus Gefitinib as First-Line Treatment in Patients With EGFR Mutation Positive, Locally Advanced or Metastatic NSCLC

This is a randomized, open-Label, multicenter, Phase III study.

NCT03849768
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: HS-10296
  2. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either or in combination with other EGFR mutations assessed by central testing using tumour tissue sample or blood sample. --- L858R ---

Primary Outcomes

Description: To assess the efficacy of HS-10296 compared with gefitinib as first line therapy to EGFRm+, locally advanced or metastatic NSCLC patients by assessment of progression free survival (PFS) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

Measure: Assess the efficacy of HS-10296: progression free survival (PFS)

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

Secondary Outcomes

Description: Overall survival (OS)

Measure: Assess the anti-tumor activity: OS

Time: Start of study drug to Survival Endpoint through study completion, an average of 3 years.

Description: Objective response rate (ORR)

Measure: Assess the anti-tumor activity: ORR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression assessed up to 24 months.

Description: Duration of response (DoR)

Measure: Assess the anti-tumor activity: DoR

Time: DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression assessed up to 24 months.

Description: Disease control rate (DCR)

Measure: Assess the anti-tumor activity: DCR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD assessed up to 24 months.

Description: Depth of response (DepOR)

Measure: Assess the anti-tumor activity: DepOR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. DepOR is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 target lesions up to 24 months.

Description: Number of adverse events (AEs)/serious adverse events (SAEs)

Measure: Assess the safety of HS-10296: Number of AEs/SAEs

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation

Description: Incidence and severity of AEs/SAEs assessed by CTCAE v4.03

Measure: Assess the safety of HS-10296: Incidence and severity of AEs/SAEs

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation

Description: Dose interruptions

Measure: Assess the safety of HS-10296: Number of Participants with Dose interruptions

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation.

Description: Dose reductions

Measure: Assess the safety of HS-10296: Number of Participants with Dose reductions

Time: Continuously throughout the study until 28 days after HS-10296 discontinuation.

257 A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center Clinical Study to Evaluate the Efficacy and Safety of Toripalimab Injection (JS001) or Placebo Combined With First-line Standard Chemotherapy in Treatment-naive Advanced Non-small Cell Lung Cancer (NSCLC)

This is one randomized, double-blind, placebo-controlled, multi-center, phase III clinical study to evaluate the efficacy and safety of Toripalimab injection (JS001) or placebo combined with standard 1st-line chemotherapy in treatment-naïve advanced non-small cell lung cancer (NSCLC); and evaluate the population with the best predictive biomarkers, i.e., positive diagnosis population. About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. The stratification will be based on the following factors: PD-L1 expression (TC≥1% vs TC<1%); Smoking state (often smoking vs no smoking or infrequent smoking); Pathological type (squamous cell carcinoma vs non-squamous cell carcinoma).

NCT03856411
Conditions
  1. Treatment-naive Advanced Non-small Cell Lung Cancer
Interventions
  1. Drug: TORIPALIMAB INJECTION (JS001 ) combine with chemotherapy
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

About 450 subjects with advanced non-small cell lung cancer without activated EGFR mutation (exon 19 deletion, or exon 21 L858R, exon 21 L861Q, exon 18 G719X or exon 20 S768I mutations) and ALK fusion will be 2:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. --- L858R ---

Primary Outcomes

Description: Progression free survival (PFS) evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST 1.1)

Measure: PFS

Time: Up to 2 approximately years

Secondary Outcomes

Description: Overall survival (OS)

Measure: OS

Time: Up to 2 approximately years

Description: PFS evaluated by the Blinded Individual Review Committee (BIRC) based on RECIST1.1 criteria

Measure: PFS

Time: Up to 2 approximately years

Description: Objective response rate (ORR) evaluated by investigators and BIRC based on RECIST1.1

Measure: ORR

Time: Up to 2 approximately years

Description: Duration of response (DOR) evaluated by investigators and BIRC based on RECIST1.1

Measure: DOR

Time: Up to 2 approximately years

Description: Disease control rate (DCR) evaluated by investigators and BIRC based on RECIST1.1

Measure: DCR

Time: Up to 2 approximately years

Description: Time to response (TTR) evaluated by investigators and BIRC based on RECIST1.1

Measure: TTR

Time: Up to 2 approximately years

Description: Overall incidence of adverse events (AEs); incidence of grade 3 and above AEs; incidence of serious adverse events (SAEs); incidence of AEs leading to termination of the investigational drug; incidence of AEs interruption of the investigational drug

Measure: Incidence of AEs/SAEs

Time: From date of consent informed until 60 days after the last investigational product administration. Up to 2 approximately years

258 A Randomized Controlled, Double-blind, Multicenter, Phase III Clinical Study to Compare Efficacy and Safety of Abivertinib Maleate Versus First-line Standard Therapy EGFR-TKI in Patients With Advanced NSCLC With Sensitive EGFR Mutation

To compare efficacy and safety of Abivertinib maleate alone versus standard first-line EGFR-TKIs for the treatment of patients with advanced non-small cell lung cancer with sensitive EGFR mutation

NCT03856697
Conditions
  1. Advanced Non-small Cell Lung Cancer
Interventions
  1. Drug: Abivertinib Maleate Capsules
  2. Drug: Placebo Gefitinib Tablets
  3. Drug: Gefitinib Tablets
  4. Drug: Placebo Abivertinib Maleate Capsules
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Tumor tissue or cytopathological specimens have any of two common sensitive EGFR mutation (Ex19del or L858R) as confirmed by tests with Cobas (Roche) kit in central lab of this study, which can be combined with other EGFR gene mutations. --- L858R ---

Primary Outcomes

Description: Progression-free survival (PFS) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation (Investigator's evaluation according to RECIST1.1 criteria)

Measure: Assess the efficacy of Abivertinib: Progression Free Survival (PFS)

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months

Secondary Outcomes

Description: Objective Response Rate (ORR) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

Description: Disease Control Rate (DCR) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Disease Control Rate (DCR)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

Description: Duration of Response (DoR) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

Description: Overall Survival (OS) of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Overall Survival (OS)

Time: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 36 months)

Description: Number and severity of AEs/SAEs of Abivertinib maleate alone versus standard first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Safety and Resistance: Number and severity of AEs/SAEs

Time: From screening to the end of survival follow-up, which is assessed through study completion until 30 days after discontinuation

Description: The mean, standard deviation, maximum, minimum, and median of drug exposures in the two groups are described

Measure: Safety and Resistance: Drug exposure

Time: Continuously throughout the study until 30days after discontinuation

Description: A general physical examination includes: general status, skin, head and neck (includes: eyes, ears, nose, throat), respiratory system, cardiovascular system, abdomen,superficial lymph nodes, thyroid, musculoskeletal system (including spine and limbs), and nervous system, and any other physical signs of clinical significance. During the treatment, physical examination of the potentially affected organs will be performed.

Measure: Safety and Resistance: General physical examination status

Time: Continuously throughout the study until 30days after discontinuation

Description: Descriptive statistical analysis of clinical diagnosis results of ECG examination and changes compared with baseline are performed at planned time points, and abnormal ECG examination results are listed.

Measure: Safety and Resistance: Electrocardiogram(ECG test)

Time: Continuously throughout the study until 30days after discontinuation

Description: ECOG (Eastern Clinical Oncology Group) Performance Status Grading Criteria: Range from 0-5, 0 considered to be the best outcome and 5 to be the worst outcome

Measure: Safety and Resistance: Eastern Clinical Oncology Group Scores

Time: Continuously throughout the study until 30days after discontinuation

Description: Quality of life questionnaire of Abivertinib maleate alone versus standard which includes 5 functional domains, 3 symptom domains, 1 overall health status/quality of life domain and 6 single entries. Standardized scores of the domains/single entries in the questionnaire are used to statistically describe the absolute values and changes from baseline at each evaluation time point; t test is used to compare changes from baseline in overall quality of life score at each evaluation time point in both groups; analysis of variance is used to compare changes in overall health status score at each evaluation time point between the two groups. first-line EGFR-TKI for the treatment of treatment-naïve patients with advanced non-small cell lung cancer with sensitive EGFR mutation

Measure: Questionnaire: Health-related quality of life (HRQoL)

Time: At baseline and every 6 weeks until the date of first documented progression or date of death from any cause ( approximately 12 months)

259 MELROSE: Phase 2 Study Evaluating MEchanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtinib Until and Beyond Radiological Progression : the MELROSE Trial

Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The AURA 3 study (T790M-positive advanced non-small-cell lung cancer in progression after first-line EGFR-TKI therapy, shown that the median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months p<0.001). In addition, clinical data show that patients with mutated EGFR NSCLC receiving osimertinib in first line, presented an objective response rate of 77 % with a disease control rate of 98 % and a median PFS was 19.3 months. Finally, The FLAURA study randomized phase 3 study clearly demonstrated the superiority of osimertinib compared with erlotinib or gefitinib in EGFR mutated nonpretreated NSCLC (median PFS of 18.9 months versus 10.2 months). However, several issues remain unknown or debated : - What are the mechanisms of resistance to osimertinib prescribed in first-line? - What are the consequences of prolonged exposure to osimertinib on the expression of markers of response to immunotherapy? - Is there an association between kinetic parameters of ctDNA (circulating tumor DNA) and prediction of response to osimertinib and/ or and prediction of therapeutic escape under osimertinib? In order to respond to all these questions, this phase II trial will be the first to systemically analyze the mechanisms of resistance to Osimertinib based on the analysis of biopsy, and collection of plasma from all patients during the course of treatment.

NCT03865511
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: TAGRISSO® 80mg (Osimertinib)
  2. Genetic: Tumor biopsies
  3. Genetic: ctDNA analysis
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19 deletions, L858R), either alone or in combination with other EGFR mutations. --- L858R ---

Primary Outcomes

Description: Analyze of the proportion of patients with a given genetic marker on tumor biopsy (including, but not limited to, EGFR mutations, HER2 (Human Epidermal Growth factor receptor 2), and cMET expression and/or amplification) at the point of clinical disease progression.

Measure: Examination of the genetic profile at the point of disease progression in EGFRm+ (mutated Epidermal Growth Factor Receptor) patients receiving osimertinib as first-line EGFR TKI therapy compared to baseline.

Time: At clinical disease progression (approximately 22 months)

Secondary Outcomes

Description: Progression free survival rate at one year defined by time from first study dose to first event between Radiological Progression Disease and death, or one year if no event. The rPFS is defined according to RECIST 1.1.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every 3 months up to one year after first study dose

Description: Radiological Progression Free Survival (rPFS): Time from first study dose to first event between rPFS or death. The rPFS is defined according to RECIST 1.1.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every 3 months until radiological disease progression (approximately 22 months)

Description: Clinical Progression Free Survival (cPFS): Time from first study dose to off-osimertinib.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every month until clinical disease progression (approximately 22 months)

Description: Overall survival

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: From first dose to end of study or date of death from any cause, whicheever comes first, assessed every 3 months (approximately 48 months)

Description: Objective Response Rate (ORR)

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: every 3 months until radiological disease progression (approximately 22 months)

Description: Duration of Response (DoR): Disease Control Rate (DCR)

Measure: Clinical objective : To assess efficacy of Osimertinib: Duration of Response (DoR): Disease Control Rate (DCR)

Time: every 3 months until radiological disease progression (approximately 22 months)

Description: Monitoring of Adverse events (grade 3 and 4)

Measure: Clinical objective : To assess safety of Osimertinib with Monitoring of Adverse events (grade 3 and 4)

Time: monthly from first study dose until 15 days after last study dose

Description: By the study of the expression of molecules involved in the efficacy of check point inhibitors determined by immunohistochemistry (PD-L1; CD73; CD4; CD8) on tumor tissue collected at progression

Measure: Biological objective : To evaluate the consequence of osimertinib treatment on the expression of targets of immune check point inhibitors

Time: At baseline and at clinical disease progression (approximately 22 months)

Description: Analyze of mutation at progression on tumor tissue and ctDNA

Measure: Biological objective : To evaluate diagnostic accuracy of ctDNA to detect mutation

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of the presence of tumors ctDNA at baseline, clinical progression disease

Measure: Biological objective : To observe if the presence of ctDNA at baseline is a prognostic factor of clinical progression disease

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of absolute quantities of ctDNA molecules presenting the EGFR mutation identified in the tumor, clinical progression disease

Measure: Biological objective : To demonstrate that the early kinetics of ctDNA is an indicator of response to osimertinib

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Serial monitoring in ctDNA of molecular alterations identified in tissues collected at progression

Measure: Biological objective : To measure the biological progression (bPFS) in patients treated with osimertinib

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of the EGFR mutation identified in the tumor biopsy and in the ctDNA

Measure: Biological objective : To compare the genetic profile of the ctDNA and the tumor biopsy

Time: At baseline and at clinical disease progression (approximately 22 months)

Description: Analyze of the absolute quantities of ctDNA molecules presenting the EGFR mutation monthly, radiological and clinical progression disease

Measure: Biological objective : To compare the kinetic of appearance of EGFR mutation and radiological and clinical progression disease

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

260 A Randomized Trial of Consolidative Immunotherapy With vs Without Thoracic Radiotherapy and / or Stereotactic Body Radiation Therapy (SBRT) After First-Line Systemic Therapy for Metastatic NSCLC

This phase III trial studies immunotherapy and stereotactic body radiation therapy to see how well it works compared with immunotherapy alone after first-line systemic therapy (therapy that goes throughout the body) in treating patients with stage IV non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving immunotherapy with stereotactic body radiation therapy may work better than immunotherapy alone in treating patients with non-small cell lung cancer.

NCT03867175
Conditions
  1. Metastatic Lung Cancer
  2. Stage IV Lung Cancer
Interventions
  1. Radiation: Stereotactic Body Radiation Therapy
  2. Biological: Pembrolizumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- Patients with major activating mutations in EGFR (del19, L858R, and T790M) or ROS 1 or ALK gene rearrangements are excluded Eligibility for Randomization - Once enrolled on study, patients will have a PET/MRI brain for restaging. --- L858R ---

Primary Outcomes

Description: Will be determined using the product-limit method of Kaplan and Meier. Will compare unadjusted median PFS between the 2 arms using a log-rank test. Will also use a proportional hazards model to compare progression-free survival between the two groups, adjusting for key covariates such as age, performance (Eastern Cooperative Oncology Group) status, response to initial systemic therapy versus (vs) stable disease, the presence or absence of brain metastases, PD-L1 [programmed death-ligand ] expression (< 1% vs > 50%), tumor histology (adenocarcinoma vs non-adenocarcinoma), and number of disease sites treated (1-3 sites vs 4-6 sites).

Measure: Progression-free survival (PFS) after completion of first line systemic therapy

Time: Up to 5 years

Secondary Outcomes

Description: Will be reported with an exact 95% confidence interval.

Measure: Overall Survival

Time: Up to 5 years

Description: In patients not receiving radiation, the investigators will assess progression at their known sites of disease prior to beginning first line systemic chemotherapy.

Measure: Time of Progression

Time: Baseline up to 5 years

Description: Investigators will assess the rate of failures inside and outside of radiation treatment.

Measure: Rate of Failure

Time: Baseline up to 5 years

Description: Investigators will assess the development of new sites of disease during or after immunotherapy

Measure: Number of Participants with New Sites of Disease

Time: Baseline up to 5 years

Description: All safety measures, including acute and late toxicity, will be reported using descriptive statistics (mean, median, standard deviation, proportions, and 95% confidence intervals). This will include calculating frequency/risk of adverse events by treatment site. Potential toxicities reported would include pneumonitis, esophagitis, chest wall pain, dermatologic toxicity, renal dysfunction, gastrointestinal toxicity including nausea, vomiting, and diarrhea, hepatotoxicity, and abdominal pain. These toxicities would be assessed according to site of irradiation by the treating physician and graded as per Common Terminology Criteria for Adverse Events 5.

Measure: Incidence of adverse events

Time: Up to 5 years

261 ALCMI-012 A Prospective Biospecimen Collection Study From Patients With EGFR Mutant Tumors

A biospecimen collection study from individuals with EGFR mutant cancers resistant to EGFR TKIs or those harboring an Exon 20 insertion mutation.

NCT03872440
Conditions
  1. Non Small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

1. EGFR T790M patients who have progressed on osimertinib or other third generation (mutant selective) EGFR TKI therapy or 2. Patients must have an EGFR exon 19 deletion or L858R and progressed on first line osimertinib or 3. Patients with an exon EGFR or HER2 20 insertion mutation. --- T790M --- --- L858R ---

No confirmed diagnosis of EGFR exon 19 deletion, L858R or EGFR or HER2 exon 20 mutation. --- L858R ---

Patients whose tumors harbor EGFR mutations other than an exon 19 deletion, L858R or exon 20 EGFR insertion or HER2 exon 20 insertions are not eligible. --- L858R ---

There are several types of EGFR mutations including both the common L858R and exon 19 deletions (accounting for 85%) or the rare exon 20 insertion (accounting for 5-8%) EGFR mutations. --- L858R ---

Osimertinib is an EGFR inhibitor approved for patients newly diagnosed with EGFR exon 19 or L858R mutations and for patients who have been treated with a prior EGFR inhibitor but have developed EGFR T790M as a resistance mechanism. --- L858R ---

Primary Outcomes

Description: Successful generation of at least fifty (50) PDX models with full characterization including whole exome sequencing (WES) and RNA sequencing. These PDX models will be used to inform the study of EGFR-driven cancers at large.

Measure: The primary objective is to develop a unique cohort of PDX models from EGFR mutant cancers as a resource to the research community.

Time: 48 months

262 An Open-Label Randomized Phase II Study of Combining Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor (TKI)-naïve Epidermal Growth Factor Receptor (EGFR)-Mutant Locally Advanced or Metastatic NSCLC

The primary objective of the study is to evaluate the efficacy of osimertinib plus ramucirumab versus osimertinib alone using progression free survival (PFS). Events associated with PFS include: disease progression per RECIST 1.1 and death due to any cause. A total of 150 patients will be enrolled and randomized in a 2:1 fashion (osimertinib plus ramucirumab vs. osimertinib) to the two treatment arms according to the following stratification factors: types of epidermal growth factor receptor (EGFR) mutations and presence of brain metastasis.

NCT03909334
Conditions
  1. Non Small Cell Lung Cancer
  2. EGFR Gene Mutation
  3. Advanced Cancer
  4. Metastatic Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Ramucirumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- NSCLC which harbors EGFR L858R mutation. --- L858R ---

Primary Outcomes

Description: Progression free survival (PFS) time will be calculated from the date of randomization to disease progression or death from any cause, whichever occurs the first.

Measure: Progression Free Survival (PFS)

Time: 3 years

Secondary Outcomes

Description: Objective Response Rate (ORR) is defined as the number (%) of subjects with measurable disease with at least one visit response of complete response (CR) or partial response (PR). Data obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of ORR.

Measure: Objective Response Rate (ORR)

Time: 1 year

Description: Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of CR or PR or stable disease (SD).

Measure: Disease control rate (DCR)

Time: 2 years

Description: Overall survival (OS) time is defined from the date of randomization to death date. A patient is censored at the last follow-up date if death has not been observed.

Measure: Overall survival (OS)

Time: 3 years

Description: Toxicities will be measured in frequency and severity using CTCAE v5

Measure: Assess frequency and severity of adverse events

Time: 2 years

263 Open Label, Multicenter, Real World Treatment Study of Single Agent Tagrisso; KOREA PLUS Study (Korea Osimertinib Real World Evidence Study to Assess Safety and Efficacy - PLUS)

This is a local, prospective, non-interventional, regulatory postmarketing surveillance study. The objectives of this study are to assess the safety and efficacy of single agent Tagrisso (Osimertinib, hereinafter "the study drug") in a real world setting according to the approved label in Korea

NCT03918304
Conditions
  1. Carcinoma, Non-Small-Cell Lung
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R ---

Primary Outcomes

Measure: Proportion (%) of patients with at least one event of adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI)

Time: for about 1 year since the first dose of the study drug

Measure: Severity of (S)AEs according to CTCAE

Time: for about 1 year since the first dose of the study drug

Secondary Outcomes

Measure: ORR (Objective response rate), if available

Time: for about 1 year since the first dose of the study drug

264 Whole Genomic Landscape of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Treated With First-Line Osimertinib (WARRIOR)

This is a phase 2 single-arm, non-randomized multicentre and tissue acquisition study to evaluate acquired resistance mechanisms, efficacy, and safety in advanced, EGFR tyrosine kinase inhibitor-naïve NSCLC patients with EGFR-activating mutations who receive a first-line osimertinib orally at a dose of 80mg once daily.

NCT03969823
Conditions
  1. Locally Advanced or Metastatic NSCLC
Interventions
  1. Drug: Tagrisso
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: 1. Provision of informed consent prior to any study specific procedures 2. Male or female must be > 19 years of age 3. Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments - Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 4. Male subjects should be willing to use barrier contraception (see Restrictions, Section 3.8) 5. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy with local confirmation of the presence of EGFR TKI-sensitizing mutation (EGFR exon 19 deletion or L858R mutation), either alone or in combination with other EGFR mutations excluding EGFR exon 20 insertion mutation 6. Mandatory provision of fresh tumor sample before osimertinib via a biopsy or surgical resection 7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 8. Patients must have a life expectancy ≥ 12 weeks. --- L858R ---

Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection Inclusion Criteria: 1. Provision of informed consent prior to any study specific procedures 2. Male or female must be > 19 years of age 3. Female subjects should be using highly effective contraceptive measures, and must have a negative pregnancy test and not be breast-feeding prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments - Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 4. Male subjects should be willing to use barrier contraception (see Restrictions, Section 3.8) 5. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy with local confirmation of the presence of EGFR TKI-sensitizing mutation (EGFR exon 19 deletion or L858R mutation), either alone or in combination with other EGFR mutations excluding EGFR exon 20 insertion mutation 6. Mandatory provision of fresh tumor sample before osimertinib via a biopsy or surgical resection 7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 8. Patients must have a life expectancy ≥ 12 weeks. --- L858R ---

Primary Outcomes

Description: Disease progression as defined by investigator assessments according to RECIST1.1

Measure: Proportion of acquired resistance mechanisms to osimertinib at disease progression

Time: Through study completion, an average of 2 years

Secondary Outcomes

Description: AEs/SAEs as defined by NCI CTCAE version 5.0

Measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

Time: Through study completion, an average of 2 years

Description: PFS as defined as the time from the date of initiation until the date of first documented progression

Measure: Progression-Free Survival (PFS)

Time: Through study completion, an average of 2 years

Description: OS as defined as the time from the date of first dose until death due to any cause

Measure: Overall Survival (OS)

Time: Through study completion, an average of 2 years

Description: ORR using investigator assessments according RECIST1.1

Measure: Objective Response Rate (ORR)

Time: Through study completion, an average of 2 years

265 A Randomized Phase 2 Study Comparing Immunotherapy With Chemotherapy in the Treatment of Elderly Patients With Advanced NSCLC (MILES-5)

This is a randomized phase 2 trial aiming to assess the early efficacy of two experimental treatment sequences. Three arms are planned; (i) standard chemotherapy followed at progression by single agent immunotherapy with durvalumab (CT), (ii) experimental single agent immunotherapy with durvalumab followed at progression by chemotherapy, (iii) experimental combination immunotherapy with durvalumab+tremelimumab followed at progression by chemotherapy. The the two experimental strategies will be compared with the standard strategy in terms of 12-month overall survival, time considered informative for the type of treatment and disease

NCT03975114
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Chemotherapy
  2. Drug: Durvalumab
  3. Drug: Tremelimumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Exclusion Criteria: Cancer related 1. Activating epidermal growth factor receptor mutation (exon19 deletion or exon 21 L858R mutation or other activating/sensitizing mutations). --- L858R ---

Primary Outcomes

Description: 12-month overall survival is defined as the Kaplan-Meier (K-M) survival probability at 12 months after randomization (Chen 2015).

Measure: 12-month overall survival

Time: 12 months

266 A Phase Ib Clinical Study With Extension Phase to Evaluate Safety and Efficacy of Genolimzumab (GB226) in Combination With Fruquintinib in the Treatment of Relapsed or Metastatic NSCLC Patients

This study is a multi-center, open-label, dose-finding phase Ib clinical study with extension phase, which is aimed at evaluating the efficacy and safety of GB226 combined with fruquintinib in treatment of relapsed or metastatic NSCLC patients with EGFR-sensitive mutations who have failed to respond to EGFR-TKI treatment,evaluating the pharmacokinetic characteristics of GB226 and fruquintinib, and the immunogenicity of GB226, and preliminarily evaluating the antitumor activity of GB226 and fruquintinib.

NCT03976856
Conditions
  1. Metastatic Non-small Cell Lung Cancer
Interventions
  1. Drug: GB226
  2. Drug: Fruquintinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

To evaluate the immunogenicity of GB226 in Chinese patients with lung cancer.. Inclusion Criteria: 1. Aged 18-75 years, male or female; 2. Understanding the procedures and contents of the study, and voluntarily signing the written informed consent form; 3. Histologically or cytology confirmed relapsed or metastatic NSCLC; 4. EGFR gene sensitive mutation is confirmed positive, any of following is met: exon 19 deletion (19DEL), exon 21 point mutation (L858R / L861Q), 18 exon point mutation (G719X), 20 exon point mutation (S768I). --- L858R ---

Inclusion Criteria: 1. Aged 18-75 years, male or female; 2. Understanding the procedures and contents of the study, and voluntarily signing the written informed consent form; 3. Histologically or cytology confirmed relapsed or metastatic NSCLC; 4. EGFR gene sensitive mutation is confirmed positive, any of following is met: exon 19 deletion (19DEL), exon 21 point mutation (L858R / L861Q), 18 exon point mutation (G719X), 20 exon point mutation (S768I). --- L858R ---

Primary Outcomes

Description: Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Assessment of serious adverse events (SAEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Serious Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Incidence of Dose Limited Toxicity

Measure: Dose Limited Toxicity

Time: Day 1 to Day 28 after first dose

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 4.03

Measure: Maximum Tolerated Dose

Time: Day 1 to Day 28 after first dose

Secondary Outcomes

Description: Cmax

Measure: Cmax

Time: up to 90 days after the last administration

Description: Tmax

Measure: Tmax

Time: up to 90 days after the last administration

Description: AUC0-t

Measure: AUC0-t

Time: up to 90 days after the last administration

Description: AUC0-∞

Measure: AUC0-∞

Time: up to 90 days after the last administration

Description: MRT

Measure: MRT

Time: up to 90 days after the last administration

Description: Vd

Measure: Vd

Time: up to 90 days after the last administration

Description: CL

Measure: CL

Time: up to 90 days after the last administration

Description: AUC 0-τ

Measure: AUC 0-τ

Time: up to 90 days after the last administration

Description: C avg

Measure: C avg

Time: up to 90 days after the last administration

Description: C min

Measure: C min

Time: up to 90 days after the last administration

Description: CL ss

Measure: CL ss

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by objective response rate in patients with lung cancer.

Measure: Objective Response Rate, ORR

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by disease control rate in patients with lung cancer.

Measure: Disease control rate,DCR

Time: up to 90 days after the last administration

Description: To evaluate the duration of response (DOR) of GB226 in patients with lung cancer

Measure: Duration of response, DOR

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by progression-free survival in patients with lung cancer

Measure: Progression-free survival, PFS

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by overall survival in patients with lung cancer.

Measure: Overall survival, OS

Time: up to 90 days after the last administration

Description: To evaluate the immunogenicity of GB226 in Chinese patients with lung cancer.

Measure: Concentration of AntiDrug Antibody, ADA

Time: up to 90 days after the last administration

267 Phase III Randomized Trial of Atezolizumab in Elderly Patients With Advanced Non-Small-Cell Lung Cancer and Receiving Monthly Carboplatin With Weekly Paclitaxel Chemotherapy

Non Small Cell Lung Cancer (NSCLC) remains the leading cause of death by cancer in the world. Because of the increase in lung cancer incidence with age and the increase of life expectancy, about half of the patients are patients aged 70 or older. Several clinical trials have shown the interest of adding immunotherapy to standard 1st line chemotherapy in NSCLC. Although in these studies there was not necessarily a higher age limit, in fact the proportion of included patients aged 75 or older remains low (between 7 and 10%). It is therefore necessary to conduct a trial dedicated to these patients in order to determine whether immunotherapy is as effective and tolerated as in the general population.

NCT03977194
Conditions
  1. Non Small Cell Lung Cance
  2. Non Small Cell Lung Cancer Metastatic
Interventions
  1. Drug: Carboplatin
  2. Drug: Paclitaxel
  3. Drug: Atezolizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: 1. Small cell lung cancer or tumors with mixt histology including a SCLC component 2. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18) or HER2 exon 20 insertion (either tissue or plasma cfDNA mutation). --- L858R ---

Primary Outcomes

Description: Time from randomization until death due to any cause

Measure: Overall Survival

Time: 11 months after randomization of the last subject

Secondary Outcomes

Description: Time from randomization to first observation of progression (according to RECIST v1.1) or date of death (from any cause).

Measure: Progression-free survival

Time: 11 months after randomization of the last subject

Description: Best response according to RECIST v1.1 from start to end of study treatment

Measure: Best overall response rate

Time: 11 months after randomization of the last subject

Description: Time from documentation of tumor response to disease progression

Measure: Duration of response

Time: 11 months after randomization of the last subject

268 Phase Ib Study to Assess Safety and Tolerability of PDR001 in Combination With Panobinostat in Metastatic Melanoma and Non-small Cell Lung Cancer After Failure of Prior Anti PD1 or PD-L1 Therapy

The purpose of this research study is to find the dose of the study drug PDR001 that, when given in combination with the drug Panobinostat, results in the best outcomes for metastatic melanoma and non-small cell lung cancer (NSCLC)

NCT03982134
Conditions
  1. Melanoma
  2. Non Small Cell Lung Cancer
Interventions
  1. Drug: PDR001
  2. Drug: Panobinostat
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Melanoma
HPO:Cutaneous melanoma Melanoma Neoplasm of the lung Non-small cell lung carcinoma

- Patients with NSCLC who are known to have targetable genomic alterations (including EGFR exon 19 deletion or L858R substitution, ALK rearrangement, ROS1 fusion, NTRK 13 fusions, BRAF V600 mutation), must have progressed on or could not tolerate FDA approved targeted therapy for the alterations mentioned above, in addition to progressed on PD-1/L1 Checkpoint blockade to be eligible for the study. --- L858R ---

Primary Outcomes

Description: The recommended Phase 2 dose will be determined by using a 3 + 3 design with 1 dose escalation and 2 dose deescalation cohorts. Safety assessments will consist of monitoring and recording all adverse events, including serious adverse events, the monitoring of hematology, chemistry, ECG and the regular monitoring of vital signs, thyroid function, pregnancy and physical exam including weight and performance status.

Measure: To assess the safety and tolerability of PDR001 in combination with panobinostat in determining a recommended Phase II dose

Time: Initiation of treatment up to 2 years

Secondary Outcomes

Description: All adverse events (AEs) will be considered in DLT assessment unless the event is clearly unrelated to trial treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 will be used.

Measure: Incidence of dose limiting toxicities (DLTs) using CTCAE, Version 5.0

Time: Initiation of treatment up to 2 years

Description: PFS is defined as the time between the first dose of study therapy and the earliest date of progression or death (participants who have neither progressed nor dies will be censored at the most recent last-known-alive date).

Measure: Progression free survival (PFS) per RECIST 1.1

Time: Initiation of treatment up to 2 years

Description: OS is calculated from time when study therapy begins to death from any cause.

Measure: Overall survival (OS)

Time: Initiation of treatment up to 2 years

Description: OS is defined as the time between the first dose of study therapy and death (participants who have not died will be censored at the most recent last-known-alive date).

Measure: Overall Response Rate (ORR) per RECIST 1.1

Time: Initiation of treatment up to 2 years

269 A Phase 2 Trial of Durvalumab (MEDI4736) and Tremelimumab With Chemotherapy in Metastatic EGFR Mutant Non-squamous Non-small Cell Lung Cancer (NSCLC) Following Progression on EGFR Tyrosine Kinase Inhibitors (TKIs)

The primary purpose of this trial is to evaluate the efficacy and tolerability of durvalumab and tremelimumab with platinum-pemetrexed in patients with metastatic NSCLC (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors.. Study population: Individuals may be eligible to enrol in this trial if aged 18 or over and have been diagnosed with advanced non-small cell lung cancer (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors. Study details: All participants enrolled in this trial will begin with induction therapy which involves 4 cycles of durvalumab 1500mg and tremelimumab 75mg with cisplatin 75mg/m2 or carboplatin AUC 5, and pemetrexed 500mg/m2 intravenously every 3 weeks. Participants will then move into a maintenance phase of durvalumab 1500mg and pemetrexed 500mg/m2 once every 4 weeks until disease progression or unacceptable side effects. All patients will be reviewed every three to four weeks by blood samples, CT scans and side effect assessments. It is hoped that the findings from this trial will provide information on whether treatment with durvalumab and tremelimumab with platinum-pemetrexed is feasible, safe and effective for the treatment of advanced non-small cell lung cancer (T790+ve or T790M-ve).

NCT03994393
Conditions
  1. EGFR Mutant Advanced Non Small Cell Lung Cancer
Interventions
  1. Drug: Tremelimumab
  2. Drug: Durvalumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Number and Severity (assessed as a composite) of Adverse Events - using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.. Inclusion Criteria: 1. Adults, aged 18 years and older with histologically and/or cytologically confirmed non-squamous non-small cell lung cancer with EGFR mutation of Exon 19 deletion or Exon 21 L858R point mutation. --- L858R ---

- Patients with co-mutations are allowed as long as one of the mutation is either Exon 19 deletion or Exon 21 L858R point mutation - Patients with mixed histology must have non-squamous NSCLC as the predominant histology. --- L858R ---

Inclusion Criteria: 1. Adults, aged 18 years and older with histologically and/or cytologically confirmed non-squamous non-small cell lung cancer with EGFR mutation of Exon 19 deletion or Exon 21 L858R point mutation. --- L858R ---

Primary Outcomes

Description: Objective tumour response rate (OTRR) as defined by RECIST 1.1. Objective tumour response (OTR) is defined as a partial response or compete response by RECIST 1.1. OTRR is defined as the proportion (percentage) of participants with a confirmed CR or PR according to RECIST 1.1.

Measure: Objective tumour response rate (OTRR) and Objective tumour response (OTR)

Time: 36 months post enrolment of first participant.

Secondary Outcomes

Description: Disease control (Disease Control Rate (DCR) = Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) as defined by RECIST 1.1.

Measure: Disease control (Disease Control Rate (DCR)

Time: 36 months post enrolment of first participant.

Description: Objective tumour response rate (OTRR) as defined by iRECIST. Objective tumour response (OTR) is defined as a partial response or compete response by iRECIST. OTRR is defined as the proportion (percentage) of participants with a confirmed CR or PR according to iRECIST.

Measure: Objective tumour response rate (OTRR) & Objective tumour response (OTR)

Time: 36 months post enrolment of first participant.

Description: Progression-free survival (PFS) as defined by RECIST 1.1 and iRECIST. PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death, whichever occurs first. Disease progression is defined according to RECIST 1.1 and iRECIST.

Measure: Progression-free survival (PFS)

Time: 36 months post enrolment of first participant.

Description: Progression-free survival at 12 months (PFS12) as defined by RECIST 1.1 and iRECIST. PFS at 12 months taken to mean 1 calendar year, i.e. 365 days. Study participants who have stable disease, partial response or complete response confirmed at the first scheduled assessment after 12 months according to RECIST v1.1 will be considered to have attained PFS at 12 months.

Measure: Progression-free survival at 12 months (PFS12)

Time: 12 months post enrolment of last participant.

Description: Overall survival (OS) is defined as the interval from the date of registration to date of death from any cause, or the date of last known follow-up alive.

Measure: Overall survival (OS)

Time: 36 months from enrolment of first participant.

Description: Number and Severity (assessed as a composite) of Adverse Events - using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.

Measure: Number and Severity (assessed as a composite) of Adverse Events

Time: 36 months post enrolment of first participant.

270 A Study of Nivolumab +/- Docetaxel in Patients Previously Treated With Advanced or Metastatic Non Small Cell Lung Cancer

This study is a randomized, single-center, open-label, phase II clinical trial designed to evaluate non-small cell lung cancer that has failed to undergo excessive platinum-based chemotherapy and has not received excessive statin chemotherapy and has not received immunotherapy. The efficacy and safety of Nivolumab in combination with docetaxel and Nivolumab in patients. Qualified patients were stratified by histological type (squamous cell carcinoma vs. non-squamous cell carcinoma) randomized to receive the following regimen in a 1:1 ratio: Group A: Nivolumab 300mg + docetaxel 75mg/m2 IV q3w Group B: Nivolumab 200mg IV q2w All patients were evaluated for tumor at baseline, and tumor evaluations were performed every 6 weeks within 48 weeks after randomization (regardless of whether dosing was delayed). After the 48th week of assessment, a tumor assessment is required every 9 weeks until disease progression, withdrawal of informed consent, sponsor termination study, or patient death.

NCT04023617
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Docetaxel
  3. Nivolumab
Interventions
  1. Drug: Nivolumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

3. The patient's tumor must be free of EGFR gene-sensitive mutations (including but not limited to exon 19 deletion mutation or exon 21 L858R mutation, exon 21 L861Q, exon 18 G719X or exon 20 S768I site Mutation) and ALK gene rearrangement. --- L858R ---

Primary Outcomes

Description: progression-free survival

Measure: PFS

Time: 24 months

Secondary Outcomes

Description: overall survival

Measure: OS

Time: 24 months

271 A Single-arm, Open-label, Phase 2 Study of Dacomitinib With or Without Dose Titration for the First-line Treatment of Locally Advanced or Metastatic Non-small Cell Lung Cancer in Subjects With an Epidermal Growth Factor Receptor (EGFR) Activation Mutation

This is a multi-national, multi-centre, single-arm, open-label, Phase 2 clinical study of the efficacy and safety of first-line treatment with dacomitinib, with or without dose titration, in subjects with newly diagnosed stage IIIB/IV or recurrent EGFR-mutation-positive non-small cell lung cancer (NSCLC). National Cancer Centre Singapore will be the lead sponsor acting in a coordinating capacity and the rest of the participating sites are sponsors of their own individual sites.

NCT04027647
Conditions
  1. NSCLC Stage IIIB
  2. NSCLC Stage IV
  3. Recurrent NSCLC
  4. EGFR Positive Non-Small Cell Lung Cancer
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Provision of a voluntarily given, personally signed and dated, written informed consent document; - Age ≥20 years in Japan and Korea, and ≥18 years in other countries, male or female; - The presence of an EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) in tumor specimen determined by the local laboratory; - Evidence of newly diagnosed stage IIIB/IV (based on Union for International Cancer Control (UICC) staging system version 8) or recurrent (minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC required) NSCLC of adenocarcinoma histo- and/or cytopathology or its pathologically accepted variants using tumor specimen (assessed according to accepted standards by a local laboratory). --- L858R ---

Primary Outcomes

Description: Percentage of subjects with PFS at 12 months

Measure: Progression-Free Survival (PFS)

Time: From the start of treatment to the date of disease progression or death due to any cause at 12 months

Secondary Outcomes

Measure: Overall Survival

Time: From the start of treatment to the date of death for any cause, up to 3 years

Description: Proportion of subjects with a best overall response of either complete response (CR) or partial response (PR)

Measure: Objective Response Rate

Time: From the start of treatment until disease progression, up to 3 years

Measure: Time to Treatment Failure

Time: From the start of treatment to the last dose of treatment, up to 3 years

Description: Proportion of subjects with a best overall response of either CR or PR of intracranial disease

Measure: Intracranial Objective Response Rate

Time: From the start of treatment until disease progression, up to 3 years

Measure: Intracranial Progression-Free Survival

Time: From the start of treatment to the date of intracranial progression or death due to any cause, up to 3 years

Measure: Number of incidences of adverse events

Time: From start of treatment to 28 days after end of treatment

272 A Multicenter, Randomized, Double-Blind Study of Gefitinib in Combination With Anlotinib or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer

Gefitinib is currently the standard-of-care for patients with activating-EGFR mutant advanced non-small cell lung cancer (NSCLC). However, ~30-40% patients are still nonresponsive, and experience significantly varying duration of response and survival rate. Anlotinib is an efficient multi-target tyrosine kinase inhibitor (TKI) that effectively block the migration and proliferation of endothelial cells and reduce tumor microvascular density by targeting VEGFRs, FGFRs, PDGFRs. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure, which can significantly extend the survival of patients and approves as a third-line treatment for advanced NSCLC. Here, we prepared to evaluate whether the combination of gefitinb and anlotinib can preferably improved survival of untreated NSCLC with EGFR activating mutation.

NCT04028778
Conditions
  1. Lung Cancer, Nonsmall Cell
Interventions
  1. Drug: Gefitinib
  2. Drug: Anlotinib Hydrochloride
  3. Other: Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- 5.Documented evidence of tumor harboring an activating EGFR mutation (exon19 del and L858R) - 6.None previous chemotherapy or targeted therapy. --- L858R ---

Primary Outcomes

Description: Progression-Free Survival (PFS) as Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)

Measure: Progress-free survival (PFS)

Time: Approximately 2 Years

Secondary Outcomes

Description: OS was defined as the time from the date of randomization to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: Approximately 5 Years

Description: PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions).

Measure: Percentage of Participants With Objective Response (Partial Response [PR] Plus Complete Response [CR]), as Assessed Using RECIST v.1.1

Time: Approximately 2 Years

Description: Clinical benefit was defined as objective response (PR+CR), or no disease progression lasting for more than or equal to (>/=) 24 weeks since randomization. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression.

Measure: Percentage of Participants With Clinical Benefit, as Assessed According to RECIST v1.1

Time: Approximately 2 Years

Description: Duration of objective response: the time from the first tumor assessment that supported the participant's objective response (CR or PR, whichever was first recorded) to first documented disease progression or death due to any cause, whichever occurred first. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression.

Measure: Duration of Objective Response, as Assessed by Investigator Using RECIST v1.1

Time: Approximately 2 Years

Other Outcomes

Description: The EORTC QLQ-C30 consists of 30 questions that comprise aspects of participant's functioning assessment (physical, emotional, role, cognitive, and social); symptom scales (fatigue; nausea, vomiting, and pain; the global health/quality of life [QoL]); and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties), within a recall period of "the past week." Most questions used a 4-point scale (1=Not at all to 4=Very much; two questions used a 7-point scale (1=Very poor to 7=Excellent). Scores were averaged and transformed to a 0-100 scale; a higher score for Global Qol/functional scales=better level of functioning; a higher score for symptom scale=greater degree of symptoms.

Measure: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Score

Time: Approximately 2 Years

273 A Multi-center, One-arm, Phase II Trial of Anlotinib Combined With Osimertinib as the Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M.

Evaluate the efficacy and safety of Anlotinib combined with Icotinib as the second-line treatment in stage IIIb-IV NSCLC patients with sensitive EGFR and T790M mutations.

NCT04029350
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib Combined With Osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

2. Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing. --- L858R ---

Primary Outcomes

Description: The PFS time is defined as time from enrollment to locoregional or systemic recurrence, second malignancy or death due to any cause; censored observations will be the last date of : "death", "last tumor assessment", "last follow up date" or "last date in drug log"

Measure: Progression-free survival (PFS)

Time: each 42 days up to PD or death (up to 24 months)

Secondary Outcomes

Description: OS was defined as time from date of enrollment to date of death due to any cause. For participants still alive at the time of analysis, OS time was censored on last date that participants were known to be alive.

Measure: OS(Overall Survival)

Time: up to 24 months

Description: To evaluate the effectiveness of Anlotinib Hydrochloric Capsule Plus Icotinib Hydrochloric Tablet by enhanced CT/MRI scan every two cycles. Objective Response Rate (ORR) is defined as participants who had complete response (CR) or partial response(PR) divided by the total number of patients.

Measure: ORR(Objective Response Rate)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: To evaluate the effectiveness of Anlotinib Hydrochloric Capsule Plus Icotinib Hydrochloric Tablet by enhanced CT/MRI scan every two cycles. Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease).

Measure: DCR(Disease Control Rate)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Adverse Events

Time: Until 30 day safety follow-up visit

274 Real World Treatment Patterns, Clinical Outcomes and EGFR / T790M Testing Practices in EGFR-Mutated Advanced Non-Small Cell Lung Cancer Patients Receiving First-Line TKI Therapy

Multinational, multi-center medical record review to describe the treatment patterns, clinical outcomes, and EGFR / T790M testing practices in EGFR-mutated advanced NSCLC patients receiving first-line EGFR TKI therapy in Europe.

NCT04031898
Conditions
  1. Lung Cancer
Interventions
  1. Other: Non Interventional
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Molecular testing patterns, including: type of sample/test used to assess the EGFR mutation, for example: primary/secondary tumor, tissue/cytology or blood sample; Molecular testing results: EGFR mutation type (exon 19 deletion, L858R mutation, other).. Proportion of patients with brain metastases (BM) among metastatic patients and the overall survival (OS) expectation in the group of patients with BM. --- L858R ---

Primary Outcomes

Description: Frequency distribution of first-line EGFR TKI of first- or second generation prescribed: erlotinib, gefitinib, or afatinib

Measure: First- or second-generation EGFR TKI used in first-line therapy

Time: From date of initiating EGFR TKI in first line until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Proportion of patients with a progression event during first-line EGFR TKI therapy or other evidence recorded in the patient's medical records deemed by the clinician to be indicative of progression; Time to progression, defined as time from EGFR TKI therapy initiation in the first-line locally advanced or metastatic setting until the earliest of progression death, or end of available follow-up (i.e., progression-free survival); Proportion of patients discontinuing first-line EGFR therapy for reasons other than progression event or death

Measure: Proportion of patients progressing on first line EGFR TKI therapy and describe the time to progression

Time: From date of initiating EGFR TKI in first line until the earliest of progression, death or end of available follow-up, whichever occur first; assessed up to 60 months

Description: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up; Frequency distribution of the second-line therapy regimen (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy) among patients initiating second-line therapy.

Measure: Proportion of patients receiving second-line therapy and type of second-line therapy among patients progressing on first line EGFR TKI therapy

Time: From date of initiating EGFR TKI in first line until date of starting second-line therapy; assessed up to 60 months

Secondary Outcomes

Description: Patients' demographics, including: sex (male/female), and age at EGFR TKI initiation. Baseline disease characteristics, including: Smoking status at initial NSCLC diagnosis, Tumor histology and disease stage at initial NSCLC diagnosis, Eastern Cooperative Oncology Group (ECOG) performance status at initial NSCLC diagnosis and at EGFR TKI initiation, Treatment history: for patients initially diagnosed at earlier-stage disease, cancer-directed and palliative therapies received before first diagnosis of or progression to advanced/metastatic EGFR-mutated NSCLC.

Measure: Patients' demographic and baseline disease characteristics

Time: From date of initial diagnosis of NSCLC or metastatic disease, whichever is diagnosed first until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Molecular testing patterns, including: type of sample/test used to assess the EGFR mutation, for example: primary/secondary tumor, tissue/cytology or blood sample; Molecular testing results: EGFR mutation type (exon 19 deletion, L858R mutation, other).

Measure: Type of sample & test used to determine the EGFR mutation and type of EGFR mutation identified

Time: From date of metastatic disease diagnostic until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Incidence and time to development of BM from first diagnosis of locally advanced or metastatic NSCLC, including: Proportion of patients with BM since diagnostic of metastatic disease and proportion of patients with BM developed during treatment, Type of test used to confirm BM diagnosis (e.g., tissue biopsy, imaging, spinal tap, neurologic exam), Proportion of patients who have BM at start of first-line EGFR TKI therapy. Proportion of patients with no development of BM, Patients' demographic and clinical characteristics associated with development of BM, Incidence of BM and time to development of BM from start of first-line EGFR TKI therapy, Proportion of patients prescribed treatments for BM and type of therapy Overall survival (in months) measured from first diagnosis of BM to the date of death from any cause, with patients last known to be alive censored at the date of last available follow-up.

Measure: Proportion of patients with brain metastases (BM) among metastatic patients and the overall survival (OS) expectation in the group of patients with BM

Time: From date of metastatic disease diagnostic until the first BM diagnosis; From first BM diagnosis to the start of first-line EGFR TKI therapy, end of available follow-up or death, if this occurs before; all assessed up to 60 months

Description: Incidence and time to development of LM disease from first diagnosis of locally advanced or metastatic NSCLC, including: Proportion of patients with LM at first diagnosis of metastatic disease, Type of test to confirm LM diagnosis (cerebrospinal fluid cytology, tissue, imaging, etc.), Proportion of patients who have LM at start of first-line EGFR TKI therapy, Proportion of patients who later develop (during treatment) LM, Proportion of patients with no development of LM, Incidence of LM and time to development of LM from start of first-line EGFR TKI therapy. Overall survival (in months) measured from first diagnosis of LM disease to the date of death from any cause, with patients last known to be alive censored at the date of last available follow-up.

Measure: Proportion of patients with leptomeningeal disease (LM) among metastatic patients and the overall survival (OS)

Time: From date of metastatic disease diagnostic until the LM diagnosis; From LM diagnosis to the start of first-line EGFR TKI therapy, end of available follow-up or death, if this occurs before; all assessed up to 60 months

Description: Proportion of patients prescribed other systemic treatments (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy) in combination with first-line EGFR TKI therapy.

Measure: Proportion of patients where the first-line therapy with first- or second-generation EGFR TKI is associated with any other systemic therapy, including the type of systemic therapy

Time: From date of initiating EGFR TKI in first line until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 60 months

Description: Proportion of patients tested for T790M mutation and among those tested, the proportion who were positive for the mutation, including: Binary distribution of T790M mutation testing and, among those tested, the proportion with a positive result, Type of test used to assess the T790M mutation (tissue/cytology or blood sample). Among patients tested and positive for T790M mutation, what proportion receives treatment with osimertinib - applicable study measures include binary distribution of osimertinib treatment initiation, and requency distribution of the line of therapy (second- or later-line in the metastatic setting) in which osimertinib was initiated.

Measure: Proportion of patients tested for T790M mutation and the proportion of patients with positive mutation among patients progressing on first-line EGFR TKI therapy

Time: From date of initiating EGFR TKI in first line until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 60 months

Description: Among patients progressing on first-line EGFR TKI therapy and tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).

Measure: Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and tested for T790M mutation

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 55 months

Description: Among patients progressing on first-line EGFR TKI therapy and not tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).

Measure: Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and not tested for T790M

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 55 months

Description: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up among patients tested and not tested for T790M mutation.

Measure: How the proportion of patients receiving second-line therapy differs between patients tested for T790M mutation and patients not tested for T790M mutations

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 55 months

Description: Proportion of patients prescribed third- or later lines of therapy and type of therapies selected (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), and how these proportion varies by the second-line therapy category received.

Measure: Proportion of patients receiving third- or later-line therapy and type of this therapy and to explore whether the proportion receiving third-/later-line therapies varies by the second-line therapy category received

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 50 months

Description: OS (in months) measured overall from first diagnosis of or progression to locally advanced or metastatic disease, OS from start of first-line EGFR TKI therapy to the date of death from any cause, with patients last known to be alive censored at the date of last available follow-up.

Measure: Overall survival (OS) expectation for all patients from first diagnosis of locally advanced or metastatic disease and from start of first-line EGFR TKI therapy

Time: From date of metastatic disease diagnostic or start of first-line EGFR TKI therapy until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Proportion of patients with other positive mutations, in case additional molecular testing were performed at the time of initial EGFR testing or at the time of T790M testing (e.g., KRAS, BRAF, ROS1 translocation, PD-L1 expression, MET amplification, ALK rearrangement, RET rearrangement, HER2 exon 20 insertion, TP53, others).

Measure: Incidence of other mutations, in case additional molecular testing was performed either at the time of initial EGFR testing or at the time of T790M testing

Time: From date of metastatic disease diagnostic until end of available follow-up or death, if this occurs before; assessed up to 60 months

275 A Phase III, Open-label, Randomized Study of Osimertinib With or Without Platinum Plus Pemetrexed Chemo, as First-line Treatment in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA2).

The reason for the study is to find out if an experimental combination of an oral medication called osimertinib (TAGRISSO®) when used in combination with chemotherapy is more effective than giving osimertinib alone for the treatment of locally advanced or metastatic non-small cell lung cancer. Some lung cancers are due to mutations in the Deoxyribonucleic acid (DNA) which, if known, can help physicians decide the best treatment for their patients. One type of mutation can occur in the gene that produces a protein on the surface of cells called the Epidermal Growth Factor Receptor (EGFR). Osimertinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets Epidermal Growth Factor Receptor (EGFR) mutations. Unfortunately, despite the benefit observed for patients treated with osimertinib, the vast majority of cancers are expected to develop resistance to the drug over time. The exact reasons why resistance develops are not fully understood but based upon clinical research it is hoped that combining osimertinib with another type of anti-cancer therapy known as chemotherapy will delay the onset of resistance and the worsening of a patient's cancer. In total the study aims to enroll approximately 586 patients, consisting of approximately 30 patients who will participate in a safety run-in component of the trial, and approximately 556 who will receive osimertinib alone or osimertinib in combination with chemotherapy in the main trial. In the main part of the trial there is a one in two chance of receiving osimertinib alone, and the treatment is decided at random by a computer. The study involves a Screening Period, Treatment Period, and Follow up Period. Whilst receiving study medication, it is expected patients will attend, on average, approximately 15 visits over the first 12 months and then approximately 4 visits per year afterwards. Each visit will last about 2 to 6 hours depending on the arrangement of medical assessments by the study centre.

NCT04035486
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Pemetrexed/Carboplatin
  3. Drug: Pemetrexed/Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Compare the local epidermal growth factor receptor mutation test result used for patient selection with the retrospective central cobas® epidermal growth factor receptor Mutation Test v2 results from baseline tumor samples.. Progression-free survival (PFS) by Investigator by plasma epidermal growth factor receptor mutation status.. Determine efficacy of osimertinib monotherapy vs. osimertinib combined with chemotherapy based on the cobas® epidermal growth factor receptor mutation Test v2 plasma screening test result for Exon 19 deletions or Exon 21 (L858R) epidermal growth factor receptor mutations.. Plasma concentration of osimertinib when given with or without chemotherapy. --- L858R ---

4. The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations known to be associated with Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination with other epidermal growth factor receptor (EGFR) mutations, which may include T790M. 5. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy. --- L858R ---

Primary Outcomes

Description: Progression-free survival (PFS) using Investigator assessment as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Progression-free survival (PFS) is defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable Response Evaluation Criteria in Solid Tumors (RECIST) assessment. The primary efficacy analysis of progression-free survival will be performed by investigator assessment Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). An additional sensitivity analysis will be performed for Progression-free survival (PFS) by Blinded Independent Central Review (BICR) assessment.

Measure: Progression-free survival (PFS)

Time: The primary analysis of Progression-free survival (PFS) based on investigator assessment will occur when PFS maturity is observed at approximately 33 months after the first patient is randomized.

Secondary Outcomes

Description: Overall survival is defined as the time from the date of randomization until death due to any cause.

Measure: Overall Survival (OS)

Time: Overall Survival will be analyzed at 2 time points: when PFS maturity is observed at approximately 33 months after the first patient is randomized, and when OS maturity is observed at approximately 70 months after the first patient is randomized

Description: Landmark Overall Survival at 1, 2, and 3 years will look at the number of patients alive at 1, 2 and 3 year time points.

Measure: Landmark Overall Survival (LOS)

Time: The analysis of Landmark Overall Survival will be conducted at 2 time points: when PFS maturity is observed at approximately 33 months, and when Overall Survival maturity is observed at approximately 70 months after the first patient is randomized.

Description: Objective Response Rate (ORR) (per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) using Investigator assessments) is defined as the number (%) of patients with at least 1 visit response of Complete Response or Partial Response. Data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of Objective Response Rate

Measure: Objective Response Rate (ORR)

Time: Objective Response Rate analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Duration of Response is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.

Measure: Duration of Response (DoR)

Time: Duration of Response analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Depth of response (ie. tumor shrinkage / change in tumor size) by Investigator is defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) target lesions at the nadir in the absence of New Lesions (NLs) or progression of Non-Target Lesions when compared to baseline.

Measure: Depth of Response

Time: Depth of Response analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by the Investigator.

Measure: Disease Control Rate (DCR) by Investigator

Time: Disease Control Rate analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Progression Free Survival 2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary Progression Free Survival (PFS), or death in absence of a first or second progression. The second progression event must have occurred after subsequent treatment administered after the initial progression free survival event.

Measure: Progression Free Survival 2 (PFS2)

Time: Progression Free Survival 2 analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Assess disease-related symptoms and health related Quality of Life (QoL) in patients treated with osimertinib plus chemotherapy compared with osimertinib.

Measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30)

Time: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire -Core 30 items analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Assess disease-related symptoms and health related Quality of Life (QoL) in patients treated with osimertinib plus chemotherapy compared with osimertinib.

Measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items (EORTC QLQ-LC13)

Time: European Organization for Research & Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized

Description: Compare the local epidermal growth factor receptor mutation test result used for patient selection with the retrospective central cobas® epidermal growth factor receptor Mutation Test v2 results from baseline tumor samples.

Measure: Concordance of epidermal growth factor receptor mutation status between the local epidermal growth factor receptor mutation test and the central cobas® epidermal growth factor receptor Mutation Test v2 results from tumor samples with evaluable results

Time: Analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Determine efficacy of osimertinib monotherapy vs. osimertinib combined with chemotherapy based on the cobas® epidermal growth factor receptor mutation Test v2 plasma screening test result for Exon 19 deletions or Exon 21 (L858R) epidermal growth factor receptor mutations.

Measure: Progression-free survival (PFS) by Investigator by plasma epidermal growth factor receptor mutation status.

Time: Analysis will occur when Progression-free survival (PFS)maturity is observed at approximately 33 months from the first patient being randomized.

Description: An analysis will be performed to assess whether the plasma concentration of osimertinib is affected when given with or without chemotherapy. Samples will be collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples will be collected pre-dose and 1, 2, 4, and 6 hours post-dose.

Measure: Plasma concentration of osimertinib when given with or without chemotherapy

Time: Plasma concentration analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: An analysis will be performed to assess whether the plasma concentration of metabolite AZ5104 is affected when given with or without chemotherapy. Samples will be collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples will be collected pre-dose and 1, 2, 4, and 6 hours post-dose.

Measure: Plasma concentration of metabolite AZ5104 when osimertinib is given with or without chemotherapy

Time: Plasma concentration analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

276 A Phase I/Ib Study of Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer

This is a phase I/Ib, open-label, single-center, single-arm study of alisertib and osimertinib for patients with stage IV EGFR-mutated lung cancer, incorporating both a dose escalation and dose-expansion phase

NCT04085315
Conditions
  1. Lung C
  2. Lung Cancer Metastatic
  3. EGFR Gene Mutation
Interventions
  1. Drug: Osimertinib
  2. Drug: Alisertib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

2. Male or female patients ≥18 years of age 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (see Appendix 1). 4. Documented activating EGFR mutation (Exon 19 deletion, Exon 19 insertion, E709K, G719X, S768I, V769L, T790M, L833F, L833V, V834L, H835L, L858R, A859S, K860I, L861Q, A871E, V843I, or H870R) on tumor sample or cell-free DNA sample performed in Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory. 5. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. --- E709K --- --- S768I --- --- V769L --- --- T790M --- --- L833F --- --- L833V --- --- V834L --- --- H835L --- --- L858R ---

Primary Outcomes

Description: ≤1 out of 6 at highest dose level below the maximal administered dose. If 0 of these 3 additional participants experience a dose limiting toxicity (DLT) (1 of 6), proceed to the next dose level. If 1 or more of the 3 additional participants experience DLT (2 of 6), then dose escalation is stopped, and this dose is declared the maximal administered dose (highest dose administered). Three (3) additional participants will be entered at the next lowest dose level if only 3 participants were treated previously at that dose.

Measure: Maximum Tolerated Dose (MTD)

Time: First 28 days of study treatment

Secondary Outcomes

Description: defined as the best overall response recorded from the start of the treatment until disease progression from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined based on RECIST 1.1 criteria. We will compute a 95% confidence interval using a binomial distribution.

Measure: Overall Response Rate (ORR)

Time: Up to 2 years

Description: The DR for CR and PR will be measured from the date that the best response if first recorded until the date that PD is documented over the period of 2 years. For patients who continue treatment post-progression, the date of PD documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum)

Measure: Duration of Response (DR)

Time: Up to 2 years

Description: The depth of response will be assessed by RECIST 1.1 criteria. The DOR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Depth of response (DOR)

Time: Up to 2 years

Description: Defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Disease Control Rate (DCR)

Time: Up to 2 years

Description: PFS will be calculated as 1+ the number of days from the first dose of alisertib to documented radiographic progression or death due to any cause over a period of 2 years. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the mean PFS with 95% confidence interval.

Measure: Progression Free Survival (PFS)

Time: Up to 2 years

Description: OS will be calculated as 1+ the number of days from the first dose of alisertib to death due to any cause over a period of 2 years. The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.

Measure: Overall Survival (OS)

Time: Up to 2 years

Description: Defined as the percentage of patients who have achieved CR, PR, or SD in the CNS for at least 12 weeks. The CNS disease control rate will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Central Nervous System (CNS) disease control rate

Time: Up to 2 years

Description: Pre-treatment tumor biopsy formalin-fixed paraffin-embedded (FFPE) samples will be stained for TPX2 expression by IHC. TPX2 IHC staining will be scored using the following scale: 0, 0-10% of tissue stained positive; 1, 10-20% stained positive; 2, 20-40% stained positive; 3, 40-70% stained positive; and 4, > 70% positive cells. The sum of staining score index (intensity + extent) will be designated as follows: 0-2, negative expression; 3-4, strong expression. The IHC score will be generated from three different areas of the slides and an average score will be calculated for each sample. We will determine whether there is a difference in TPX2 staining between responders and non-responders to alisertib + osimertinib treatment by the Fisher's exact test.

Measure: Intratumoral TPX2 expression by Immunohistochemistry (IHC)

Time: From pretreatment biopsy to time of response, up to 2 years

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and area under curve (AUC) 0-24 hours. The area under the curve (AUC) is the definite integral in a plot of drug concentration in blood plasma vs. time

Measure: Area Under Curve (AUC)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Cmax will be calculated. It is a standard measurement in pharmacokinetics

Measure: Maximum (or peak) serum concentration (Cmax)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Tmax will be calculated. It is a standard measurement in pharmacokinetics

Measure: Amount of time (maximum) drug concentration in serum (Tmax)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

277 Single Arm Phase 2 Trial of Atezolizumab and Bevacizumab in Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer in Patients With Progressive Disease After Receiving Osimertinib (TOP 1901)

The purpose of this study is to investigate the safety and efficacy of giving atezolizumab combined with bevacizumab in patients with stage 4 epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) whose cancer has gotten worse while receiving osimertinib.

NCT04099836
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Atezolizumab
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Disease Progression
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Age ≥18 years 2. Histologic documentation of primary lung carcinoma, non-squamous histology with EGFR exon deletion 19 or exon 21 L858R mutation 3. Stage IV disease according to the 8th Edition of the American Joint Committee on Cancer staging system 4. Disease progression on osimertinib 5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 (appendix 1) 6. Measureable disease as defined by RECIST 1.1 (appendix 2) 7. The following laboratory values obtained ≤ 30 days prior to starting study therapy 1. ANC ≥ 1, 500 / mm3 2. Platelet count, ≥ 100,000 / mm3 3. Hemoglobin ≥ 9.0 g / dL 4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 5. Serum Glutamic Oxaloacetic Transaminase (SGOT) (Aspartate Aminotransferase, AST) and Serum Glutamic Pyruvic Transaminase (SGPT) (Alanine Aminotransferase, ALT) ≤2.5 x ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or bone metastases. --- L858R ---

Prior therapy with anti-PD-1 or anti-PD-L1 immunotherapy, 18. Prisoners, participants who are involuntarily incarcerated, or participants who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness Inclusion Criteria: 1. Age ≥18 years 2. Histologic documentation of primary lung carcinoma, non-squamous histology with EGFR exon deletion 19 or exon 21 L858R mutation 3. Stage IV disease according to the 8th Edition of the American Joint Committee on Cancer staging system 4. Disease progression on osimertinib 5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 (appendix 1) 6. Measureable disease as defined by RECIST 1.1 (appendix 2) 7. The following laboratory values obtained ≤ 30 days prior to starting study therapy 1. ANC ≥ 1, 500 / mm3 2. Platelet count, ≥ 100,000 / mm3 3. Hemoglobin ≥ 9.0 g / dL 4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) 5. Serum Glutamic Oxaloacetic Transaminase (SGOT) (Aspartate Aminotransferase, AST) and Serum Glutamic Pyruvic Transaminase (SGPT) (Alanine Aminotransferase, ALT) ≤2.5 x ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or bone metastases. --- L858R ---

Patients who have one of the following EGRF mutations: exon 19 or exon 21 L858R with progressive disease on osimertinib may be eligible to participate in this study. --- L858R ---

Primary Outcomes

Description: RECIST 1.1 will be used to measure confirmed partial or complete responses to the study drug.

Measure: Objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors RECIST 1.1 (brand name)

Time: Up to 3 years

Secondary Outcomes

Description: Progression will be defined as time from start of study therapy to disease progression or death

Measure: Progression free survival as measured by Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name) as assessed by the investigator.

Time: Up to 5 years

Description: Overall survival (OS) is defined as the time from start of study therapy to death from any cause, and patients who are alive at the time of analysis will be censored at the last date of contact.

Measure: Overall survival as noted by follow-up via composite of telephone or medical record review.

Time: Up to 3 years

Description: Evaluation of safety using the National Cancer Institute (NCI) CTCAE version 4.03

Measure: AEs as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Time: Up to 5 years]

278 A Randomized Phase 3 Multicenter Open-label Study to Compare the Efficacy of TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations

The purpose of this study is to compare the efficacy of TAK-788 as first-line treatment with that of platinum-based chemotherapy in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

NCT04129502
Conditions
  1. Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: TAK-788
  2. Drug: Pemetrexed
  3. Drug: Cisplatin
  4. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Higher scores represent a high level of symptomatology/problems.. Inclusion Criteria: - Histologically or cytologically confirmed nonsquamous cell locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) non-small cell lung cancer (NSCLC) - Documented epithelial growth factor receptor (EGFR) in-frame exon 20 insertion mutation assessed by a clinical laboratory improvements amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laboratory The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR mutations for which there are approved anti-EGFR TKIs (ie, exon 19 del, L858R, T790M, L861Q, G719X, or S768I, where X is any other amino acid) - Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR exon 20 insertion mutation - At least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 - Life expectancy ≥3 months - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Exclusion Criteria: - Received prior systemic treatment for locally advanced or metastatic disease - Received radiotherapy ≤14 days before randomization or has not recovered from radiotherapy-related toxicities - Received a moderate or strong cytochrome P-450 (CYP)3A inhibitor or moderate or strong CYP3A inducer within 10 days before randomization - Have been diagnosed with another primary malignancy other than NSCLC - Have current spinal cord compression or leptomeningeal disease - Have uncontrolled hypertension. --- L858R ---

Participants with hypertension should be under treatment on study entry to control blood pressure - Received a live vaccine within 4 weeks before randomization per Summary of product characteristics (SmPCs) for pemetrexed, cisplatin, and carboplatin Inclusion Criteria: - Histologically or cytologically confirmed nonsquamous cell locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) non-small cell lung cancer (NSCLC) - Documented epithelial growth factor receptor (EGFR) in-frame exon 20 insertion mutation assessed by a clinical laboratory improvements amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laboratory The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR mutations for which there are approved anti-EGFR TKIs (ie, exon 19 del, L858R, T790M, L861Q, G719X, or S768I, where X is any other amino acid) - Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR exon 20 insertion mutation - At least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 - Life expectancy ≥3 months - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Exclusion Criteria: - Received prior systemic treatment for locally advanced or metastatic disease - Received radiotherapy ≤14 days before randomization or has not recovered from radiotherapy-related toxicities - Received a moderate or strong cytochrome P-450 (CYP)3A inhibitor or moderate or strong CYP3A inducer within 10 days before randomization - Have been diagnosed with another primary malignancy other than NSCLC - Have current spinal cord compression or leptomeningeal disease - Have uncontrolled hypertension. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time interval from the date of randomization until the first date at which the criteria for PD according to RECIST version 1.1 are met or death, whichever occurs first.

Measure: Progression Free Survival (PFS) as Assessed by Blinded Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Time: Up to approximately 40 months after the first participant is randomized

Secondary Outcomes

Description: Confirmed ORR is defined as the proportion of participants who are confirmed to have achieved complete response (CR) or partial response (PR). Confirmed responses are responses that persist on repeat imaging ≥4 weeks after initial response.

Measure: Confirmed Objective Response Rate (ORR) as Assessed by Blinded Independent Review Committee (IRC) per RECIST Version 1.1

Time: Up to approximately 40 months after the first participant is randomized

Description: OS is defined as the interval from the date of randomization until death.

Measure: Overall Survival (OS)

Time: Up to approximately 40 months after the first participant is randomized

Description: PFS is defined as the time interval from the date of randomization until the first date at which the criteria for progressive disease (PD) according to RECIST version 1.1 are met or death, whichever occurs first.

Measure: Progression Free Survival (PFS) as Assessed by the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Confirmed ORR is defined as the proportion of participants who are confirmed to have achieved CR or PR. Confirmed responses are responses that persist on repeat imaging ≥4 weeks after initial response.

Measure: Confirmed Objective Response Rate (ORR) as Assessed by the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that PD is objectively documented.

Measure: Duration of Response, as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Time to response is defined as the time interval from the date of randomization until the initial observation of CR or PR.

Measure: Time to Response, as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: DCR is defined as the percentage of participants who have achieved CR, PR, or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks) after the initiation of study drug.

Measure: Disease Control Rate (DCR) as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: EORTC QLQ-C30 is a cancer-specific questionnaire which comprises of 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and a global health status/quality-of-life (QoL) scale. Six single-item scales are also included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores will be converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QoL scale, higher scores represent better HRQoL, whereas for the symptom scales lower scores represent better HRQoL (i.e., a low level of symptomatology/problems).

Measure: Patient-reported Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30

Time: Up to approximately 40 months after the first participant is randomized

Description: EORTC QLQ-LC13 is a cancer-specific questionnaire which comprises of 13 questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Raw scores will be converted into scale scores ranging from 0 to 100. Higher scores represent a high level of symptomatology/problems.

Measure: Participant-reported Symptoms as Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, Lung Cancer Module (QLQ-LC13)

Time: Up to approximately 40 months after the first participant is randomized

279 A Phase III,Double-Blind, Randomised Study to Assess the Efficacy and Safety of ASK120067 Versus Gefitinib as First-Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

To assess the efficacy and safety of ASK120067 versus a standard of care epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

NCT04143607
Conditions
  1. Locally Advanced or Metastatic NSCLC
Interventions
  1. Drug: ASK120067
  2. Drug: Placebo Gefitinib 250 mg
  3. Drug: Gefitinib
  4. Drug: Placebo ASK120067

4. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R). 5. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status. --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdrew from randomized therapy prior to progression and was used to assess the efficacy of single agent ASK120067 compared with Gefitinib as measured by PFS.

Measure: Median Progression Free Survival (PFS)

Time: CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years

Secondary Outcomes

Description: ORR was defined as the number (%) of patients with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of ASK120067 compared with Gefitinib defined as the number (%) of patients with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of ASK120067 compared with Gefitinib

Measure: Objective Response Rate (ORR)

Time: CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years

Description: Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of ASK120067 compared with Gefitinib

Measure: Duration of Response (DoR)

Time: CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years

Description: The DCR was defined as the percentage of participants who had a best overall response (BOR) of Complete response (CR), Partial response (PR) or Stable disease (SD) ≥6 weeks prior to any Progressive disease (PD) event and was used to further assess the efficacy of ASK120067 compared with Gefitinib

Measure: Disease Control Rate (DCR)

Time: CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years

Description: The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions

Measure: Depth of Response

Time: CT or MRI at screening and every 2 Cycles until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years

Description: Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of ASK120067 compared with Gefitinib

Measure: Overall Survival (OS)- Number of Participants With an Event

Time: Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 5 years

280 A Phase II Study of Atezolizumab in Combination With Bevacizumab, Carboplatin or Cisplatin, and Pemetrexed for EGFR-mutant Metastatic Non-small Cell Lung Cancer Patients After Failure of EGFR Tyrosine Kinase Inhibitors.

using Atezolizumab, a PD-L1 inhibitor, in combination with bevacizumab, platinum and pemetrexed to treat patients with EGFR mutated, advanced non-small cell lung cancer (NSCLC) after failure of EGFR tyrosine kinase inhibitors.

NCT04147351
Conditions
  1. NSCLC Stage IIIB~IV
Interventions
  1. Drug: Atezolizumab Injection; bevacizumab Injection
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

EGFR activating mutations include exon19 deletion, L858R, G719X, L861Q, or S768I. --- L858R ---

Primary Outcomes

Description: The percentage of patients with radiologically complete or partial response as determined by the investigator according to RECIST version 1.1.

Measure: Objective response rate (ORR)

Time: 9 MONTHS

Secondary Outcomes

Description: PFS is measured from the date of study enrollment to radiographically documented progression according to RECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment.

Measure: Progression-free Survival (PFS)

Time: about 9 months

281 Track and Treat in NSCLC (TATIN) - ctDNA Guided Treatment of Early Resistance to Targeted Treatment in Patients With EGFR Positive NSCLC

The current strategy is to test for treatment resistance at the time of radiological progression and design subsequent treatment based on the mechanism of resistance. However, upon disease progression patients tend to deteriorate quickly and 30% - 40% of patients will not be in the clinical condition to receive next line treatment. Therefore, there is a potential for early resistance identification and directing treatment against it in order to improve patient outcome.

NCT04148066
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Diagnostic Test: ctDNA blood sample
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

To determine the success rate of crizotinib and osimertinib combination treatment to eliminate MET amplification, defined by disappearance of the MET amplification clone in a subsequent ctDNA sample.. Inclusion Criteria: 1. Histologically confirmed metastatic NSCLC, characterized by a sensitizing exon 19 deletion or exon 21 L858R EGFR mutation. --- L858R ---

Inclusion Criteria: 1. Histologically confirmed metastatic NSCLC, characterized by a sensitizing exon 19 deletion or exon 21 L858R EGFR mutation. --- L858R ---

This technique might identify drug resistant clones before subclonal resistance (resistance of the new clone to targeted treatment) develops and allow to eliminate the new clone with short-term additional treatment, while continuing treatment of the main oncogenic driver (EGFR exon 19 del / exon 21 L858R) with the EGFR TKI. --- L858R ---

Primary Outcomes

Description: To identify the percentage of patients in which a drug resistant clone can be detected with ctDNA before the emergence of radiological progression.

Measure: percentage of patients in which a drug resistant clone can be detected with ctDNA

Time: Trough study completion, an average of 2 years

Secondary Outcomes

Description: To determine the success rate of crizotinib and osimertinib combination treatment to eliminate MET amplification, defined by disappearance of the MET amplification clone in a subsequent ctDNA sample.

Measure: the success rate of crizotinib and osimertinib combination treatment to eliminate MET amplification

Time: Trough study completion, an average of 2 years

282 A Phase 2 Study of Poziotinib in Patients With EGFR or HER2 Activating Mutations in Advanced Malignancies

This is a Phase 2, open-label, multicenter study to evaluate the efficacy and the safety/tolerability of poziotinib in five patient cohorts for up to 150 previously treated patients with any systemic therapy (Cohort 1: 30 Patients that have HER2-positive or HER2-negative breast cancer with HER2 activating mutations, Cohort 2: 30 Patients that have colorectal cancer with HER2 activating mutations, Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal cancer) with HER2 activating mutations, Cohort 4: 30 Patients that have high-grade glioma with EGFR activating mutations, and Cohort 5: 30 Patients that have solid tumors (except NSCLC or high-grade glioma) with EGFR activating mutations.

NCT04172597
Conditions
  1. Breast Cancer
  2. Colorectal Cancer
  3. Solid Tumor
  4. High Grade Glioma
Interventions
  1. Drug: Poziotinib Hydrochloride
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

EGFR Activating Mutations (at least one of the following) Extracellular & Transmembrane: EGFRvIII, R108K, R222C, A289T, P596L, G598V Kinase Domain: Exon 20 insertion, E709K, G719X, V742I, E746_A750del, S768I, V769M, V774M, R831C, R831H, L858R, L861Q, A864V 5. Patient has measurable disease, as per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and/or RANO Criteria for Cohort 4. These target lesion(s) must be radiographically measurable. --- R108K --- --- R222C --- --- A289T --- --- P596L --- --- G598V --- --- E709K --- --- V742I --- --- S768I --- --- V769M --- --- V774M --- --- R831C --- --- R831H --- --- L858R ---

Primary Outcomes

Description: Proportion of patients whose best overall response is confirmed CR or PR

Measure: Objective Response Rate (ORR)

Time: 24 months

Secondary Outcomes

Description: Time from the first CR or PR until progressive disease or death

Measure: Duration of Response (DoR)

Time: 24 months

Description: Proportion of patients whose best overall response is CR, PR, or SD

Measure: Disease Control Rate (DCR)

Time: 24 months

283 UpSwinG: Real World Study on TKI Activity in Uncommon Mutations and Sequencing Giotrif®

Non-interventional, multi-country, multi-centre cohort study based on existing data from medical records (paper or electronic) or electronic health records of patients with advanced NSCLC harbouring EGFR mutations and treated with an EGFR-TKI

NCT04179890
Conditions
  1. Non-squamous, Non-Small Cell Lung Cancer
Interventions
  1. Drug: Epidermal Growth Factor Tyrosine Kinase Inhibitor
  2. Drug: Afatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Sequencing cohort: 5. Patients with common EGFR mutations (Del19, L858R) 6. Patients were treated with afatinib (Gi(l)otrif®) in the first-line setting and for acquired T790M mutation with osimertinib in the second line; 7. Patients must have started osimertinib treatment at least 10 months prior to data entry. --- L858R ---

Primary Outcomes

Description: assessed as the time from start of EGFR-TKI treatment until the end of treatment or death date by any cause.

Measure: Time on treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Time: Up to 30 months

Secondary Outcomes

Measure: Rate of overall response

Time: Up to 30 months

Measure: Rate of overall survival

Time: Up to 30 months

Description: uncommon mutation cohort only

Measure: Time on treatment until failure of second-line (TTF2)

Time: Up to 30 months

284 Randomized Phase III Study of Combination AZD9291 (Osimertinib) and Bevacizumab Versus AZD9291 (Osimertinib) Alone as First-Line Treatment for Patients With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase III trial compares the effect of bevacizumab and AZD9291 (osimertinib) combination vs. osimertinib alone for the treatment of non-small cell lung cancer that has spread outside of the lungs (stage IIIB-IV) and has a change (mutation) in a gene called EGFR. The EGFR protein is involved in cell signaling pathways that control cell division and survival. Sometimes, mutations in the EGFR gene cause EGFR proteins to be made in higher than normal amounts on some types of cancer cells. This causes cancer cells to divide more rapidly. Osimertinib may stop the growth of tumor cells by blocking EGFR that is needed for cell growth in this type of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with bevacizumab may control cancer for longer and help patients live longer as compared to osimertinib alone.

NCT04181060
Conditions
  1. Advanced Lung Non-Squamous Non-Small Cell Carcinoma
  2. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  3. Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  4. Stage IIIB Lung Cancer AJCC v8
  5. Stage IV Lung Cancer AJCC v8
  6. Stage IVA Lung Cancer AJCC v8
  7. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Biological: Bevacizumab
  2. Drug: Osimertinib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Cox regression analysis will be used to assess whether EGFR ctDNA clearance is an independent predictor for PFS (and OS), adjusted by treatment effect, the presence of brain metastasis (yes versus [vs.] no), EGFR exon 19 deletion/L858R vs other, Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2) and other possible clinical and biological risk factors.. Inclusion Criteria: - Patient must have a pathologically-confirmed diagnosis of non-squamous, non-small cell lung cancer (NSCLC) - Patient must have advanced disease, defined as - either stage IV disease, stage IIIB disease not amenable to definitive multi-modality therapy, or recurrent disease after a prior diagnosis of stage I-III disease. --- L858R ---

All staging is via the American Joint Committee on Cancer (AJCC)/International Association for the Study of Lung Cancer (IASLC) 8th edition staging criteria - Patient must have somatic activating sensitizing mutation in EGFR (e.g. but not limited to Exon 19 deletion, L858R, G709X, G719X, exon 19 insertions, L861Q, S768I). --- L858R ---

Primary Outcomes

Description: Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. PFS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 2.5%.

Measure: Progression-free survival (PFS)

Time: From randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first, assessed up to 10 years

Secondary Outcomes

Description: Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. OS will be tested at the one-sided 10% level.

Measure: Overall survival (OS)

Time: From randomization to death from any cause, assessed up to 10 years

Description: Best objective response will be evaluated via RECIST 1.1 criteria. Will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Best objective response rate

Time: Up to 10 years

Description: Will be estimated using competing risks methodology, adjusting for death and progression as competing events. Regular central nervous system imaging will occur when patients are on treatment. After they discontinue study treatment, central nervous system imaging will be symptom-prompted during follow up.

Measure: Time to central nervous system progression

Time: From study randomization to evidence of central nervous system progressive disease, with death and progression as competing events, assessed up to 10 years

Description: Will be estimated using the Kaplan-Meier method.

Measure: Central nervous system progression-free survival

Time: From study randomization to evidence of central nervous system progressive disease or death from any cause, whichever occurs first, assessed up to 10 years

Description: Toxicity will be determined using the Common Terminology Criteria for Adverse Events (CTCAE). Will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

Measure: Incidence of adverse events

Time: Up to 30 days after the last administration of investigational agent

Other Outcomes

Description: Preliminary analyses of these data will utilize tests for association comparing the frequency of a particular genomic aberration at baseline and at progression (for example, using McNemar's test) and association between alterations and baseline characteristics (for example, using Fisher's exact test). More sophisticated analyses may include multivariable logistic regression modeling and/or competing risks analysis.

Measure: Mechanisms of resistance to AZD9291 (osimertinib) and AZD9291 (osimertinib) with bevacizumab first-line therapy through post-progression circulating tumor-derived deoxyribonucleic acid (ctDNA)

Time: Up to 10 years

Description: Will assess ctDNA clearance on study treatment and associate ctDNA clearance with clinical outcomes. Cox regression analysis will be used to assess whether EGFR ctDNA clearance is an independent predictor for PFS (and OS), adjusted by treatment effect, the presence of brain metastasis (yes versus [vs.] no), EGFR exon 19 deletion/L858R vs other, Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2) and other possible clinical and biological risk factors.

Measure: ctDNA clearance on study treatment

Time: Up to 10 years

285 Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of WSD0922-FUFU

This phase I trial studies the side effects and best dose of WSD0922-FU for the treatment of glioblastoma, anaplastic astrocytoma, or non-small cell lung cancer that has spread to the central nervous system (central nervous system metastases). WSD0922-FU is a targeted treatment which blocks the EGFR protein - a strategy that has led to a lot of benefit in patients with many different cancers. WSD0922-FU may also be able to get into cancers in the brain and spinal cord and help patients with brain and spinal cord cancers.

NCT04197934
Conditions
  1. Anaplastic Astrocytoma, IDH-Wildtype
  2. Glioblastoma, IDH-Wildtype
  3. Lung Non-Small Cell Carcinoma
  4. Metastatic Malignant Neoplasm in the Central Nervous System
  5. Metastatic Malignant Neoplasm in the Leptomeninges
Interventions
  1. Drug: EGFR/EGFRvIII Inhibitor WSD0922-FU
  2. Procedure: Therapeutic Conventional Surgery
MeSH:Neoplasms Glioblastoma Astrocytoma Neoplasms, Second Primary Carcinoma, Non-Small-Cell Lung
HPO:Astrocytoma Glioblastoma multiforme Neoplasm Non-small cell lung carcinoma Subependymal giant-cell astrocytoma

Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R ---

Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R --- --- G719A --- --- L861Q --- --- L858R ---

Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than three years prior to registration - Any of the following cardiac criteria: - A marked baseline prolongation of QT/corrected QT (QTc) interval - (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fridericia's QT correction formula - A history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome) - The use of concomitant medications that prolong the QT/QTc interval - Patients confirmed to have a cis double mutation (Del19/T790M or L858R/T790M) or cis triple mutation (Del19/T790m/C797S or L858R/T790M/C797S) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. --- T790M --- --- L858R ---

Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than three years prior to registration - Any of the following cardiac criteria: - A marked baseline prolongation of QT/corrected QT (QTc) interval - (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fridericia's QT correction formula - A history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome) - The use of concomitant medications that prolong the QT/QTc interval - Patients confirmed to have a cis double mutation (Del19/T790M or L858R/T790M) or cis triple mutation (Del19/T790m/C797S or L858R/T790M/C797S) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. --- T790M --- --- L858R --- --- C797S --- --- L858R ---

History of hypersensitivity to active or inactive excipients of WSD0922-FU or drugs with a similar chemical structure or class to WSD0922-FU - Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of WSD0922-FU - Inadequate bone marrow reserve or organ function - Patients with NSCLC LM who are unable to undergo collection of CSF Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R ---

History of hypersensitivity to active or inactive excipients of WSD0922-FU or drugs with a similar chemical structure or class to WSD0922-FU - Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of WSD0922-FU - Inadequate bone marrow reserve or organ function - Patients with NSCLC LM who are unable to undergo collection of CSF Inclusion Criteria: - Pre-Registration - Inclusion Criteria Specific to Dose Escalation Cohort - Histological confirmation of either glioblastoma, IDH wildtype (GBM), anaplastic astrocytoma, IDH wildtype (AA) or non-small cell lung cancer (NSCLC) - EGFR Status: - GBM/AA must have EGFR amplification and/or EGFRvIII mutation - NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Pre-Registration - Inclusion Criteria Specific to Dose Expansion Cohorts - Glioblastoma, IDH wildtype/Anaplastic astrocytoma, IDH wildtype (GBM/AA) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have EGFR amplification and/or EGFRvIII mutation - Brain Tumor Penetration (BTP) Cohort: - Diagnosis: Histological confirmation of either glioblastoma, IDH wildtype (GBM) or anaplastic astrocytoma, IDH wildtype (AA) - EGFR status: GBM/AA must have been previously demonstrated to have EGFR amplification and/or EGFRvIII mutation based on any prior resection - Non-Small Cell Lung Cancer Leptomeningeal Metastases (NSCLC LM) cohort: - Diagnosis: Histological confirmation of non-small cell lung cancer (NSCLC) - EGFR status: NSCLC must have confirmed activating EGFR mutation (including Del19, L858R, EGFRvIII, G719A, L861Q) - Registration -Inclusion Criteria Specific to Dose Escalation Cohort - Previous treatments: - Patients with GBM/AA must have been previously treated with radiation and temozolomide - Patients with NSCLC must have been previously treated with at least one line of single-agent therapy with an EGFR TKI e.g. --- L858R --- --- G719A --- --- L861Q --- --- L858R ---

Primary Outcomes

Description: The RP2D is either the maximum tolerated dose (MTD) or the highest dose tested (in the case that none of the doses are deemed higher than the MTD), whichever is higher.

Measure: Recommended phase 2 dose

Time: Up to 28 days

Secondary Outcomes

Measure: Incidence of adverse events

Time: Up to 4-6 weeks after study completion

Description: The overall response rate will be defined as the number of patients with a partial response (PR) or better that is confirmed in consecutive evaluations (at least 8 weeks apart) divided by the total number of evaluable patients. A 95% confidence interval will also be constructed using the properties of the binomial distribution.

Measure: Overall response rate

Time: Up to 5 years

Description: Duration of response is defined as the number of days between a patient's first occurrence of a PR (or better) and progression. If a patient goes off study prior to progression (for another reason) then they will be censored at that time. A time to event analysis will be performed utilizing the Kaplan-Meier method which will yield a median DOR.

Measure: Duration of response (DOR)

Time: From the first occurrence of a PR (or better) and progression, assessed up to 5 years

Description: A patient's progression free survival time is the number of days between study entry and disease progression. These data will be analyzed utilizing the Kaplan-Meier method which will yield a median PFS time.

Measure: Progression Free Survival (PFS)

Time: From study entry to disease progression, assessed up to 5 years

Other Outcomes

Measure: Maximum plasma Concentration [Cmax] of WSD0922-FU after a single dose of WSD0922-FU

Time: Cycle 1 Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours

Measure: Area under the plasma concentration versus time curve (AUC) of WSD022-FU after a single dose of WSD0922-FU

Time: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours of day 1 of cycles 1 and 2; and pre-dose day 1 of cycles 3 and 4

Measure: Maximum plasma Concentration [Cmax] of WSD0922-FU after multiple doses of WSD0922-FU

Time: Cycle 1 Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours

Measure: Area under the plasma concentration versus time curve (AUC) of WSD022-FU after multiple doses of WSD0922-FU

Time: Cycle 1 Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours

Measure: CSF concentration of WSD0922-FU after multiple doses of WSD0922-FU (Dose Expansion - NSCLC leptomeningeal metastases (NSCLC LM) cohort only).

Time: Cycle 2 Day 1

Measure: Brain tumor concentration of WSD0922-FU after a single dose of WSD0922-FU (Dose Expansion - Brain tumor penetration (BTP) cohort only).

Time: Cycle 0 Day 1

Measure: Tumor EGFR inhibition after a single dose of WSD0922-FU (Dose Expansion - Brain tumor penetration (BTP) cohort only).

Time: Cycle 0 Day 1

Measure: Effect of food on Maximum plasma Concentration [Cmax] of WSD0922-FU after a single dose of WSD0922-FU (Dose Expansion - NSCLC LM cohort only).

Time: Cycle 0 Day 1 and Cycle 0 Day 4

Measure: Effect of food on Area under the plasma concentration versus time curve (AUC) of WSD022-FU after a single dose of WSD0922-FU (Dose Expansion - NSCLC LM cohort only).

Time: Cycle 0 Day 1 and Cycle 0 Day 4

286 A Phase II/III, Open-Label, Randomised Study to Assess the Safety and Efficacy of D-0316 Versus Icotinib as First Line Treatment in Patients With EGFR Sensitising Mutation, Locally Advanced or Metastatic NSCLC

To assess the efficacy and safety of D-0316 versus Icotinib, a standard of care epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in patients with locally advanced or Metastatic Non Small Cell Lung Cancer (NSCLC).

NCT04206072
Conditions
  1. Non-Small Cell Lung Cancer
  2. EGFR Gene Mutation
Interventions
  1. Drug: D-0316 Capsule
  2. Drug: Icotinib Hydrochloride Tablets
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- The tumour tissues harbour one of the two common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by central laboratory. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from randomization until the date of objective disease progression or death by any cause, whichever occurs first. The primary endpoint of PFS was based on independent review committee (IRC) assessment.

Measure: Median Progression Free Survival (PFS) assessed by IRC

Time: From randomization to objective disease progression or death, whichever came first, assessed up to 20 months

Secondary Outcomes

Description: PFS is defined as the time from randomization until the date of objective disease progression or death by any cause, whichever occurs first.

Measure: Median Progression Free Survival (PFS) assessed by Investigator

Time: From randomization to objective disease progression or death, whichever came first, assessed up to 20 months

Description: ORR is defined as the percentage (%) of participants with measurable disease with a best overall response of complete response (CR) or partial response (PR). ORR was based on investigator and IRC assessment.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks (±4 days) until disease progression, up to 20 months

Description: DoR is defined as the time from the date of first documented response (CR or PR) until the date of documented progression or death in the absence of disease progression. DoR was based on both Investigator and IRC assessment.

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks (±4 days) until disease progression, up to 20 months

Description: DCR is defined as the percentage (%) of participants who had a best overall response (BOR) of CR, PR or Stable disease (SD) ≥6 weeks prior to any progressive disease (PD) event, assessed by investigator and IRC.

Measure: Disease Control Rate (DCR)

Time: At baseline and every 6 weeks (±4 days) until disease progression, up to 20 months

Description: OS is defined as the time from randomization until the date of death due to any cause.

Measure: Overall Survival (OS)

Time: From randomization to date of death from any cause, whichever came first, up to 36 months

Description: iORR is calculated as the ORR (CR+PR) of lesions in the brain for patients who have measurable disease in the brain at baseline. iORR was based on both Investigator and IRC assessment.

Measure: Intracranial ORR (iORR)

Time: At baseline and every 6 weeks (±4 days) until disease progression, up to 20 months

Description: iPFS is defined as time from randomization to intracranial disease progression or death due to any causes, assessed by investigator and IRC.

Measure: Intracranial PFS (iPFS)

Time: From randomization to objective intracranial disease progression or death, whichever came first, up to 20 months

Description: AE is defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study medication, whether or not considered related to the study medication. AEs are summarized by type, incidence, severity and relationship to study medication.

Measure: Adverse event (AE)

Time: At baseline and every 3 weeks (±4 days) for the first 6 weeks, and then every 6 weeks (±4 days) until objective disease progression or meet other withdrawal criteria, up to 36 months

Other Outcomes

Description: The FACT-L questionnaire consists of several major aspects of life (Physical, social/family, emotional, and functional well-being) as well as lung cancer subscale (symptoms, cognitive function, regret of smoking). Scores for item ranging from 0 (not at all) to 4 (very much).

Measure: Change From Baseline Scores on the functional assessment of cancer therapy - Lung (FACT-L) quality of life questionnaire

Time: At baseline and every 6 weeks (±4 days) until disease progression, up to 20 months

287 MasterKey-01: A Phase 1/2, Open-label, Two-part, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics & Antitumor Activity of BDTX-189, an Inhibitor of Allosteric ErbB Mutations, in Patients w/ Advanced Solid Malignancies

This is a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that have select mutations or alterations in human epidermal growth factor receptor 2 (HER2/ErbB2) genes or epidermal growth factor receptor (EGFR/ErbB1). The main goals of this study are to: - Find the recommended dose of BDTX-189 that can be given safely to participants - Learn more about the side effects of BDTX-189 - Learn what the body does to BDTX-189 after it has been taken (pharmacokinetics or PK) - Determine the antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

NCT04209465
Conditions
  1. Solid Tumor
Interventions
  1. Drug: BDTX-189

Overall survival is the time from first study dose until death from any cause or study discontinuation.. Main Inclusion Criteria: - Histologically- or cytologically-confirmed locally advanced or metastatic solid tumor with documented recurrence or disease progression from standard anticancer therapy in the advanced/metastatic setting - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- L858R ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >470 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies Main Inclusion Criteria: - Histologically- or cytologically-confirmed locally advanced or metastatic solid tumor with documented recurrence or disease progression from standard anticancer therapy in the advanced/metastatic setting - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S --- --- C805S --- --- L858R ---

Phase 1 will focus on patients with a solid tumor with alterations such as: - Allosteric HER2 or HER3 mutation(s) - EGFR or HER2 exon 20 insertion mutation(s) - HER2 amplified or overexpressing tumors - EGFR exon 19 deletion or L858R mutation Following selection of the RP2D, a Phase 2 portion will be initiated to further evaluate the clinical activity of BDTX-189. --- L858R ---

Primary Outcomes

Description: Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease.

Measure: Incidence of dose limiting toxicities as a determinant of the Recommended Phase 2 Dose (RP2D)

Time: After the first dose of treatment for up to 21 days.

Description: Objective response rate is defined as the proportion of participants who achieve a confirmed complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 2: Objective response rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Secondary Outcomes

Description: Adverse events will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Measure: Phase 1 and Phase 2: Incidence of treatment-emergent adverse events as a measure of safety and tolerability of BDTX-189

Time: From Cycle 1 Day 1 (each cycle is 21 days) until 30 days post last dose

Description: Blood samples will be taken to measure the plasma concentrations of BDTX-189 in both a fed and fasted state.

Measure: Phase 1 and Phase 2: Plasma concentration of BDTX-189 as a measure of pharmacokinetics

Time: Multiple time points during Cycles 1-4 (each cycle is 21 days)

Description: Objective response is defined as the proportion of participants who achieved a complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 1: Objective response rate as a preliminary measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Duration of response is the time from first documentation of a response to first evidence of progressive disease per RECIST version 1.1 or death. A response is defined as either a complete response (CR; disappearance of all target lesions and non-target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions). Progressive disease is defined by a target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions.

Measure: Phase 1 and Phase 2: Duration of response as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Disease control rate is defined as the proportion of participants achieving: a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; at least a 30% decrease in the sum of diameters of target lesions), or stable disease (SD; neither sufficient shrinkage to qualify for a PR nor sufficient increase in lesions) per RECIST version 1.1.

Measure: Phase 1 and Phase 2: Disease control rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Progression-free survival is the time from first study dose until disease progression (PD; target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions) per RECIST v1.1.

Measure: Phase 1 and Phase 2: Progression-free survival as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Overall survival is the time from first study dose until death from any cause or study discontinuation.

Measure: Phase 2: Overall survival as a measure of clinical activity

Time: Assessed every 12 weeks after treatment discontinuation for up to 1 year

288 A Phase II, Multi-centre Study, to Evaluate the Efficacy and Safety of Osimertinib Treatment for Patients With EGFR-mutated Non-small Cell Lung Cancer (NSCLC) With Brain or Leptomeningeal Metastases

Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of Progression-Free Survival (PFS) when used as 1st line treatment. In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. In case of local progression, treatment of the site in progression by radiotherapy and/or surgery is considered. As these local treatments can cause long-term adverse effects, systemic treatments are increasingly being considered in this indication. Brain and leptomeningeal metastases are the most frequent isolated site of progression in EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. However, its efficacy in patients with cerebral or leptomeningeal metastases is still poorly understood.

NCT04233021
Conditions
  1. Non Small Cell Lung Cancer Metastatic
  2. Leptomeningeal Metastasis
  3. Brain Metastases
  4. EGFR Activating Mutation
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Meningeal Carcinomatosis
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The following mutations are considered to be activating: L858R, exon 19 deletions, exon 19 insertions, L861Q, G719X. --- L858R ---

Primary Outcomes

Description: Objective Response Rate at 6 months using EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)

Measure: Objective Response Rate

Time: 6 months

Secondary Outcomes

Description: Time from enrollment until death due to any cause

Measure: Overall Survival

Time: About 24 months

Description: Time from enrollment to first observation of progression (EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)) or date of death (from any cause)

Measure: Progression-free survival

Time: About 24 months

Description: Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Measure: Incidence, type and severity of adverse event

Time: From time of informed consent through treatment period and up to 30 days post last dose of study treatment (about 24 months)

Description: EORTC QLQ-C30-LC13 (Qualify of Life Questionnaire C30 and Lung Cancer 13) questionnaire

Measure: Evaluate the Quality of life

Time: From time of randomisation through treatment period (about 24 months)

Description: QLQ BN20 (Brain Neoplasm N20) questionnaire

Measure: Evaluate the Quality of life

Time: From time of randomisation through treatment period (about 24 months)

289 A Phase III, Double-blind, Randomised Study of SH-1028 Tablets Versus Gefiitinib as First Line Treatment in Patients With Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non Small Cell Lung Cancer

To assess the efficacy and safety of SH-1028 tablets versus Gefitinib, a standard of care epidermal growth factor receptor tyrosine kinase inhibitor, in patients with locally advanced or Metastatic Non Small Cell Lung Cancer

NCT04239833
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: SH-1028 tablets
  2. Drug: Placebo SH-1028 tablets
  3. Drug: Gefitinib
  4. Drug: Placebo Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- 3. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either or in combination with other EGFR mutations assessed by central testing using tumour tissue sample or cytology sample. --- L858R ---

Primary Outcomes

Description: Progression-free survival was defined as the time from randomization until the date of objective disease progression regardless of whether the participant withdrew from randomized therapy and was used to assess the efficacy of SH-1028 tablets compared with Gefitinib (SoC EGFR-TKI therapy) as measured by PFS. The primary endpoint of PFS was based on Investigator assessment.

Measure: Median Progression Free Survival (PFS)

Time: At baseline and every 6 weeks relative to randomisation until progression,up to 24 months.

Secondary Outcomes

Description: ORR was defined as the number (%) of participants with measurable disease with at least 1 visit response of Complete response (CR) or Partial response (PR) and it was used to further assess the efficacy of SH-1028 tablets compared with Gefitinib (SoC EGFR-TKI therapy). ORR was based on Investigator assessment.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks relative to randomisation until progression,up to 24 months.

Description: Duration of response was defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression and was used to further assess the efficacy of SH-1028 tablets compared with Gefitinib (SoC EGFR-TKI therapy).

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks relative to randomisation until progression,up to 24 months.

Description: The DCR was defined as the percentage of participants who had a best overall response (BOR) of Complete response (CR), Partial response (PR) or Stable disease (SD) ≥6 weeks prior to any Progressive disease (PD) event and was used to further assess the efficacy of SH-1028 tablets compared with Gefitinib (SoC EGFR-TKI therapy).

Measure: Disease Control Rate (DCR)

Time: At baseline and every 6 weeks relative to randomisation until progression,up to 24 months.

Description: The Depth of response was defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) Target lesions (TLs) at the nadir, in the absence of new lesions (NLs) or progression of Non-target lesions (NTLs), compared to baseline and was used to further assess the efficacy of SH-1028 tablets compared with Gefitinib (SoC EGFR-TKI therapy).

Measure: Depth of Response(DepOR)

Time: At baseline and every 6 weeks relative to randomisation until progression,up to 24 months.

Description: Overall survival was defined as the time from the date of randomisation until death from any cause and was used to further assess the efficacy of SH-1028 tablets compared with Gefitinib (SoC EGFR-TKI therapy).

Measure: Overall Survival (OS)

Time: From first dose to end of study or date of death from any cause, whichever comes first, assessed every 6 weeks (approximately 30 months)

Description: The EORTC QLQ-LC13 was a lung-cancer-specific module comprising 13 questions to assess lung cancer symptoms (cough, haemoptysis, dyspnoea, and site-specific pain); treatment related side-effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia); and pain medication. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items. Higher scores on the global health status/QoL and functioning scales indicated better health status/QoL and function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit, including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QLQ) Questionnaires Lung Cancer 13 (QLQ-LC13)

Time: At baseline and every 6 weeks relative to randomisation until progression,up to 24 months.

Description: The EORTC QLQ-C30 cancer-specific questionnaire consisted of 30 questions, combined to produce 5 functional scales, 3 symptom scales, 6 individual items, and a global measure of health status/QoL. An outcome variable consisting of a score from 0 to 100 was derived for each of the symptom scales/symptom items, the functional scales, and the global health status/QoL scale in the EORTC QLQ-C30. Higher scores on the global health status and functioning scales indicated better health status/function. Higher scores on the symptoms scales indicated greater symptom burden. The analysis was performed using a Mixed-effects model for repeated measures analysis on the change from baseline in PRO symptom score at each visit, including participants, treatment, visit and treatment by visit interaction as explanatory variables, the baseline PRO score as a covariate along with the baseline PRO score by visit interaction, using an unstructured covariance structure.

Measure: Change From Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 Items (EORTC QLQ-C30)

Time: At baseline and every 6 weeks relative to randomisation until progression,up to 24 months.

Description: Number of adverse events (AEs) assessed by CTCAE 5.0 was one of main outcome measures to compare the safety of SH-1028 Tablets and Gefitinib.

Measure: Number of adverse events (AEs)

Time: From first dose to 28 days after SH-1028 tablets discontinuation.

Description: Incidence rate of serious adverse events (SAEs) was one of main outcome measures to compare the safety of SH-1028 Tablets and Gefitinib.

Measure: Incidence rate of serious adverse events (SAEs)

Time: From first dose to 28 days after SH-1028 tablets discontinuation.

290 A Randomised Non-comparative Open Label Phase II Trial of Atezolizumab Plus Bevacizumab, With Carboplatin-paclitaxel or Pemetrexed, in EGFR-mutant Non-small Cell Lung Carcinoma With Acquired Resistance

ETOP 15-19 ABC-lung is an international, multi-centre open-label, randomized phase II trial with two non-comparative parallel arms of atezolizumab plus bevacizumab with carboplatin-paclitaxel (Arm A) or atezolizumab, bevacizumab and pemetrexed (Arm B) in patients with stage IIIB-IV non-squamous non-small cell lung cancer (NSCLC) harbouring EGFR mutations after failure of standard EGFR tyrosine kinase inhibitors (TKIs).

NCT04245085
Conditions
  1. EGFRmutant Stage IIIB/C or IV Non-squamous NSCLC
Interventions
  1. Drug: Atezolizumab
  2. Drug: Bevacizumab
  3. Drug: Carboplatin
  4. Drug: Paclitaxel
  5. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Known EGFR mutations genotypes by tissue or ctDNA, patients with common mutations (L858R or Del19) and other rare mutations (e.g. --- L858R ---

afatinib, dacomitinib, erlotinib, gefitinib): - Patient must be known to be tissue EGFR T790M wild type (local test) on most recent line of EGFR TKI or if no tissue re-biopsy, no evidence of T790M on ctDNA but identified L858R, del19, S768I or G719X genotypes (informative ctDNA test, local test) 6. Treatment with an EGFR TKI therapy for at least 10 days 7. Adequate haematological function: - Haemoglobin greater or equal 90 g/L - Absolute neutrophils count (ANC) greater or equal 1.5× 109/L - Platelet count greater or equal 100× 109/L 8. Adequate renal function: - Creatinine less or equal 1.5× ULN OR - Creatinine clearance greater or equal 45 mL/min (using the Cockcroft-Gault formula) 9. Adequate liver function: - ALT and AST less or equal 2.5× ULN. --- T790M --- --- T790M --- --- L858R ---

Primary Outcomes

Description: The primary objective of this study is to explore the clinical efficacy of atezolizumab and bevacizumab combined with chemotherapy in patients with EGFR-mutant advanced NSCLC after failure of standard EGFR TKIs.

Measure: Progression-free survival (PFS) rate at 12 months according to RECIST v1.1

Time: 12 months from randomisation

Secondary Outcomes

Description: To assess the safety and tolerability of the treatment.

Measure: Adverse events according to CTCAE v5.0

Time: from the date of randomisation until 90 days after the last dose of protocol treatment

Description: OS is defined as the time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.

Measure: Overall survival

Time: through study completion, from the date of randomisation until death, including OS rate at 12 months.

Description: Objective response is defined as best overall response (CR or PR) across all assessment time-points according to RECIST criteria v1.1, from randomisation until the end of protocol treatment.

Measure: Objective response

Time: From date of randomisation until date of treatment completion (until documented disease progression, death or any other causes), assessed up to 2 years.

Description: Quality of life will be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). The key QoL outcome is the time to deterioration (TTD) in the QLQ-C30 global health status/global QoL.

Measure: Quality of Life Core Questionnaire (EORTC QLQ-C30)

Time: from baseline up to 12 months or until disease progression, whatever is first.

Description: Lung cancer associated symptoms will be measured by the lung cancer-specific module (QLQ-LC13).

Measure: Quality of Life lung cancer-specific module (QLQ-LC13)

Time: from baseline up to 12 months or until disease progression, whatever is first.

Description: Extra-cranial progression-free-survival is the time from randomisation to documentation of disease progression outside the central nervous system (CNS) as per RECIST criteria or death, whichever occurred first.

Measure: Extra-cranial PFS

Time: through study completion, from date of randomisation to documentation of PD outside the CNS, assessed up to 2 years

Description: Intracranial progression-free-survival is defined as the time from randomisation to first documented radiographic evidence of CNS progression. CNS progression is defined as progression due to newly developed CNS lesions and/or progression of pre-existing baseline CNS lesions.

Measure: Intracranial PFS

Time: through study completion, from date of randomisation to first documented radiographic evidence of CNS progression, assessed up to 2 years.

291 A Phase III, Randomized, Double-blind Study to Assess the Efficacy and Safety of Lazertinib Versus Gefitinib as the First-line Treatment in Patients With Epidermal Growth Factor Receptor Sensitizing Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

This Phase III study will be conducted to evaluate the efficacy and safety of YH25448 as first-line treatment in locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) patients with EGFR mutations

NCT04248829
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Lazertinib 240 mg/160 mg
  2. Drug: Gefitinib 250 mg
  3. Drug: Lazertinib-matching placebo 240 mg/160 mg
  4. Drug: Gefitinib-matching placebo 250 mg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Pathologically confirmed adenocarcinoma of the lung - Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy - At least 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations - Treatment-naïve for locally advanced or metastatic NSCLC - WHO performance status score of 0 to 1 with no clinically significant deterioration over the previous 2 weeks before randomization - At least 1 measurable lesion, not previously irradiated and not chosen for biopsy during the study Screening period Exclusion Criteria: - Symptomatic and unstable brain metastases - Leptomeningeal metastases - Symptomatic spinal cord compression - History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD - Any medical conditions requiring chronic continuous oxygen therapy - History of any malignancy other than the disease under study within 3 years before randomization - Any cardiovascular disease as follows: - History of symptomatic chronic heart failure or serious cardiac arrhythmia requiring active treatment - History of myocardial infarction or unstable angina within 24 weeks of randomization Inclusion Criteria: - Pathologically confirmed adenocarcinoma of the lung - Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy - At least 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations - Treatment-naïve for locally advanced or metastatic NSCLC - WHO performance status score of 0 to 1 with no clinically significant deterioration over the previous 2 weeks before randomization - At least 1 measurable lesion, not previously irradiated and not chosen for biopsy during the study Screening period Exclusion Criteria: - Symptomatic and unstable brain metastases - Leptomeningeal metastases - Symptomatic spinal cord compression - History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD - Any medical conditions requiring chronic continuous oxygen therapy - History of any malignancy other than the disease under study within 3 years before randomization - Any cardiovascular disease as follows: - History of symptomatic chronic heart failure or serious cardiac arrhythmia requiring active treatment - History of myocardial infarction or unstable angina within 24 weeks of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) that targets both the T790M mutation and activating EGFR mutations while sparing wild type EGFR. --- L858R ---

Inclusion Criteria: - Pathologically confirmed adenocarcinoma of the lung - Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy - At least 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations - Treatment-naïve for locally advanced or metastatic NSCLC - WHO performance status score of 0 to 1 with no clinically significant deterioration over the previous 2 weeks before randomization - At least 1 measurable lesion, not previously irradiated and not chosen for biopsy during the study Screening period Exclusion Criteria: - Symptomatic and unstable brain metastases - Leptomeningeal metastases - Symptomatic spinal cord compression - History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD - Any medical conditions requiring chronic continuous oxygen therapy - History of any malignancy other than the disease under study within 3 years before randomization - Any cardiovascular disease as follows: - History of symptomatic chronic heart failure or serious cardiac arrhythmia requiring active treatment - History of myocardial infarction or unstable angina within 24 weeks of randomization Inclusion Criteria: - Pathologically confirmed adenocarcinoma of the lung - Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy - At least 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations - Treatment-naïve for locally advanced or metastatic NSCLC - WHO performance status score of 0 to 1 with no clinically significant deterioration over the previous 2 weeks before randomization - At least 1 measurable lesion, not previously irradiated and not chosen for biopsy during the study Screening period Exclusion Criteria: - Symptomatic and unstable brain metastases - Leptomeningeal metastases - Symptomatic spinal cord compression - History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD - Any medical conditions requiring chronic continuous oxygen therapy - History of any malignancy other than the disease under study within 3 years before randomization - Any cardiovascular disease as follows: - History of symptomatic chronic heart failure or serious cardiac arrhythmia requiring active treatment - History of myocardial infarction or unstable angina within 24 weeks of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) that targets both the T790M mutation and activating EGFR mutations while sparing wild type EGFR. --- L858R --- --- L858R ---

Primary Outcomes

Description: To assess the efficacy of lazertinib compared with gefitinib as measured by PFS

Measure: Progression-Free Survival (PFS) according to RECIST v1.1 by Investigator assessment

Time: The primary analysis of PFS based on investigator assessment will occur when PFS maturity is observed at approximately 27 months after the first patient is randomized

Secondary Outcomes

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Objective Response Rate (ORR) according to RECIST v1.1 by Investigator assessments

Time: ORR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Duration of Response (DoR) according to RECIST v1.1 by Investigator assessments

Time: DoR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Disease Control Rate (DCR) according to RECIST v1.1 by Investigator assessments

Time: DCR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Depth of Response according to RECIST v1.1 by Investigator assessments

Time: Depth of Response analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Time to Response according to RECIST v1.1 by Investigator assessments

Time: Time to Response analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess OS of lazertinib compared with gefitinib

Measure: Overall survival (OS)

Time: OS will be analyzed at 2 time points: when PFS maturity is observed at approximately 27 months after the first patient is randomized, and when OS maturity is observed at approximately 45 months after the first patient is randomized

Description: To characterize the pharmacokinetics (PK) of lazertinib

Measure: Plasma concentrations of lazertinib

Time: Plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib metabolite YH26334

Measure: Plasma concentrations of Metabolite YH26334

Time: Plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib and YH26334

Measure: Ratio of YH26334 to lazertinib plasma concentration

Time: Ratio of YH26334 to lazertinib plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib

Measure: Cerebrospinal fluid (CSF) concentrations of lazertinib

Time: CSF concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib metabolite YH26334

Measure: CSF concentrations of Metabolite YH26334

Time: CSF concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib and YH26334

Measure: Ratio of CSF to plasma concentration of lazertinib and YH26334

Time: Ratio of CSF to plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: The EORTC QLQ-C30 consists of 30 items and measures cancer patients' functioning (health related quality of life (HRQoL)) and symptoms for all cancer types. Questions can be grouped into 5 multi item functional scales (physical, role, emotional, cognitive, and social); 3 multi item symptom scales (fatigue, pain, nausea/vomiting); a 2 item global HRQoL scale; 5 single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation, diarrhea) and 1 item on the financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. a high score for a functional scale represents a high / healthy level of functioning a high score for the global health status / QoL represents a high QoL but a high score for a symptom scale / item represents a high level of symptomatology / problems

Measure: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 items (QLQ-C30)

Time: EORTC-QLQ-C30 analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: The EORTC QLQ-LC13 includes questions assessing cough, hemoptysis, dyspnea, site specific pain (symptoms), sore mouth, dysphagia, peripheral neuropathy, and alopecia (treatment related side effects), and pain medication. The items on both measures were scaled and scored using the recommended EORTC procedures. Raw scores were transformed to a linear scale ranging from 0 to 100, with a higher score representing a higher level of functioning or higher level of symptoms. Provided at least half of the items in the scale were completed, the scale score was calculated using only those items for which values existed.

Measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Lung Cancer 13 items (EORTC QLQ-LC13)

Time: EORTC QLQ-LC13 analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: The EQ-5D comprises the following two questionnaires: The EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension comprises five levels (no problems, slight problems, moderate problem, severe problem, unable/extreme problems). The EQ VAS records the patients self-rated health status on a vertical graduated (0-100) visual analogue scale. The patient's self-rated health is assessed on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by the EQ-VAS.

Measure: Change From Baseline in Euro-Quality of Life-5 Dimension-5 level (EQ-5D-5L)

Time: EQ-5D-5L analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Other Outcomes

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with brain metastases (BM) at baseline

Measure: Intracranial PFS according to RECIST v1.1 by Investigator assessment and blinded independent central review (BICR)

Time: Intracranial PFS based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Intracranial ORR according to RECIST v1.1 by Investigator assessments and BICR

Time: Intracranial ORR based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Intracranial DoR according to RECIST v1.1 by Investigator assessment and BICR

Time: Intracranial DoR based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Intracranial DCR according to RECIST v1.1 by Investigator assessment and BICR

Time: Intracranial DCR based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Depth of intracranial response according to RECIST v1.1 by Investigator assessment and BICR

Time: Depth of intracranial response based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Time to intracranial response according to RECIST v1.1 by Investigator assessment and BICR

Time: Time to intracranial response analysis based on Investigator assessment and BICR will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: PFS according to RECIST v1.1 by Investigator assessment

Time: PFS analysis will occur when OS maturity is observed at approximately 45 months from the first dosing date of lazertinib

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: ORR according to RECIST v1.1 by Investigator assessments

Time: ORR analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: DoR according to RECIST v1.1 by Investigator assessments

Time: DoR analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: DCR according to RECIST v1.1 by Investigator assessments

Time: DCR analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: Depth of Response according to RECIST v1.1 by Investigator assessments

Time: Depth of Response analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: Time to Response according to RECIST v1.1 by Investigator assessments

Time: Time to Response analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To compare plasma-derived cfDNA EGFR mutation status at baseline and at progression

Measure: Change from baseline for EGFR mutation status in plasma samples

Time: EGFR mutation status in plasma samples analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To compare the tumor sample EGFR mutation status at baseline and from an optional tumor sample taken at progression

Measure: Change from baseline for EGFR mutation status in tumor samples

Time: EGFR mutation status in tumor samples analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

292 UCLA L-08: A Phase Ib/II Study of Combined HER Inhibition Adding Necitumumab and Trastuzumab to Osimertinib in Patients With Refractory EGFR-Mutated Lung Cancer

This phase Ib/II trial studies the side effects and best dose of trastuzumab and necitumumab together with osimertinib, and to see how well they work for the treatment of stage IV non-small cell lung cancer that is EGFR-mutated, resistant to osimertinib, and has not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as trastuzumab and necitumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving trastuzumab and necitumumab together with osimertinib may work better than osimertinib alone in treating patients with stage IV EGFR-mutated non-small cell lung cancer.

NCT04285671
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Refractory Lung Non-Small Cell Carcinoma
  3. Stage IV Lung Cancer American Joint Committee on Cancer (AJCC) v8
  4. Stage IVA Lung Cancer AJCC v8
  5. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Biological: Necitumumab
  2. Drug: Osimertinib
  3. Other: Quality-of-Life Assessment
  4. Other: Questionnaire Administration
  5. Biological: Trastuzumab
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Enrollment of patients with mutations other than exon 19 deletion and the L858R point mutation require literature supporting sensitivity to EGFR tyrosine kinase inhibitors - Progressed on osimertinib. --- L858R ---

Primary Outcomes

Measure: Identification of the recommended phase II dose (R2PD) regimen for combination osimertinib, necitumumab, trastuzumab (ONT) therapy (Phase Ib)

Time: Up to 1 year

Description: Will be defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0).

Measure: Incidence of adverse events (Phase Ib)

Time: Up to 1 year

Description: Will be based on the Full Analysis Set (FAS) of the phase II portion of the trial and the phase Ib patients treated at the recommended phase II dose (RP2D). ORR is defined as defined as complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Will be determined by the investigator. A Cox proportional hazards model will be used to estimate the hazard ratio and its 95% confidence interval (CI).

Measure: Objective response rate (ORR) (Phase II)

Time: Up to 1 year

Secondary Outcomes

Description: PFS is defined as the time from trial initiation to cancer progression per RECIST 1.1 based on investigator assessment or death due to any cause.

Measure: Progression free survival (PFS) (Phase II)

Time: Up to 1 year

Description: DoR is time from documentation of tumor response to disease progression.

Measure: Duration of response (DoR) (Phase II)

Time: Up to 1 year

Description: OS is defined as time from randomization to death by any cause.

Measure: Overall survival (OS) (Phase II)

Time: Up to 1 year

Measure: Time to response (TTR)

Time: Up to 1 year

Description: Will be assessed using Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE).

Measure: Patient reported outcomes (PROs)

Time: Up to 1 year

Other Outcomes

Description: Will be obtained from the Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire. Will be analyzed by the clinical biostatisticians in the University of California, Los Angeles (UCLA) Department of Medicine Medical Statistics Core.

Measure: Quality of life data questionnaire

Time: Up to 1 year

Description: Will be assessed using response from liquid biopsies and optional but recommended baseline tissue biopsy. Will correlate pre-and post-treatment biopsies molecular changes (i.e. expression of HER2, HER3, AXL, MET) with response.

Measure: Potential biomarkers associated with response from liquid biopsies

Time: Up to 1 year

Description: Will be assessed using liquid biopsy with response.

Measure: Mutant allele fraction in circulating tumor deoxyribonucleic acid (DNA) (ctDNA)

Time: Up to 1 year

293 A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC

This phase II trial compares cabozantinib alone and the combination of cabozantinib and nivolumab to standard chemotherapy in the treatment of patients with non-squamous non-small cell lung cancer (NSCLC). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as docetaxel, gemcitabine hydrochloride, paclitaxel, and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cabozantinib alone or in combination with nivolumab may be more effective than standard chemotherapy in treating patients with non-small cell lung cancer.

NCT04310007
Conditions
  1. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  3. Stage III Lung Cancer AJCC v8
  4. Stage IIIA Lung Cancer AJCC v8
  5. Stage IIIB Lung Cancer AJCC v8
  6. Stage IIIC Lung Cancer AJCC v8
  7. Stage IVA Lung Cancer AJCC v8
  8. Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
Interventions
  1. Drug: Cabozantinib S-malate
  2. Drug: Docetaxel
  3. Drug: Gemcitabine Hydrochloride
  4. Drug: Nab-paclitaxel
  5. Biological: Nivolumab
  6. Drug: Paclitaxel
  7. Biological: Ramucirumab
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

If small cell elements are present the patient is ineligible - ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient's tumor(s) must be tested and known negative for EGFR tyrosinase kinase inhibitor (TKI) sensitizing mutations (EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by fluorescence in situ hybridization [FISH], next generation sequencing [NGS], or immunohistochemistry [IHC]) by routine Clinical Laboratory Improvement Act (CLIA)-certified clinical testing methods. --- L858R ---

Primary Outcomes

Description: The final analysis of PFS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). The two primary comparisons of PFS will each use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of PFS including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. At the final analyses, in the event that both primary PFS comparisons of the combination of nivolumab with cabozantinib and cabozantinib alone versus the standard chemotherapy are statistically significant, PFS will be compared between the two experimental arms (combination of nivolumab with cabozantinib versus [vs.] cabozantinib alone), using a stratified log rank test with a one-sided type I error rate of 10%.

Measure: Progression-free survival (PFS) for patient population with non-squamous no-small cell lung cancer (NSCLC)

Time: After 58 events (From time of randomization to documented disease progression [site review of imaging] or death from any cause, whichever occurs first)

Secondary Outcomes

Description: The final analysis of OS will be performed when the full information of PFS is reached (i.e., 58 events for each of the two primary comparisons). OS will be tested in a hierarchical fashion if the primary comparison of PFS between treatment arms is statistically significant, using a log rank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Estimates of OS, including medians and confidence intervals, will be calculated using the Kaplan-Meier method. Cox proportional hazards models, stratified, on the same factors, will be used to estimate the treatment hazard ratios. OS will be further tested in a hierarchical fashion if the comparison of PFS between the two experimental arms is statistically significant. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals. Subset analyses of PFS and OS by treatment arm will be estimated and compared within subsets.

Measure: Overall survival (OS) for each arm

Time: From time of randomization to documented disease progression (site review of imaging) or death from any cause, whichever occurs first, assessed up to 3 years

Description: Will be evaluated via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response rates (complete response [CR] + partial response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.

Measure: Best objective response for each arm

Time: Every 6 weeks for the first year on study, and then every 12 weeks after year one

Description: Will be determined using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Response rates (complete response [CR] + pathologic response [PR]) and toxicity will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Modeling procedures will implement backward selection; variables significant at the 0.10 level in the univariate setting will be chosen for inclusion in an initial full model, and at each step the least significant variable will be removed from the model. Only those covariates with p < 0.05 will remain in any final models, unless there are factors identified by the study team as crucial to model interpretation. Point estimates of all endpoints will be accompanied by the corresponding two-sided 80% confidence intervals.

Measure: Toxicity profile of monotherapy with cabozantinib, and the combination of nivolumab and cabozantinib

Time: Up to 3 years after completion of study treatment

Other Outcomes

Description: The measurement of each time point will be performed using the revised CHOI criteria will be only applied to arms A, B, and T, which will include anti-angiogenic therapy. Both the RECIST1.1 and revised CHOI criteria will assess the overall best response as CR, partial PR, stable disease (SD), or progressive disease (PD). Their concordance will be assessed using the weighted Cohen's kappa coefficient (k) with quadratic weights. As a rule of thumb, the level of concordance between the two criteria will be considered poor (k <0), slight (k 0-0.20), fair (k 0.21-0.40), moderate (k 0.41-0.60), substantial (k 0.61-0.80), and almost perfect (k 0.81 - 1).

Measure: The RECIST1.1 response at each time point

Time: Every 6 weeks for the first year on study, and then every 12 weeks after year one

Description: The progression status and the progression time will be assessed in agreement. The progression status is a binary measurement and the agreement will be assessed using the Cohen's kappa coefficient. For progression time, will assess the temporal agreement using the method developed by Zeng et al.

Measure: Agreement between central view and site review in terms of progression-free survival

Time: After the completion of study treatment

Description: Correlative biomarker research will be performed on tissue and blood specimens collected within this trial.

Measure: Correlative biomarker research

Time: After the completion of study treatment

294 A RANDOMIZED, DOUBLE-BLIND BRIDGING SAFETY AND EFFICACY STUDY OF PF-06439535 (CN) PLUS PACLITAXEL-CARBOPLATIN VERSUS BEVACIZUMAB PLUS PACLITAXEL-CARBOPLATIN FOR THE FIRST-LINE TREATMENT OF CHINESE PARTICIPANTS WITH ADVANCED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER

The current study will compare the efficacy, safety, pharmacokinetics and immunogenicity of PF-06439535 (CN) in combination with paclitaxel and carboplatin versus bevacizimab sourced from the European Union (bevacizumab-EU) with paclitaxel and carboplatin in Chinese participants with advanced non-squamous NSCLC in the first-line treatment setting.

NCT04325698
Conditions
  1. Advanced Non-squamous NSCLC
Interventions
  1. Drug: PF-06439535 (CN)
  2. Drug: Bevacizumab-EU
  3. Drug: Paclitaxel
  4. Drug: Carboplatin

- Known EGFR activating mutations (for example, exon 19 deletion or exon 21 L858R substitution mutations) or ALK rearrangements. --- L858R ---

Primary Outcomes

Description: ORR refers to percentage of participants who achieved complete response (CR) or partial response (PR) by Week 19 of the study in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 which was subsequently confirmed by Week 25. A participant achieved CR if both target and non-target lesions achieved CR, no new lesions; achieved PR if target lesions achieved CR or PR, non-target lesions were assessed as non-CR/non-PD (non-progressive disease), indeterminate or missing, and no new lesions. For target lesions, CR: complete disappearance of all target lesions, normal nodes (target nodes must decrease to normal size); PR: >= 30% decrease under baseline of the sum of diameters of all target measurable lesions. For non-target lesions, CR: disappearance of all non-target lesions and normalization of tumor marker levels and all lymph nodes must be normal in size; non-CR/non-PD: persistence of any non-target lesions and/or tumor marker level above the normal limits.

Measure: 1. Objective Response Rate (ORR) by Week 19

Time: 25 weeks

Secondary Outcomes

Description: Safety characterized by type, incidence, severity, timing, seriousness, and relationship to investigational product of adverse events, including cardiotoxicity and infusion related reactions, and laboratory abnormalities

Measure: Adverse events

Time: From time of ICD signed to 2 years

Measure: Serum Concentration of Bevacizumab

Time: up to 2 years

Measure: Number of Participants With Anti-Drug Antibody (ADA)

Time: up to 2 years

Description: Only samples that were confirmed positive for ADA were further tested for NAb.

Measure: Number of Participants With Neutralizing Antibody (NAb)

Time: up to 2 years

295 An Open Label, Multicenter, Phase II Study of Dacomitinib for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases

This is a multi-center, single-arm, open-label, Phase 2 clinical study of Dacomitinib for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases.

NCT04339829
Conditions
  1. Dacomitinib for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Brain Neoplasms
HPO:Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive.. Inclusion Criteria: - Provision of a voluntarily given, personally signed and dated, written informed consent document; - Age≥18 years, male or female; - The presence of an EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) in tumor specimen determined by the local laboratory. --- L858R ---

It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study; - Evidence of newly diagnosed stage IIIB/IV (based on Union for International Cancer Control (UICC) staging system version 7) or recurrent (minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC required) NSCLC of adenocarcinoma histo- and/or cytopathology or its pathologically accepted variants using tumor specimen (assessed according to accepted standards by a local laboratory). --- T790M --- --- L858R ---

Variations of adenocarcinoma are allowed, however no squamous element can be present; - Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R ---

Both mutations (exon 19 deletion and L858R mutation in exon 21) within a tumor sample; - Symptomatic brain or leptomeningeal metastases, who are neurologically unstable or require increasing doses of steroids to manage CNS symptoms within two weeks prior to starting dacomitinib; - Any previous anti-cancer systemic treatment of locally advanced, or metastatic NSCLC including but not limited to chemotherapy, targeted therapies, small molecules, EGFR-TKIs and other TKIs, monoclonal antibodies, anti-cancer vaccines, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, i.e., non-target lesions). --- L858R ---

Inclusion Criteria: - Provision of a voluntarily given, personally signed and dated, written informed consent document; - Age≥18 years, male or female; - The presence of an EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) in tumor specimen determined by the local laboratory. --- L858R ---

Primary Outcomes

Description: Progression Free Survival (PFS)is defined as the time from start of treatment to the date of disease progression as defined by RECIST v1.1 per investigator review or death due to any cause, whichever occurred first.

Measure: Progression Free Survival (PFS)

Time: 20 months

Secondary Outcomes

Description: Intracranial Objective Response Rate is defined as the proportion of subjects with a BOR of either CR or PR of intracranial disease, where BOR is the best response recorded from the start of treatment until disease progression or start of other anticancer therapy. As per RECIST v1.1 guidelines, PR and CR do not need to be confirmed following initial response documentation.

Measure: Intracranial Objective Response Rate

Time: 20 months

Description: Objective Response Rate is defined as the proportion of subjects with a BOR of either CR or PR, where BOR is the best response recorded from the start of treatment until disease progression or start of other anticancer therapy. As per RECIST v1.1 guidelines, PR and CR do not need to be confirmed following initial response documentation.

Measure: Objective Response Rate

Time: 20 months

Description: Disease control rate is defined as the proportion of patients with complete response (CR) or partial response (PR) or subjects with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria.

Measure: Disease control rate

Time: 20 months

Description: Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death due to any cause, according to RECIST 1.1 criteria

Measure: Duration of response

Time: 20 months

Description: Intracranial Progression Free Survival is defined as confirmed by investigator with morphologically proven intracranial PD [presence of at least one key symptom in combination with radiologic evidence including CT or MRI of PD in the brain on follow-up or death due to any cause, whichever occurred first.

Measure: Intracranial Progression Free Survival

Time: 20 months

Description: Overall Survival is defined as the time from start of treatment to the date of death for any cause. In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive.

Measure: Overall Survival

Time: 48 months

296 A Phase III, Randomised, Controlled, Multi-center, 3-Arm Study of Neoadjuvant Osimertinib as Monotherapy or in Combination With Chemotherapy Versus Standard of Care Chemotherapy Alone for the Treatment of Patients With Epidermal Growth Factor Receptor Mutation Positive, Resectable Non-small Cell Lung Cancer

This is a Phase III, randomised, controlled, 3-arm, multi-centre study of neoadjuvant osimertinib as monotherapy or in combination with chemotherapy, versus SoC chemotherapy alone, for the treatment of patients with resectable EGFRm Non-Small Cell Lung Cancer

NCT04351555
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Cisplatin
  3. Drug: Carboplatin
  4. Drug: Placebo
  5. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing - A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (ie, T790M, G719X, Exon20 insertions, S7681 and L861Q). --- L858R ---

Primary Outcomes

Description: Defined as ≤10% residual cancer cells in the main tumour, as assessed per central pathology laboratory post-surgery

Measure: Major Pathological Response (MPR)

Time: From date of randomization to an average of 12 weeks after the first dose

Secondary Outcomes

Description: Defined as absence of any residual cancer cells in the dissected tumour samples, including the main tumour and lymph nodes, assessed post-surgery

Measure: Pathological complete response (pCR)

Time: From date of randomization to an average of 12 weeks after the first dose

Description: An event is defined as documented disease progression that precludes surgery or requires non-protocol therapy; recurrence or a new lesion, local or distant (a new primary malignancy confirmed by pathology is not considered to be an EFS event.); death due to any cause

Measure: Event-free survival (EFS)

Time: Up to approximately 42 months after the last patient is randomized

Description: Patients will be followed up to approximately 5.5 years after they are randomized.

Measure: Overall Survival (OS)

Time: Up to approximately 5.5 years after the last patient is randomized

Description: DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first.

Measure: Disease free survival (DFS)

Time: From date of randomization up to approximately 42 months after date of resection

Description: Measured using pathologic mediastinal lymph node evaluation

Measure: Downstaging

Time: From date of randomization to an average of 12 weeks after the first dose

Description: Assess disease-related symptoms, functioning, and global health status/quality-of-life in patients

Measure: Difference between treatment arms in change from baseline in EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items)

Time: From randomization to 264 weeks post-surgery

Measure: Concordance of EGFRm status between tumour tissue DNA and patient-matched plasma-derived ctDNA

Time: Baseline

Measure: Corcordance of EGFR mutation status between the local and central cobas EGFR mutation test results from baseline tumour samples

Time: Baseline

Measure: PK plasma concentrations of osimertinib

Time: From the pre-dose of Cycle 2 to post-dose of Cycle 3 (each cycle is 21 days)

Description: Assess lung cancer-associated symptoms and side effects from conventional chemotherapy and radiotherapy

Measure: Difference between treatment arms in change from baseline in EORTC QLQ-LC13 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items)

Time: From randomization to 264 weeks post-surgery

Other Outcomes

Description: The cure rate is defined as the percentage of people in this study who are still alive and disease free for a certain period of time after they finished the surgery. Here 5-year landmark cure rate will be calculated in the same time as OS analysis.

Measure: Cure rate

Time: From the surgery until 5 years after surgery

Description: Other clinical variables include deaths, laboratory data, vital signs (pulse and BP), ECG, LVEF, ECOG performance status, and ophthalmologic assessment

Measure: Number of adverse events as assessed by CTCAE 5.0 and other clinical variables for safety and tolerability profile of neoadjuvant osimertinib as monotherapy or in combination with chemotherapy prior to surgery compared with chemotherapy alone

Time: From the time of enrollment to either 28-days after the last dose of last study treatment for patients who do not undergo surgery, or 90-days post-surgery

Measure: MPR using plasma-derived circulating-free tumour DNA (ctDNA)

Time: From randomization to 5 years post-surgery

297 A Randomized Phase II Trial of Gefitinib With Anlotinib in Advanced Non-squamous NSCLC Patients With Uncleared Plasma ctDNA EGFRm After First-line Treatment With Gefitinib

TKIs therapy is the first-line treatment of patients with EGFR mutation advanced NSCLC.However, some patients have poor prognosis of drug resistance in the early stage. The dynamic alterations of ctDNA-based EGFR mutation after TKIs treatment is a predictor of the efficacy of TKIs treatment, which can be used to identify this part of patients in the early stage.Drug resistance can be overcome when TKIs is combined with drugs in different mechanisms of action, such as chemotherapy and anti-angiogenesis therapy.Gefitinib is the first-generation oral EGFR TKIs. Anlotinib is a domestic oral small molecule inhibitor of multireceptor tyrosine kinase, which has extensive inhibitory effect on tumor angiogenesis and growth.Gefitinib combined with anlotinib is a new option in the treatment of patients with uncleared plasma EGFRm after gefitinib treatment.

NCT04358562
Conditions
  1. Non-small Cell Lung Cancer
  2. EGFR Gene Mutation
Interventions
  1. Drug: Gefitinib
  2. Drug: Anlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Histologically confirmed that EGFR sensitive mutation (ex19del or L858R mutation) in tumor tissue was detected by non-squamous NSCLC, and EGFR mutation (ex19del or L858R mutation) in ctDNA before treatment; - Staging is IVB stage (AJCC 8th Edition) ; - According to the comprehensive judgment of many disciplines, it is impossible to be treated by operation; - PS score 0-1; - The patient has at least one measurable tumor injury (the tumor is considered unmeasurable at the site of previous radiotherapy); - Systemic anti-tumor therapy such as chemotherapy, immunotherapy and targeted therapy were not performed before entering the group; - There is no history of malignant tumor and no serious medical disease; - FEV1 ≥ 1.2L/ seconds or ≥ 50% predicted value; - Laboratory examination: White blood cell count ≥ 4 *10^9/L, neutrophil count ≥ 2.0 *10^9, platelet count ≥ 100 *10^9, hemoglobin ≥ 10 g / L, liver and kidney function and ECG were normal; - The pregnancy test was negative within 3 days before entering the group, and agreed to use medically effective contraceptive measures during the trial; - Life expectancy is more than 12 weeks; - Sign informed consent form; cooperate with regular follow-up. --- L858R ---

Inclusion Criteria: - Histologically confirmed that EGFR sensitive mutation (ex19del or L858R mutation) in tumor tissue was detected by non-squamous NSCLC, and EGFR mutation (ex19del or L858R mutation) in ctDNA before treatment; - Staging is IVB stage (AJCC 8th Edition) ; - According to the comprehensive judgment of many disciplines, it is impossible to be treated by operation; - PS score 0-1; - The patient has at least one measurable tumor injury (the tumor is considered unmeasurable at the site of previous radiotherapy); - Systemic anti-tumor therapy such as chemotherapy, immunotherapy and targeted therapy were not performed before entering the group; - There is no history of malignant tumor and no serious medical disease; - FEV1 ≥ 1.2L/ seconds or ≥ 50% predicted value; - Laboratory examination: White blood cell count ≥ 4 *10^9/L, neutrophil count ≥ 2.0 *10^9, platelet count ≥ 100 *10^9, hemoglobin ≥ 10 g / L, liver and kidney function and ECG were normal; - The pregnancy test was negative within 3 days before entering the group, and agreed to use medically effective contraceptive measures during the trial; - Life expectancy is more than 12 weeks; - Sign informed consent form; cooperate with regular follow-up. --- L858R --- --- L858R ---

Primary Outcomes

Description: The period from the start of treatment to the progression or death of a patient

Measure: progression-free survival, PFS

Time: Every 6 weeks up to 2 years

Secondary Outcomes

Description: time from the beginning of study to death due to any cause or last follow-up

Measure: overall survival, OS

Time: Every 6 weeks up to 2 years, and then every 3 months up to 5 years

Description: ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)

Measure: Objective Response Rate, ORR

Time: 6 weeks after treatment

Description: Number of patients with adverse events (AEs) as a measure of safety and tolerability

Measure: adverse events

Time: Every 6 weeks up to 2 years

298 Synergistic Real-World Study and Evidence-based Medicine Evaluation of Elemene Combined With Tyrosine Kinase Inhibitors(TKIs)in the Treatment of Advanced Non-small Cell Lung Cancer (NSCLC): Prospective Study

This is a nationwide, multicenter and prospective cohort study. The purpose of this study is to evaluate the synergistic effect and safety of Elemene plus TKIs in EGFR-mutated advanced non-small cell lung cancer.

NCT04401059
Conditions
  1. Carcinoma
  2. Non-Small-Cell Lung Cancer
  3. Adenocarcinoma
Interventions
  1. Drug: Elemene plus First-generation EGFR-TKIs
  2. Drug: First-generation EGFR-TKIs
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Patients with EGFR mutations (deletions in exon 19 and L858R in exon 21 of the EGFR gene), plan to receive First-generation EGFR-TKIs (Gefitinib, Erlotinib, Icotinib) monotherapy for the first time. --- L858R ---

Primary Outcomes

Description: PFS was defined as the interval from the date of randomization to the date of the first evidence of disease progression or death, whichever occurs first. Disease progression was defined according to RECIST 1.1.

Measure: PFS

Time: Start of treatment until 1-year follow-up

Secondary Outcomes

Description: ORR was defined as the percentage of participants with the best overall response (BOR) of complete response (CR) or partial response (PR) based on RECIST 1.1.

Measure: ORR

Time: Start of treatment until 1-year follow-up

Description: Disease Control Rate (DCR) = Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) as defined by RECIST 1.1.

Measure: DCR

Time: Start of treatment until 1-year follow-up

Description: Overall survival (OS) was defined as the interval from the date of randomization to date of death from any cause, or the date of last known follow-up alive.

Measure: OS

Time: Start of treatment until 1-year follow-up

Description: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect

Measure: Incidence and severity of AE or SAE

Time: Start of treatment until 30 days after the last treatment

Description: All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. A SADR is a serious ADR according to the above criteria of SAE.

Measure: Incidence and severity of ADR or SADR

Time: Start of treatment until 30 days after the last treatment

Other Outcomes

Description: Quality of Life (QOL) was measured using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30 + LC 13).

Measure: Quality of life (QOL)

Time: Start of treatment until 1-year follow-up

Description: KPS: Performance status were measured using Karnofsky Performance Scale (KPS)

Measure: Karnofsky Performance Scale (KPS)

Time: Start of treatment until 1-year follow-up

Description: TCM symptom score: Traditional Chinese Medical symptoms were measured from these eight aspects: chest pain, oppression in the chest, blood stasis, shortness of breath, weakness, palpitations, dry mouth, vexation. Particular attention should be paid to chest pain and weakness.

Measure: Traditional Chinese Medical(TCM) symptoms score

Time: Start of treatment until 1-year follow-up

Description: Including but not limited to drug-resistant genes and circulating tumor cells. Such as PD-L1、MSI-H/dMMR、TMB、HLA、POLE、POLD1、DDR、TP53、KRAS、BRCA2、PBRM1、MDM2/4、EGFR、ALK、PTEN、JAK1/2、DNMT3A、STK11.

Measure: Molecular biomarkers

Time: Start of treatment until 1-year follow-up

299 A Phase II, Open-Label, Multicenter, Single-Arm, Prospective Clinical Study to Investigate the Efficacy and Safety of Tislelizumab Combined With Chemotherapy in Non-squamous NSCLC With EGFR Sensitizing Mutation Who Failed EGFR TKI Therapy

A phase II, open-label, multicenter, single-arm, prospective clinical study to investigate the efficacy and safety of tislelizumab (anti-pd1 antibody) combined with chemotherapy in non-squamous non-small cell lung cancer patients with EGFR sensitizing mutation who failed EGFR TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) therapy.

NCT04405674
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Tislelizumab
  2. Drug: Carboplatin and Nab-paclitaxel
  3. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

2. Documentation of tumor EGFR sensitizing mutation before EGFR TKI treatment, including 19del, L858R, G719X, S786I and L861Q. --- L858R ---

Primary Outcomes

Description: Progression-free survival (per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first. Subjects who do not have disease progression will be censored at their last valid tumor assessment. PFS rate at 1 year as estimated by Kaplan-Meier method.

Measure: 1-Year Progression-Free Survival Rate (1-Year PFS Rate)

Time: up to 24 months after enrollment or study close

Secondary Outcomes

Description: Progression-free survival (PFS per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.

Measure: Progression-Free Survival (PFS)

Time: up to 24 months after enrollment or study close

Description: ORR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).

Measure: Objective Respond Rate (ORR)

Time: up to 24 months after enrollment or study close

Description: DCR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR), or stable disease (SD).

Measure: Disease Control Rate (DCR)

Time: up to 24 months after enrollment or study close

Description: OS is defined as the time from the starting date of study drug to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: up to 24 months after enrollment or study close

Description: DoR (per RECIST 1.1) is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first.

Measure: Duration of Response (DoR)

Time: up to 24 months after enrollment or study close

300 A Phase 2 Randomized Study of Osimertinib Versus Osimertinib Plus Chemotherapy for Patients With Metastatic EGFR-Mutant Lung Cancers That Have Detectable EGFR-Mutant cfDNA in Plasma After Initiation of Osimertinib

This study will compare the effectiveness of osimertinib alone with the combination of osimertinib and chemotherapy (carboplatin and pemetrexed) in people with metastatic lung cancer that has a change (mutation) in the gene EGFR. Osimertinib alone is the usual treatment for metastatic EGFR-mutant lung cancer. Researchers think adding chemotherapy to osimertinib could possibly add to the anticancer effects of the usual treatment and help stop cancer from growing or spreading.

NCT04410796
Conditions
  1. Metastatic Non-small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Carboplatin
  3. Drug: Pemetrexed
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Patients will be seen on C1D1 for osimertinib start (telemedicine visits for C1D1 assessments are acceptable) Randomization/treatment portion: Patients will be randomized to continue osimertinib alone (Arm A) or addition of carboplatin/pemetrexed chemotherapy to osimertinib (Arm B).Randomization will be accomplished by the method of random permuted block and patients will be stratified by type of EGFR mutation (EGFR exon 19/EGFR L858R or other) and presence of CNS metastases (absent, present). --- L858R ---

Primary Outcomes

Description: As the primary endpoint for the treatment comparison, it is the duration of time from randomization to the time of disease progression (in the CNS or systemically) or death. In addition, as a secondary endpoint, PFS is measured from the start of treatment to disease progression or death. Intracranial progression-free survival (PFS) is defined as the duration of time from time of randomization to time of progression (in the CNS) or death, whichever occurs first. Overall survival (OS) is defined as the duration of time from first treatment to time of death.

Measure: Determine the progression-free survival

Time: 2 years

Secondary Outcomes

Description: Best overall response rate (confirmed partial and complete responses) will be assessed as part of this study. All responses must be confirmed on subsequent scan to be considered a true response. Tumor response will be assessed using RECIST 1.1

Measure: overall response rate

Time: 2 years

301 Platform Study of Genotyping Guided Precision Medicine for Rare Tumors in China

A Phase II, open label, non-randomized, multiple-arm, single-center clinical trial in patients with advanced rare solid tumors who failed to standard treatment.

NCT04423185
Conditions
  1. Rare Tumor
Interventions
  1. Drug: Almonertinib 110 MG
  2. Drug: Dacomitinib 45 MG
  3. Drug: Alectinib 150 MG
  4. Drug: Crizotinib 250 MG
  5. Drug: Pyrotinib 160/80 MG
  6. Drug: Imatinib 400 MG
  7. Drug: Niraparib 200/300 MG
  8. Drug: Palbociclib 125mg
  9. Drug: Vemurafenib 240 MG
  10. Drug: Sintilimab 100MG
  11. Drug: Atezolizumab 1680 MG
MeSH:Neoplasms
HPO:Neoplasm

Patients with advanced rare tumors who failed to standardized treatment carrying actionable alterations as "EGFR mutation (exon 19 deletion mutation, L858R replacement mutation), ALK gene fusion, ROS-1 gene fusion, C-MET gene amplification or mutation (D1010 mutation, 14 exon mutation, y1003 mutation), BRAF mutation, CDKN2A mutation, BRCA1/2 mutation, HER-2 mutation, HER-2 over expression/amplification, C-KIT mutation", will enroll targeted therapy arms and be given corresponding targeted drugs (Dacomitinib, Crizotinib). --- L858R ---

Primary Outcomes

Description: The percentage of patients with a confirmed Blinded Independent Central Review (BICR) and investigator-assessed complete or partial response according to Response Evaluation Criteria In Solid Tumours (RECIST) 1.1.

Measure: Objective Response Rate (ORR)

Time: Measured from first dose until confirmed response or progression, assessed up to 2 years.

Secondary Outcomes

Description: The time from first dose until the date of objective disease progression or death (by any cause in the absence of progression).

Measure: Progression-Free Survival (PFS)

Time: Measured from first dose until progression, assessed up to 2 years.

Description: The interval between the initiation of study treatment and the first documentation of CUPD (second confirmation of Disease Progression) or death due to any cause as defined by the iRECIST standard in the single drug immunotherapy group

Measure: iRECIST Evaluated Progression Free Survival (iPFS)

Time: Measured from response until progression, assessed up to 2 years.

Description: The time from the date of first response until date of disease progression or death in the absence of disease progression.

Measure: Duration of Response (DoR)

Time: Measured from response until progression, assessed up to 2 years.

Description: The percentage of patients treated with targeted and single immunotherapy assessed by the investigator,

Measure: Disease Control Rate (DCR)

Time: Measured from first dose until confirmed response or progression, whichever came first, assessed up to 2 years.

Description: Partial Response (PR) or Complete Response (CR) or Stable Disease (SD) in the single drug immunotherapy group and without Disease Progression at more than six months.

Measure: Durable Clinical Benefit (DCB)

Time: Measured from first dose until confirmed response or progression, whichever came first, assessed up to 2 years.

Description: The median survival time of patients

Measure: Overall survival (OS)

Time: Measured from first dose until death or final cohort data cut-off, whichever came first, assessed up to 2 years.

Description: Percentage of patients who is alive at 1-year from first dose of treatment.

Measure: One year of Overall Survival rate (1-year OS rate)

Time: Measured from first dose until death, assessed up to 2 years.

Description: To evaluate safety and tolerability of each study treatment.

Measure: Incidence of Adverse Events (AE) in subjects

Time: Continuously from first dose to end of safety follow up after study treatment discontinuation, assessed up to 2 years.

Description: The proportion of patients who are alive and progression-free more than 6 months after the first dose of study therapy Progression-free Survival (PFS) the proportion of patients with PFS ≥ 6 months in the total enrollment since the start of the study.

Measure: The 6-month PFS rate

Time: Measured from response until progression, assessed up to 2 years.

302 Bevacizumab Combined With Gefitinib in the Treatment of Advanced NSCLC Clinical Study of L858R Positive Mutation Patients

To compare the efficacy and safety of gefitinib combined with bevacizumab and gefitinib in the treatment of L858R positive mutation in exon 21 of EGFR gene in advanced NSCLC.

NCT04425187
Conditions
  1. PFS
Interventions
  1. Drug: Gefitinib
  2. Drug: Bevacizumab Combined With Gefitinib

Bevacizumab Combined With Gefitinib in the Treatment of Advanced NSCLC Clinical Study of L858R Positive Mutation Patients. --- L858R ---

Bevacizumab Combined With Gefitinib in the Treatment of Advanced NSCLC To compare the efficacy and safety of gefitinib combined with bevacizumab and gefitinib in the treatment of L858R positive mutation in exon 21 of EGFR gene in advanced NSCLC. --- L858R ---

The PFS of gefitinib combined with bevacizumab and gefitinib alone were compared in patients with L858R mutation in exon 21 of EGFR gene in stage IIIB-IV local advanced, recurrent or metastatic NSCLC.. Inclusion Criteria: 1. Age ≥ 18 years old, gender unlimited. --- L858R ---

4. According to the method of second-generation sequencing, L858R point mutation in exon 21 of EGFR gene was found in primary NSCLC with or without any other coexisting mutations. --- L858R ---

Primary Outcomes

Description: The PFS of gefitinib combined with bevacizumab and gefitinib alone were compared in patients with L858R mutation in exon 21 of EGFR gene in stage IIIB-IV local advanced, recurrent or metastatic NSCLC.

Measure: Progression-free survival (PFS)

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 18 months

303 A Phase III, Randomized, Controlled, Open-label, Multicenter, Global Study of Capmatinib Versus SoC Docetaxel Chemotherapy in Previously Treated Patients With EGFR wt, ALK Negative, Locally Advanced or Metastatic (Stage IIIB/IIIC or IV) NSCLC Harboring MET Exon 14 Skipping Mutation (METΔex14).

The purpose of the study is to learn whether the study drug (capmatinib) helps to control lung cancer better compared to a single agent chemotherapy (docetaxel) and whether it is safe when given to patients suffering from a particular type of lung cancer. This type of cancer is called non-small cell lung cancer (NSCLC) with certain specific genetic alterations (called mutations) of a gene called MET, within a specific part of the gene called exon 14. Approximately 90 people with advanced or metastatic lung cancer, with these specific mutations in the MET gene but without changes in their epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genes, will be enrolled in this study. The study drug, capmatinib (also known as INC280), is an oral drug that is called a 'targeted' medicine, which means it targets particular processes that may not be working properly in cancer cells (called dysregulation). The dysregulation of the MET signaling in cancer cells of patients with NSCLC is believed to make the cancer worse. Capmatinib has been shown to selectively block the effects of the MET gene and therefore may help in keeping the disease under control, stopping cancer cells from growing. Docetaxel is a standard chemotherapy medicine commonly used to treat your type of lung cancer. This standard, anti-cancer medicine is a cytotoxic chemotherapy. The reason for this study is to find out if capmatinib can control lung cancer better. Patients will be randomly assigned to get either capmatinib or docetaxel in a 2 to 1 ratio: - Capmatinib: 2 out of 3 possibility or 66% chance of getting this treatment, - Docetaxel: 1 out of 3 possibility or 33% chance of getting this treatment. During treatment, visits will be scheduled every 21 days.

NCT04427072
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Capmatinib
  2. Drug: Docetaxel
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The EGFR wt status (for EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 L858R substitution mutations. --- L858R ---

Primary Outcomes

Description: Progression free survival is defined as the time from the date of randomization to the date of the first documented progression assessed by BIRC according to RECIST 1.1, or death due to any cause

Measure: Progression free survival (PFS) per blinded independent review committee (BIRC) using RECIST v1.1

Time: From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months

Secondary Outcomes

Description: Proportion of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR), assessed by BIRC according to RECIST 1.1.

Measure: Overall response (ORR) per RECIST 1.1 by BIRC

Time: Up to approximately 21 months

Description: Proportion of participants with confirmed BOR of CR or PR, assessed by local review according to RECIST 1.1.

Measure: Overall response (ORR) per RECIST 1.1 by investigator

Time: Up to approximately 21 months

Description: Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by BIRC according to RECIST 1.1.

Measure: Time to response (TTR) per RECIST 1.1 by BIRC

Time: From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months

Description: Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by local review according to RECIST 1.1.

Measure: Time to response (TTR) per RECIST 1.1 by investigator

Time: From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months

Description: Time from the date of first documented response (CR or PR) to the first documented progression by BIRC per RECIST 1.1 or death due to any cause.

Measure: Duration of response (DOR) per RECIST 1.1 by BIRC

Time: From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months

Description: Time from the date of first documented response (CR or PR) to the first documented progression by local review per RECIST 1.1 or death due to any cause.

Measure: Duration of response (DOR) per RECIST 1.1 by investigator

Time: From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months

Description: Proportion of participants with a BOR of confirmed CR, PR and stable disease (SD) assessed by BIRC according to RECIST 1.1

Measure: Disease Control Rate (DCR) per RECIST 1.1 by BIRC

Time: Up to approximately 21 months

Description: Proportion of participants with a BOR of confirmed CR, PR and SD assessed by local review according to RECIST 1.1

Measure: Disease Control Rate (DCR) per RECIST 1.1 by investigator

Time: Up to approximately 21 months

Description: Time from the date of randomization to the date of the first documented progression assessed by local review according to RECIST 1.1, or death due to any cause

Measure: Progression free survival (PFS) per investigator using RECIST v1.1

Time: From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months

Description: OS is defined as the time from the date of randomization to the date of death due to any cause.

Measure: Overall survival (OS)

Time: From randomization to death due to any cause, assessed up to approximately 42 months

Description: Safety profile of capmatinib. Incidence of Adverse Events and Serious Adverse events, including abnormal laboratory values or test results.

Measure: Percentage of patients with Adverse Events and Serious Adverse events.

Time: Up to approximately 42 months

Description: Plasma concentrations of capmatinib. Blood samples will be collected at indicated time points for pharmacokinetic analysis.

Measure: Plasma capmatanib concentration

Time: Cycle (C) 1 Day (D) 15 pre-dose, 1 and 4 hours post-dose, C3 D1 pre-dose. Each cycle duration is 21 days.

Description: EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients.

Measure: Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30

Time: Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months. Each cycle duration is 21 days.

Description: EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire.

Measure: Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13)

Time: Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months. Each cycle duration is 21 days.

Description: EQ-5D-5L is a standardized measure to assess the overall health-related quality of life in patients.

Measure: Change from baseline in score as per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire

Time: Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months. Each cycle duration is 21 days.

Description: Proportion of participants with confirmed best overall intracranial response (BOIR) of CR or partial response (PR), as assessed by BIRC review per RANO-BM criteria.

Measure: Overall intracranial response rate (OIRR)

Time: Up to approximately 21 months

Description: Time from date of first documented intracranial response (CR or PR) to first documented intracranial progression per RANO-BM or date of death due to underlying cause of cancer.

Measure: Duration of intracranial response (DOIR)

Time: From date of first documented intracranial response (CR or PR) to first documented intracranial progression, assessed up to approximately 21 months

Description: Time from date of randomization to first documented intracranial response of either CR or PR, per RANO-BM criteria and assessed by BIRC, which must be subsequently confirmed.

Measure: Time to intracranial response (TTIR)

Time: From date of randomization to first documented intracranial response of either CR or PR, assessed up to approximately 21 months

Description: Proportion of participants with a BOR of confirmed CR, PR and stable disease (SD) (or non-CR/non-PD) per RANO-BM, assessed by BIRC.

Measure: Intracranial disease control rate (IDCR)

Time: Up to approximately 21 months

304 Almonertinib Vs. Erlotinib/Chemotherapy for Neo-adjuVant Treatment of Stage IIIA-N2 EGFR-mutated NSCLC: a Multicenter, Open-label, Phase II Randomized Controlled Trial

This is a multicenter, randomized, controlled, phase II study assessing the efficacy and safety of Almonertinib compared Erlotinib or platinum doublet chemotherapy (carboplatin or cisplatin + pemetrexed) as neoadjuvant therapy to EGFRm+ IIIA-N2 NSCLC patients.

NCT04455594
Conditions
  1. Non-Small Cell Lung Cancer Stage IIIA
Interventions
  1. Drug: Almonertinib
  2. Drug: Erlotinib
  3. Drug: Cisplatin
  4. Drug: Carboplatin
  5. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

3. Tumor tissue samples or blood samples are confirmed as EGFR sensitive mutations by central laboratory tests (including Ex19del or L858R, both alone or with other EGFR mutations). --- L858R ---

Primary Outcomes

Description: Objective Response Rate (ORR) is defined as participants who had complete response (CR) or partial response(PR) divided by the total number of patients.

Measure: Objective response rate (ORR)

Time: From date of randomization to an average of 6 weeks after the first dose

Secondary Outcomes

Description: Defined as absence of any residual cancer cells in the surgical specimen assessed post-surgery

Measure: Pathological complete response (pCR)

Time: From date of randomization to an average of 12 weeks after the first dose

Description: Defined as ≤10% residual cancer cells in the surgical specimen, as assessed per central pathology laboratory post-surgery

Measure: Major Pathological Response (MPR)

Time: From date of randomization to an average of 12 weeks after the first dose

Description: DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first. If there is residual disease after surgery (eg. positive margins), the DFS event is the date of surgery.

Measure: Disease free survival (DFS)

Time: From date of randomization up to approximately 18 months after date of resection

Description: Patients will be followed up to approximately 5.5 years after they are randomized.

Measure: Overall Survival (OS)

Time: Up to approximately 5.5 years after the last patient is randomized

Measure: R0 resection rate

Time: Up to 1 week after surgery

Description: Measured using lymph node staging

Measure: Downstaging rate

Time: From date of randomization to an average of 12 weeks after the first dose

Measure: Concordance of EGFRm status between plasma-derived ctDNA

Time: Baseline, up to 1 week before surgery and up to 1 week after surgery

Description: According to CTCAE4.0

Measure: Incidence of Adverse Events (AEs)

Time: Up to 80 weeks

305 A Ph1b Study of Osimertinib + Alisertib or Sapanisertib for Osimertinib-Resistant EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (Crossover Study)

This phase Ib trial studies the side effects and best dose of alisertib or sapanisertib, in combination with osimertinib, in treating patients with EGFR mutated stage IIIB or IV non-small cell lung cancer that remains despite treatment with osimertinib (osimertinib resistant). Osimertinib, alisertib, and sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The goal of part 1 of this trial is to find the highest tolerable dose of alisertib or sapanisertib in combination with osimertinib that can be given to patients with EGFR mutated non-small cell lung cancer. The goal of part 2 of this trial is to learn if the dose of alisertib or sapanisertib found in part 1 can help control EGFR mutated non-small cell lung cancer when given in combination with osimertinib.

NCT04479306
Conditions
  1. EGFR T790M Mutation Positive Non-Small Cell Lung Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage IIIB Lung Cancer AJCC v8
  4. Stage IV Lung Cancer AJCC v8
  5. Stage IVA Lung Cancer AJCC v8
  6. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Alisertib
  2. Drug: Osimertinib
  3. Drug: Sapanisertib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Estimated using the method of Kaplan and Meier.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - EGFR exon 21 L858R or exon 19 deletion mutation, or T790M mutation that was acquired following treatment with first or second generation tyrosine kinase inhibitor (TKI). --- L858R ---

- Female patient who intend to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug(s) - Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s) Inclusion Criteria: - Patients must have histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - EGFR exon 21 L858R or exon 19 deletion mutation, or T790M mutation that was acquired following treatment with first or second generation tyrosine kinase inhibitor (TKI). --- L858R ---

Primary Outcomes

Description: Will employ the Bayesian optimal interval (BOIN) design to find the maximum tolerated dose (MTD) in each treatment arm. RP2D will be the same as the MTD or a lower dose level if pharmacokinetic/pharmacodynamics data indicate that the lower dose level can be as efficacious with possible lower toxicities

Measure: Recommended phase 2 dose (RP2D) of osimertinib and alisertib combination (Arm A)

Time: Up to 30 days

Description: Will employ the BOIN design to find the MTD in each treatment arm. RP2D will be the same as the MTD or a lower dose level if pharmacokinetic/pharmacodynamics data indicate that the lower dose level can be as efficacious with possible lower toxicities

Measure: RP2D of osimertinib and sapanisertib combination (Arm B)

Time: Up to 30 days

Measure: Dose-limiting toxicity (DLT)

Time: During cycle 1 (28 days)

Description: Toxicity will be evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Will be estimated with 95% confidence intervals.

Measure: Incidence of adverse events

Time: Up to 30 days after last dose

Secondary Outcomes

Description: Will be estimated with 95% confidence intervals.

Measure: Objective response rate

Time: At end of 4th cycle (1 cycle = 28 days)

Description: Estimated using the method of Kaplan and Meier.

Measure: Progression-free survival

Time: Up to 30 days after last dose

306 A Phase 3, Randomized Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib Versus Lazertinib as First-Line Treatment in Patients With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer.

The purpose of this study is to assess the efficacy of the amivantamab and lazertinib combination, compared with osimertinib, in participants with epidermal growth factor receptor (EGFR) mutation (Exon 19 deletions [Exon 19del] or Exon 21 L858R substitution) positive, locally advanced or metastatic non-small cell lung cancer (NSCLC).

NCT04487080
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Amivantamab
  2. Drug: Osimertinib
  3. Drug: Lazertinib
  4. Drug: Placebo
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Study of Amivantamab and Lazertinib Combination Therapy Versus Osimertinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer The purpose of this study is to assess the efficacy of the amivantamab and lazertinib combination, compared with osimertinib, in participants with epidermal growth factor receptor (EGFR) mutation (Exon 19 deletions [Exon 19del] or Exon 21 L858R substitution) positive, locally advanced or metastatic non-small cell lung cancer (NSCLC). --- L858R ---

EORTC-QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies.. Inclusion Criteria: - Participant must have histologically or cytologically confirmed, locally advanced or metastatic non-small cell lung cancer (NSCLC) not amenable to curative therapy - Participant must have a tumor that was previously determined to have exon 19 deletions (Exon 19del) or Exon 21 L858R substitution, as detected by an food and drug administration (FDA)-approved or other validated test in a clinical laboratory improvement amendments (CLIA) certified laboratory (sites in the United states [US]) or an accredited local laboratory (sites outside of the US) in accordance with site standard of care. --- L858R ---

A participant with asymptomatic or previously treated and stable brain metastases may participate in this study Inclusion Criteria: - Participant must have histologically or cytologically confirmed, locally advanced or metastatic non-small cell lung cancer (NSCLC) not amenable to curative therapy - Participant must have a tumor that was previously determined to have exon 19 deletions (Exon 19del) or Exon 21 L858R substitution, as detected by an food and drug administration (FDA)-approved or other validated test in a clinical laboratory improvement amendments (CLIA) certified laboratory (sites in the United states [US]) or an accredited local laboratory (sites outside of the US) in accordance with site standard of care. --- L858R ---

Lazertinib inhibits primary activating Exon 19dell and Exon 21 L858R substitution EGFR mutations, and the EGFR T790M+ resistance mutation. --- L858R ---

Primary Outcomes

Description: PFS is defined as the time from randomization until the date of objective disease progression or death, whichever occured first, based on BICR using response evaluation criteria in solid tumors (RECIST) v1.1.

Measure: Progression-Free Survival (PFS) According to RECIST v1.1 by Blinded Independent Central Review (BICR)

Time: Up to approximately 42 months

Secondary Outcomes

Description: Overall Survival is defined as the time from the date of randomization to the date of participant's death due to any cause.

Measure: Overall Survival (OS)

Time: Up to approximately 60 months (time from the date of randomization until the date of death due to any cause)

Description: ORR is defined as the percentage of participants who achieve either a complete response (CR) or partial response (PR) as defined by BICR using RECIST v1.1 criteria.

Measure: Objective Response Rate (ORR)

Time: Up to approximately 42 months

Description: DOR is defined as the time from the date of first documented response (CR or PR) until the date of documented progression or death, whichever comes first, only for participants who achieve CR or PR as determined by the investigator using RECIST v1.1 criteria.

Measure: Duration of Response (DOR)

Time: Up to approximately 42 months

Description: The PFS2 is defined as the time from randomization until the date of second objective disease progression, after initiation of subsequent anticancer therapy, based on investigator assessment (after that used for PFS) or death, whichever comes first.

Measure: Progression-Free Survival After First Subsequent Therapy (PFS2)

Time: Up to approximately 42 months

Description: TTSP is defined as the time from randomization to documentation in the electronic case report form (eCRF) of any of the following (whichever occurs earlier): onset of new symptoms or symptom worsening that is considered by the investigator to be related to lung cancer and requires either a change in anticancer treatment and/or clinical intervention to manage symptoms.

Measure: Time to Symptomatic Progression (TTSP)

Time: Up to approximately 42 months

Description: Intracranial PFS is defined as the time from randomization until the date of objective intracranial disease progression or death, whichever comes first, based on BICR using RECIST v1.1.

Measure: Intracranial PFS

Time: Up to approximately 42 months

Description: Incidence and severity of treatment emergent adverse events (TEAEs) will be reported. Any adverse event occurring at or after the initial administration of study treatment through the day of last dose plus 30 days, or until the start of subsequent anticancer therapy (if earlier), is considered to be treatment emergent.

Measure: Incidence and Severity of Adverse Events (AEs)

Time: Up to approximately 60 months

Description: Number of participants with clinical laboratory abnormalities (serum chemistry, hematology, blood coagulation, and urine samples) will be reported.

Measure: Number of Participants with Clinical Laboratory Abnormalities

Time: Up to approximately 60 months

Description: Number of participants with vital signs abnormalities (temperature, heart rate, respiratory rate, oxygen saturation, blood pressure) will be reported.

Measure: Number of Participants with Vital Signs Abnormalities

Time: Up to approximately 60 months

Description: Number of participants with physical examination abnormalities will be reported.

Measure: Number of Participants with Physical Examination Abnormalities

Time: Up to approximately 60 months

Description: Serum samples will be analyzed to determine concentrations of amivantamab.

Measure: Serum Concentration of Amivantamab

Time: Up to approximately 42 months

Description: Plasma samples will be analyzed to determine concentrations of lazertinib.

Measure: Plasma Concentration of Lazertinib

Time: Up to approximately 42 months

Description: Number of participants with antibodies to amivantamab will be reported.

Measure: Number of Participants with Anti-Amivantamab Antibodies

Time: Up to approximately 42 months

Description: The NSCLC-SAQ contains 7 items that assess cough, pain, dyspnea, fatigue, and poor appetite over a 7-day recall period. Each multi-item scale and individual item will be summarized using count and percent by visit.

Measure: Change from Baseline in Non-Small Cell Lung Cancer - Symptom Assessment Questionnaire (NCSLC-SAQ)

Time: Baseline Up to approximately 42 months

Description: EORTC-QLQ-C30 is a core 30-item questionnaire for evaluating the health-related quality of life (HRQoL) of participants participating in cancer clinical studies.

Measure: Change from Baseline in European Organization of Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30)

Time: Baseline Up to approximately 42 months

307 A Phase II Trial of Durvalumab (MEDI4736) in Combination With Chemotherapy in Virus-infected Patients With Non-small Cell Lung Cancer

This is a phase II trial of durvalumab in combination of platinum-based chemotherapy. Patients with stage IV Non-Small-Cell-Lung Cancer (NSCLC) with human immunodeficiency virus (HIV) infection (cohort 1) or hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (cohort 2) will be eligible. Patients will receive standard platinum-based chemotherapy plus durvalumab for 4 cycles (every 3 weeks), followed by durvalumab (with or without pemetrexed for non-squamous NSCLC) maintenance therapy. We hypothesized that Durvalumab in combination with standard chemotherapy is safe and effective for the treatment of stage IV NSCLC in patients with HIV, HBV, or HCV infection.

NCT04499053
Conditions
  1. Carcinoma, Non-Small Cell Lung
Interventions
  1. Drug: Durvalumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: 1. Sensitizing EGFR mutations (deletion in exon 19, L858R in exon 21, G719X, and L861Q) and/or ALK translocations by locally approved laboratory testing including blood-based liquid biopsy. --- L858R ---

Primary Outcomes

Description: Incidence of treatment-emergent Adverse Events according to NCI CTCAE v5.0.

Measure: Adverse Events

Time: At the end of Cycle 4 (each cycle is 3 weeks)

Description: Radiological response will be evaluted using Recist Version 1.1 Criteria

Measure: Radiological Response

Time: At the end of Cycle 4 (each cycle is 3 weeks)

Secondary Outcomes

Description: Evaluate changes in viral load with study treatment

Measure: Changes in Viral Load

Time: At the end of Cycle 4 (each cycle is 3 weeks)

Description: Cytokine secretion assays will be performed on blood samples before, during, and after treatment.

Measure: Change in Cytokine Secretion Assays

Time: 36 months

Description: Baseline immune biomarkers (e.g. PD-L1 expression, composition of T cells in tumor microenvironment) using multiplex IHC will be compared between responders and non-responders to find predictive biomarkers associated with response to treatment.

Measure: Correlation of Multiplex IHC to response

Time: 36 months

Description: The blood tumor mutational burden (bTMB) between responders and non-responders will be compared.

Measure: Correlation of bTMB and treatment outcome

Time: 36 months

308 Almonertinib Alone Versus Almonertinib Plus Chemotherapy as First-line Treatment in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation Positive With Concomitant Non-EGFR Driver Gene Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer: A Multicenter, Open-label, Randomized, Control Phase III Study (ACROSS 1)

This is a multicenter, randomized, controlled, phase III study.

NCT04500704
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Almonertinib
  2. Drug: Almonertinib plus carboplatin and pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), in combination with non-EGFR driver genes mutations assessed by central testing using tumour tissue sample. --- L858R ---

Primary Outcomes

Description: To assess the efficacy of Almonertinib compared with Almonertinib Plus carboplatin and pemetrexed as first line therapy to EGFRm+, locally advanced or metastatic NSCLC patients by assessment of progression free survival (PFS) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

Measure: Progression Free Survival (PFS)

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

Secondary Outcomes

Description: Overall survival (OS)

Measure: Assess the anti-tumor activity: OS

Time: Start of study drug to Survival Endpoint through study completion, an average of 3 years.

Description: ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression assessed up to 24 months

Measure: Assess the anti-tumor activity: ORR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression assessed up to 24 months.

Description: Disease control rate (DCR)

Measure: Assess the anti-tumor activity: DCR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD assessed up to 24 months.

Description: Duration of response (DoR)

Measure: Assess the anti-tumor activity: DoR

Time: DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression assessed up to 24 months.

Description: Depth of response (DepOR)

Measure: Assess the anti-tumor activity: DepOR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. DepOR is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 target lesions up to 24 months.

Description: Number of adverse events (AEs)/serious adverse events (SAEs)

Measure: Assess the safety of Almonertinib and Almonertinib plus pemetrexed and carboplatin: Number of AEs/SAEs

Time: Continuously throughout the study until 28 days after Termination of the treatment

309 Almonertinib Alone Versus Almonertinib Plus Chemotherapy as First-Line Treatment in Locally Advanced Or Metastatic NSCLC Patients With Concomitant EGFR and Tumor Suppressor Gene Mutation: A Multicenter, Open-Label, Randomized, Controlled Phase III Study (ACROSS2)

This is a multicenter, randomized, controlled, phase III study.

NCT04500717
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Almonertinib
  2. Drug: Almonertinib plus carboplatin and pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), in combination with tumor suppressor genes mutations assessed by central testing using tumour tissue sample. --- L858R ---

Primary Outcomes

Description: To assess the efficacy of Almonertinib compared with Almonertinib Plus carboplatin and pemetrexed as first line therapy to EGFRm+, locally advanced or metastatic NSCLC patients by assessment of progression free survival (PFS) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

Measure: Progression Free Survival (PFS)

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

Secondary Outcomes

Description: Overall survival (OS)

Measure: Assess the anti-tumor activity: OS

Time: Start of study drug to Survival Endpoint through study completion, an average of 3 years.

Description: ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression assessed up to 24 months

Measure: Assess the anti-tumor activity: ORR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. ORR is defined as the percentage of patients who have at least 1 response of CR or PR prior to any evidence of progression assessed up to 24 months.

Description: Disease control rate (DCR)

Measure: Assess the anti-tumor activity: DCR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. The DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD assessed up to 24 months.

Description: Duration of response (DoR)

Measure: Assess the anti-tumor activity: DoR

Time: DoR is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression assessed up to 24 months.

Description: Depth of response (DepOR)

Measure: Assess the anti-tumor activity: DepOR

Time: From baseline, then every 6 weeks, until disease progression or discontinuation from study. DepOR is defined as the sum of the lengths of the longest diameters of the RECIST 1.1 target lesions up to 24 months.

Description: Number of adverse events (AEs)/serious adverse events (SAEs)

Measure: Assess the safety of Almonertinib and Almonertinib plus pemetrexed and carboplatin: Number of AEs/SAEs

Time: Continuously throughout the study until 28 days after Termination of the treatment

310 Dacomitinib in Advanced Non-small Cell Lung Cancer Patients With Uncommon EGFR Mutations: A Single Center and Exploratory Study

This is a single center and exploratory study, aiming to analyze the efficacy and safety of dacomitinib-a pan-HER and irreversible TKI in subjects with diagnosed stage IIIB/IV or recurrent NSCLC. All subjects will have tumors that test positive for at least one uncommon EGFR activating mutation (do not have drug-resistant pattern, e.g. 20 insertion or 20T790M). All patients will be of histo- and/or cytopathology confirmed. Determination of the EGFR mutation type will be performed in the pathological department of Shanghai Chest Hospital. Both ARMS method or targeted sequencing are acceptable. It is not acceptable for subjects with the presence of the exon 20T790M mutation or insertion together with either EGFR activating mutations (exon 19 deletion or the L858R mutation in exon 21) or uncommon EGFR mutations. 10ml peripheral blood must be available for concomitant study. All eligible subjects must have adequate renal, hepatic, and hematologic function, as defined in "inclusion criteria". Patients will receive continuous oral therapy with the study drugs (dacomitinib 45 mg) until progressive disease as defined by RECIST version 1.1 or judged by investigator that the patient no longer derives clinical benefit from study treatment. At the time of progression and removal from study treatment, the subject may receive any regulatory approved therapy at the judgment of the investigator. Timely and complete disease assessments in this study are important. Every effort should be made to ensure disease assessments performed as scheduled to prevent the introduction of bias into the assessment of efficacy. Failure to perform any of the required disease assessments will result in the inability to determine disease status for that time point. Frequent off schedule or incomplete disease assessments have the potential to weaken the study conclusion. Subjects who have progressive disease per RECIST version 1.1 confirmed by the investigator believes it is in their best interest to continue on their study therapy, will be allowed to continue on their therapy with or without local therapy (e.g. surgical removal and/or radiation of a single lesion), at the discretion of the investigator until any alternate or additional systemic anti-cancer therapy regimen is implemented. The subsequent new cancer therapy (including, for systemic therapy, drugs administered, date of initiation and discontinuation of each drug) and OS will be recorded. Each subject will be followed for survival status and subsequent cancer therapies up to 48 months from the date of first dosing. This data may be collected from subjects by telephone, and if collected should be entered into the CRF.

NCT04504071
Conditions
  1. Non-small Cell Lung Cancer Metastatic
  2. EGF-R Positive Non-Small Cell Lung Cancer
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

It is not acceptable for subjects with the presence of the exon 20T790M mutation or insertion together with either EGFR activating mutations (exon 19 deletion or the L858R mutation in exon 21) or uncommon EGFR mutations. --- L858R ---

Primary Outcomes

Description: ORR was defined as the proportion of patients with a complete response (CR) or partial response (PR) per the investigator's assessment using RECIST 1.1 criteria

Measure: Objective response rate (ORR)

Time: 6-12 weeks

Secondary Outcomes

Description: The disease control rate (DCR) was defined as the sum of the proportions of patients who had CR, PR, and stable disease (SD) using RECIST 1.1 criteria

Measure: Disease control rate

Time: 6-12 weeks

Description: PFS was defined as the time from study treatment initiation to the first occurrence of documented disease progression or death from any cause during the study, whichever occurred first.

Measure: PFS

Time: 13-15months

Description: OS was defined as the time from the first dose of study treatment to the time of death from any cause during the study.

Measure: Overall survival

Time: 22-25months

311 A Single-arm, Open-label, Phase 1b Study Evaluating the Efficacy and Safety of Olmutinib 600 mg QD in Patients With T790M-positive NSCLC After Treatment With an EGFR-TKI

The purpose of this study is to evaluate the efficacy and safety of olmutinib 600 mg QD in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT04510415
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Olmutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q). --- L858R ---

Primary Outcomes

Description: Defined as a best overall confirmed response of either CR or PR according to the RECIST version 1.1

Measure: Objective response rate (ORR)

Time: 24 months

Secondary Outcomes

Description: Defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Measure: Disease control rate (DCR)

Time: 24 months

Description: Defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Measure: Duration of overall tumor response (DR)

Time: 24 months

Description: Defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Measure: Progression-free survival (PFS)

Time: 24 months

Description: Defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Measure: Time to progression (TTP)

Time: 24 months

312 SINGLE ARM STUDY TO EVALUATE THE SAFETY OF DACOMITINIB FOR THE FIRST-LINE TREATMENT OF PARTICIPANTS IN INDIA WITH METASTATIC NON-SMALL CELL LUNG CANCER WITH EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)-ACTIVATING MUTATIONS

This is a Phase 4, open label, single arm, multi-center, prospective clinical trial of dacomitinib that will be performed in India. This study will enroll a sufficient number of participants to ensure that 100 participants are treated with dacomitinib. The primary objective of this study is to assess the safety and tolerability of dacomitinib. The secondary objective is to evaluate antitumor activity of dacomitinib by objective response rate and duration of response.

NCT04511533
Conditions
  1. Metastatic Non Small Cell Lung Cancer
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R ---

Primary Outcomes

Description: The incidence of adverse events will be assessed for all participants who receive at least one dose of dacomitinib, regardless of dosing interruptions or dosing compliance.

Measure: Incidence of Adverse events (AEs)

Time: From the time of first dose to 28 days post last dosing date or the date of initiation of a new anticancer therapy, whichever occurs first

Secondary Outcomes

Description: The secondary outcome measure is the treatment effect of dacomitinib as assessed by the investigator for all participants who receive at least one dose of dacomitinib without regard to tolerability or discontinuation from treatment.

Measure: Confirmed Objective Response Rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1

Time: From time of first dose until disease progression, death or initiation of a new anticancer therapy, whichever occurs first, assessed for up to 3 years

Description: The secondary outcome measure is the treatment effect of dacomitinib as assessed by the investigator for all participants who receive at least one dose of dacomitinib without regard to tolerability or discontinuation from treatment.

Measure: Confirmed Duration of Response (DoR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1

Time: From time of first tumor response until disease progression, death or initiation of a new anticancer therapy, whichever occurs first, assessed for up to 3 years

313 A Phase 1 Study of Temozolomide in Combination With Targeted Therapy for NSCLC Patients With CNS Progression on Either Osimertinib or Lorlatinib

This trial is testing two novel combinations (temozolomide plus osimertinib OR temozolomide plus lorlatinib) which have not been evaluated in clinical trials. Thus, the exact benefits of these novel combinations are unclear. However, based on the mechanism of action of temozolomide and CNS(Central Nervous System) penetration/activity in other tumor types, it is hypothesized that adding temozolomide to osimertinib or temozolomide to lorlatinib may provide improvement in CNS disease control in patients with CNS progression on either of these latter two TKIs (Tyrosine kinase inhibitors).

NCT04541407
Conditions
  1. Non Small Cell Lung Cancer
  2. CNS Progression
Interventions
  1. Drug: Temozolomide plus Osimertinib
  2. Drug: Temozolomide plus Lorlatinib
MeSH:Disease Progression

3. Male or female subject ≥ 18 years old 4. ECOG performance status 0-2 5. Stage IV NSCLC with progression of disease in the CNS on osimertinib 80 mg daily for patients with EGFR activating mutations (EGFR exon 19 deletions or EGFR L858R exon 21 point mutations) -OR- Stage IV NSCLC with progression of disease in the CNS on lorlatinib 100 mg daily for patients with ALK fusions 6. Evaluable CNS disease is required, measurable CNS disease is not required 7. Patients who are on corticosteroids must be on stable or decreasing doses of corticosteroids for at least 14 days. --- L858R ---

Primary Outcomes

Description: Adverse events will be determined by the common terminology criteria for adverse events version 5.0

Measure: Adverse events

Time: Up to 3.5 years

Secondary Outcomes

Description: Central Nervous System response rate according to the Response assessment in neuro-oncology (RANO) criteria per investigator assessment. Evaluable CNS lesions may not have been previously irradiated unless they are definitively progressing following radiation and prior to enrollment on the study.

Measure: CNS response rate

Time: Up to 3.5 years

Description: Extra-CNS response rate according to response evaluation criteria in solid tumors (RECIST) v1.1 per investigator assessment.

Measure: Extra-CNS response rate

Time: Up to 3.5 years

Description: Overall response rate including both RANO criteria for CNS response rate and RECIST v1.1 for extra-CNS response rate per investigator assessment.

Measure: Overall response rate

Time: Up to 3.5 years

Description: Incidence of improvement in neurological function on two successive exams when compared to baseline as determined by one of two study neuro-oncologists

Measure: Incidence of improvement in neurological function

Time: Up to 3.5 years

Description: PFS will be defined as time from enrollment until development of CNS progressive disease according to the RANO criteria, development of extra-CNS disease progression according to RECIST v1.1 or death.

Measure: Progression free survival (PFS)

Time: Up to 3.5 years

Description: CNS PFS will be defined as time from enrollment until development of CNS progressive disease per investigator assessment according to the RANO criteria or death.

Measure: CNS PFS

Time: Up to 3.5 years

Description: Extra-CNS PFS will be defined as time from enrollment until development of progressive disease outside the CNS per investigator assessment according RECIST v1.1 or death.

Measure: Extra-CNS PFS

Time: Up to 3.5 years

Description: OS will be defined as time from enrollment until death.Patients alive at date of end of study visit will be censored for survival.

Measure: Overall Survival

Time: Up to 3.5 years

314 A Phase II Trial of Osimertinib and Abemaciclib With a Focus on Non-Small Cell Lung Cancer Patients With EGFR Activating Mutations With Osimertinib Resistance

Lung cancer is the leading cause of cancer deaths. Advances in the systemic treatment of non-small cell lung cancer (NSCLC) have increased survival in metastatic EGFR-mutated NSCLC. However resistance to therapy can develop. NSCLC tumors with EGFR-activating mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors with overall response rates approximating 80%. The third generation EGFR compound osimertinib is a standard first line option. Resistance to the third generation EGFR-TKI osimertinib can develop with a median PFS of 18.9 months. Current research examining acquired resistance to EGFR-TKIs has focused on overcoming these main mechanisms of EGFR-TKI resistance and understanding the impact of co-occurring alterations. Frequently altered pathways concomitantly affected with EGFR in lung cancer are cell cycle genes. This study will explore a strategy to inhibit EGFR and CD4/6 in resistant EGFR mutated lung cancer patients post progression on osimertinib.

NCT04545710
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Abemaciclib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- Tumor must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q). --- L858R ---

Primary Outcomes

Description: Rate of Progression Free Survival at 6 months on the combination.

Measure: Progression Free Survival at 6 months

Time: 6 months

315 Mechanisms of Resistance to 3rd Generation Thyrosine Kinase Inhibitors in Lung Cancer

In the management of non-small cell lung cancer of the adenocarcinoma type, different therapeutic strategies can be proposed. These strategies are defined according to the results of a biological analysis of blood and/or tissue samples from the lung tumor. Mutations in the tumor DNA are sought. Thus, patients with sensitizing mutations can benefit from a treatment with a 3rd generation tyroine kinase inhibitor (TKI) whose efficacy has been widely demonstrated. Patients without tumor mutations will not benefit. However, resistance to TKIs appears after a certain time, often linked to the appearance of new mutations in the tumor. For this reason, blood biologic analyses are regularly performed to search for the emergence of resistance mutations and to propose a therapeutic alternative as soon as possible. These analyses are performed routinely in the laboratory. In the course of these analyses, the investigators have identified conventional mutations but also new mutations not previously described in the literature. Our objective is to list all the molecular abnormalities revealed during blood biological analyses, to determine their frequency and to study whether certain abnormalities can be linked to resistance to TKI.

NCT04546282
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Other: Description of the molecular alterations detected in blood samples of patients treated by osimertinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - advanced non-small cell lung cancer stage IIIB/IV - Documentation of activating EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) at the time of initial diagnosis - Patient may receive up to one line of third EGFR TKI - Plasma sample testing performed to detect EGFR TKI resistance Exclusion Criteria: - Patients have other concurrent cancers - Patients who are not eligible receive TKI Inclusion Criteria: - advanced non-small cell lung cancer stage IIIB/IV - Documentation of activating EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) at the time of initial diagnosis - Patient may receive up to one line of third EGFR TKI - Plasma sample testing performed to detect EGFR TKI resistance Exclusion Criteria: - Patients have other concurrent cancers - Patients who are not eligible receive TKI Non Small Cell Lung Cancer Lung Neoplasms null --- L858R ---

Inclusion Criteria: - advanced non-small cell lung cancer stage IIIB/IV - Documentation of activating EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) at the time of initial diagnosis - Patient may receive up to one line of third EGFR TKI - Plasma sample testing performed to detect EGFR TKI resistance Exclusion Criteria: - Patients have other concurrent cancers - Patients who are not eligible receive TKI Inclusion Criteria: - advanced non-small cell lung cancer stage IIIB/IV - Documentation of activating EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations) at the time of initial diagnosis - Patient may receive up to one line of third EGFR TKI - Plasma sample testing performed to detect EGFR TKI resistance Exclusion Criteria: - Patients have other concurrent cancers - Patients who are not eligible receive TKI Non Small Cell Lung Cancer Lung Neoplasms null --- L858R --- --- L858R ---

Primary Outcomes

Description: This retrospective study will collate the molecular alterations detected during routine analysis. The elements extracted from the file will be age, sex, type of tumor and clinical-histological characteristics, dates of diagnosis and start of treatment. In addition, information on the dates of appearance of resistances (radiographic or clinical) will also be provided. No additional analysis will be performed since the study will consist of the analysis of data generated by the analyses performed in the context of patient management and biological monitoring. This research does not aim to modify your care. There will be no additional consultation or examination, nor will there be any changes in the treatment prescribed by your doctor.

Measure: Description of the molecular alterations detected in patients treated with 3rd TKI and assessment link with progression free survival and overall survival features.

Time: The analysis of the TKI effectiveness and the appearance of mutations will be performed over a period of 24 months.

Secondary Outcomes

Description: Frequency of detected molecular alterations

Measure: Frequency of detected molecular alterations

Time: The analysis of the TKI effectiveness and the appearance of mutations will be performed over a period of 24 months.

316 Phase 2 Study of PD-1 Inhibitor JTX-4014 Alone and in Combination With Vopratelimab, an ICOS Agonist, in Biomarker-selected Subjects With Metastatic NSCLC After One Prior Platinum-containing Regimen

This is a Phase 2, open-label study to evaluate PD-1 inhibitor JTX-4014 alone and in combination with vopratelimab, an ICOS agonist, in biomarker-selected adult subjects with metastatic NSCLC who are PD-1/PD-L1 inhibitor naïve and have progressed on a platinum based chemotherapy regimen.

NCT04549025
Conditions
  1. NSCLC
Interventions
  1. Drug: JTX-4014
  2. Drug: Vopratelimab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Current or past participation in a study of an investigational agent or using an investigational device in the metastatic setting - Chemotherapy < 28 days prior to planned C1D1 - Prior immunotherapy including, but not limited to PD-1 or PD-L1 inhibitor mAb at any time, including JTX-4014; therapy with any mAb that specifically binds to ICOS, including vopratelimab; or chimeric antigen receptor T cell therapy - Use of anticancer therapies listed below in the metastatic setting (allowed as prior treatment for localized disease): 1. Biologic therapy 2. Targeted small molecule therapy 3. Organ transplantation, including allogeneic or autologous stem cell transplantation - Positive test for any of the following epidermal growth factor receptor gene mutations in blood or tumor: Exon 18 G719A; Exon 18 G719C; Exon 18 G719S; Exon 19 Del; Exon 20 S768I; Exon 20 T790M; Exon 20 Ins; Exon 21 L858R; Exon 21 L861Q - Prior whole brain radiation Inclusion Criteria: - Able and willing to participate and comply with all study requirements - Histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) with evaluable or measurable disease according to RECIST v1.1 with at least 1 measurable lesion - Confirmed tumor RNA signature score - Experienced progression of locally advanced or metastatic NSCLC after 1 prior systemic antineoplastic platinum-containing regimen (adjuvant therapy will count as a regimen if administered within 1 year before the relapse) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Predicted life expectancy of ≥ 3 months - Adequate organ function - WOCBP must agree to use highly effective birth control Exclusion Criteria: - Concurrent anticancer treatment or subject is expected to require any other form of antineoplastic therapy while on study, either approved or investigational. --- G719A --- --- G719C --- --- G719S --- --- S768I --- --- T790M --- --- L858R ---

- Current or past participation in a study of an investigational agent or using an investigational device in the metastatic setting - Chemotherapy < 28 days prior to planned C1D1 - Prior immunotherapy including, but not limited to PD-1 or PD-L1 inhibitor mAb at any time, including JTX-4014; therapy with any mAb that specifically binds to ICOS, including vopratelimab; or chimeric antigen receptor T cell therapy - Use of anticancer therapies listed below in the metastatic setting (allowed as prior treatment for localized disease): 1. Biologic therapy 2. Targeted small molecule therapy 3. Organ transplantation, including allogeneic or autologous stem cell transplantation - Positive test for any of the following epidermal growth factor receptor gene mutations in blood or tumor: Exon 18 G719A; Exon 18 G719C; Exon 18 G719S; Exon 19 Del; Exon 20 S768I; Exon 20 T790M; Exon 20 Ins; Exon 21 L858R; Exon 21 L861Q - Prior whole brain radiation NSCLC Carcinoma, Non-Small-Cell Lung JTX-4014 is a fully human IgG4 monoclonal antibody designed to specifically bind to PD-1 and block its interaction with its ligands, PD-L1 and PD-L2, to augment anti-tumor T cell activity. --- G719A --- --- G719C --- --- G719S --- --- S768I --- --- T790M --- --- L858R ---

Primary Outcomes

Description: Mean percent change from baseline in all measurable lesions

Measure: Change in measurable lesion size

Time: averaged over 9 and 18 weeks

Secondary Outcomes

Description: ORR according to RECIST v1.1

Measure: ORR

Time: up to 24 months

Description: PFS according to RECIST v1.1

Measure: PFS

Time: up to 24 months

Description: Landmark progression free survival (PFS)

Measure: Landmark progression free survival (PFS)

Time: 9months

Description: Disease control rate (DCR) according to RECIST v1.1

Measure: Disease control rate (DCR)

Time: up to 24 months

Description: Median duration of response (DOR) according to RECIST v1.1

Measure: Median duration of response (DOR)

Time: up to 24 months

Description: Median overall survival (OS)

Measure: Median overall survival (OS)

Time: up to 24 months

317 Atezolizumab Plus 8 Gy Single-fraction Radiotherapy for Advanced, Oligoprogressive NSCLC After Upfront Chemotherapy and Anti-PD1 Immunotherapy: A Multicentre, Single Arm, Phase II Study

Multicentre, phase II, open-label, single-arm study evaluating the preliminary efficacy, safety and tolerability of atezolizumab in association with palliative radiotherapy in adult patients diagnosed with advanced (stage IV) NSCLC, irrespective of PD-L1 status, and who have oligoprogressed to both immunotherapy with an anti PD-1 agent (e.g., pembrolizumab or nivolumab) and 1 line of chemotherapy.

NCT04549428
Conditions
  1. NSCLC Stage IV
Interventions
  1. Drug: Atezolizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Signed Informed Consent Form - Histologically or cytologically confirmed diagnosis of metastatic (Stage IV) - NSCLC as per the American Joint Committee on Cancer (AJCC) 8th edition - No sensitizing EGFR mutation (L858R or exon 19 deletions), ALK fusion oncogene or ROS1 rearrangement detected - Progressing to one line of chemotherapy defined as follows: 1. --- L858R ---

Primary Outcomes

Description: Percentage of patients with a complete response or partial response

Measure: Objective Response Rate

Time: 3 months

Secondary Outcomes

Description: Time in months from the first day of study treatment to the date of death

Measure: Overall Survival

Time: 12 months

Description: Time in months from the first day of study treatment until the first evidence of tumour progression

Measure: Progression Free-Survival

Time: 12 months

318 Almonertinib as Upfront Treatment for Uncommon EGFR Mutation Harboring Non-Small-Cell Lung Cancer Patients: A Multicenter, Open-Label, Phase II Trial

This is a Phase 2 study to evaluate the efficacy and the safety/ tolerability of Almonertinib in NSCLC patients with uncommon EGFR Mutation or EGFR exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have to had at least one prior systemic treatment for locally advanced or metastatic NSCLC.

NCT04553887
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Almonertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. 18-75years#ECOG PS#0-2#Life expectancy of more than 3 months#with measurable lesion ( RECIST1.1). 2. Cohort A: Patients with EGFR exon 20 insertion, failure of first-line standard chemotherapy, or intolerance to chemotherapy Cohort B: Patients with uncommen EGFR mutations but without exon 19 deletion, L858R, T790M, and exon 20 insertion 3. ≥1 target lesion that has not received radiotherapy in the past 3 months and can be accurately measured in at least 1 direction#Previously received radiation therapy, but the radiotherapy area must be <25% of the bone marrow area, and radiation therapy must have closed for at least≥4 weeks at the time of enrollment. --- L858R ---

The currently approved TKIs (ie, erlotinib, gefitinib, afatinib, osimertinib) are not considered to be exon 20 insertion-selective and are permissible 1. Patients with EGFR 19 exon deletion mutation, 21 exon L858R mutation or 20 exon T790M mutation. --- L858R ---

Judgment by the investigator that should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: 1. 18-75years#ECOG PS#0-2#Life expectancy of more than 3 months#with measurable lesion ( RECIST1.1). 2. Cohort A: Patients with EGFR exon 20 insertion, failure of first-line standard chemotherapy, or intolerance to chemotherapy Cohort B: Patients with uncommen EGFR mutations but without exon 19 deletion, L858R, T790M, and exon 20 insertion 3. ≥1 target lesion that has not received radiotherapy in the past 3 months and can be accurately measured in at least 1 direction#Previously received radiation therapy, but the radiotherapy area must be <25% of the bone marrow area, and radiation therapy must have closed for at least≥4 weeks at the time of enrollment. --- L858R ---

Primary Outcomes

Description: The proportion of subjects who achieve Complete Response (CR) and Partial Response (PR) by the best response from the first dose of Almonertinib to the end of study.

Measure: Objective Response Rate

Time: To evaluate objective response rate 6-8 weeks after the initiation of Almonertinib

Secondary Outcomes

Description: The PFS time is defined as time from enrollment to locoregional or systemic recurrence, second malignancy or death due to any cause; censored observations will be the last date of : "death", "last tumor assessment", "last follow up date" or "last date in drug log"

Measure: Progression Free Survival

Time: 30 months

Description: Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease).

Measure: Disease Control Rate

Time: 30 months

Description: OS was defined as time from date of enrollment to date of death due to any cause. For participants still alive at the time of analysis, OS time was censored on last date that participants were known to be alive.

Measure: Overall Survival

Time: 30 months

Description: Number of days from the date that measurement criteria are first met for CR or PR (whichever status is recorded first) until the first subsequent date that progressive disease or death is documented.

Measure: Duration of Response

Time: 30 months

Description: Number of Participants with treatment related Adverse Events as Assessed by CTCAE v5.0

Measure: Safety and Tolerability

Time: 30 months

319 A Phase II, Open-label, Single-arm, Multicenter, Efficacy and Safety of 80mg Osimertinib in Patients With Leptomeningeal Metastases(LM) Associated With EGFR Mutation-positive Non-small Cell Lung Cancer(NSCLC)

This will be a Phase II, open-label, single-arm, multicenter study of the efficacy and safety of osimertinib (80 mg orally once daily) in patients with LM associated with EGFRm+ NSCLC.

NCT04563871
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: 80mg Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Male and female patients must be at least 18 years of age. 4. Patients must have documented (only allowed for EGFRm+ [exon 19 deletions or L858R] in pre-treated patients) and/or confirmed central/local test result showing eligible EGFR mutation status as specified below: - EGFR TKI pre-treated patients: EGFRm+ (exon 19 deletions or L858R), along with valid T790M mutation status 5. --- L858R ---

3. Male and female patients must be at least 18 years of age. 4. Patients must have documented (only allowed for EGFRm+ [exon 19 deletions or L858R] in pre-treated patients) and/or confirmed central/local test result showing eligible EGFR mutation status as specified below: - EGFR TKI pre-treated patients: EGFRm+ (exon 19 deletions or L858R), along with valid T790M mutation status 5. --- L858R --- --- L858R ---

Primary Outcomes

Description: To investigate the efficacy of osimertinib on LM as measured by OS

Measure: Overall survival

Time: Up to 30 months

Secondary Outcomes

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM ORR(Objective response rate)

Time: Up to 30 months

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM DoR(Duration of response)

Time: Up to 30 months

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM DCR(Disease control rate)

Time: Up to 30 months

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM PFS(Progression-free survival)

Time: Up to 30 months

Description: To investigate the efficacy of osimertinib in patients with LM associated with EGFRm+ NSCLC on the CSF cytological clearance

Measure: CSF response rate based on CSF cytology

Time: Up to 30 months

320 Bevacizumab Plus EGFR Tyrosine Kinase Inhibitors in Chinese Patients With Stage IIIB-IV EGFR-mutant Non-small Cell Lung Cancer: a Prospective,Multicenter, Non-interventional,Real-world Study

This study is a prospective, multicenter, real-world study to investigate the efficacy and safety of bevacizumab plus epidermal growth factor (EGFR) Tyrosine Kinase Inhibitors in Chinese Patients With Stage IIIB/IV EGFR-mutant Non-small Cell Lung Cancer.

NCT04575415
Conditions
  1. NSCLC
Interventions
  1. Drug: Bevacizumab
  2. Drug: Erlotinib
  3. Drug: Gefitinib
  4. Drug: Icotinib
  5. Drug: Afatinib
  6. Drug: Dacomitinib
  7. Drug: Osimertinib

An exon 19 deletion mutation or exon 21 L858R mutation in EGFR has been found clinically, with or without EGFR T790M mutation 5. Eastern Cooperative Oncology Group performance status 0-2 or KPS ≥60 6. --- L858R ---

Primary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with first-generation EGFR-TKIs in patients with EGFR-mutant NSCLC as measured by investigators

Measure: Progression-free survival (PFS) for bevacizumab plus first-generation EGFR-TKIs by investigator using RECIST v1.1

Time: This is a real-world study. The estimated median PFS for bevacizumab plus first-generation EGFR-TKIs is 18 months according to previous data.

Description: To evaluate the efficacy of bevacizumab combined with second-generation EGFR-TKIs in patients with EGFR-mutant NSCLC as measured by investigators.

Measure: Progression-free survival (PFS) for bevacizumab plus second-generation EGFR-TKIs by investigator using RECIST v1.1

Time: This is a real-world study. The estimated median PFS for bevacizumab plus second-generation EGFR-TKIs is 20 months according to previous data.

Description: To evaluate the efficacy of bevacizumab combined with third-generation EGFR-TKIs in patients with EGFR-mutant NSCLC as measured by investigators.

Measure: Progression-free survival (PFS) for bevacizumab plus third-generation EGFR-TKIs by investigator using RECIST v1.1

Time: This is a real-world study. The estimated median PFS for bevacizumab plus third-generation EGFR-TKIs is 22 months according to previous data.

Secondary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations, with or without EGFR T790M mutation,as measured by investigators assessed objective response rate using RECIST v1.1

Measure: Objective response rate (ORR) by investigator using RECIST v1.1

Time: Baseline overall tumor assessment can be performed up to 28 days after the first-dose of treatment. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: Disease control rate (DCR) will be analyzed using similar method as objective response rate.

Measure: Disease control rate (DCR) by investigator using RECIST v1.1

Time: Baseline overall tumor assessment can be performed up to 28 days after the first-dose of treatment. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: To evaluate the efficacy of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations,with or without EGFR T790M mutation,as measured by investigators assessed overall survival.

Measure: Overall survival

Time: The primary analysis on overall survival is espected to perform on 48 months of follow-up.

Description: To evaluate the incidence of Treatment-Emergent Adverse Events of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations,with or without EGFR T790M mutation.

Measure: Incidence of Treatment-Emergent Adverse Events using CTCAE V5.0

Time: This is a real-world study. Safety of the combination treatment is expected to perform until the study completion, an average of 1.5 years,according to CTCAE V5.0.

321 A Phase II, Open Label, Randomized Study of Osimertinib to Suppress the Progression of Remaining Ground-glass Opacity Nodule (GGN) in Other Lobes After Curative Resection for Actionable EGFR Mutation-positive Stage I Lung Adenocarcinoma

This study designed to assess the efficacy of osimertinib (80 mg, orally, once daily) to suppress the progression of remaining GGN(s) in other lobes following surgical resection for actionable EGFR mutation-positive stage I lung adenocarcinoma.

NCT04591002
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Osimertinib 80 MG
MeSH:Disease Progression

Incidence of adverse events and grades based on CTCAE (Common Terminology Criteria for Adverse Events) version 5.0.. Inclusion Criteria: 1. Provision of informed consent prior to any study specific procedures 2. Adult male or female patients, aged from 30 to 75 years 3. Pathologic proven stage I lung adenocarcinoma with additional persistent GGNs in at least one other lobe: GGN is defined as a ground glass-opacity with well-defined margin, mean density above -500 HU and greater than 7.5 mm in its maximum diameter 4. The resected lung adenocarcinoma should have actionable EGFR mutation, which is limited to L858R or exon 19 deletion. --- L858R ---

Inclusion Criteria: 1. Provision of informed consent prior to any study specific procedures 2. Adult male or female patients, aged from 30 to 75 years 3. Pathologic proven stage I lung adenocarcinoma with additional persistent GGNs in at least one other lobe: GGN is defined as a ground glass-opacity with well-defined margin, mean density above -500 HU and greater than 7.5 mm in its maximum diameter 4. The resected lung adenocarcinoma should have actionable EGFR mutation, which is limited to L858R or exon 19 deletion. --- L858R ---

Primary Outcomes

Description: Regression rate of additional GGNs using investigator assessments by comparing the size of GGN(s) on the initial CT scan (at randomization) to that in the last follow-up scan. We will conduct the quantitative analysis of GGNs on the initial and follow-up CT scans via VOI (Volume of Interest) segmentation. VOI is measured with the unit of mm3.

Measure: To assess the efficacy of osimertinib on the regression of additional GGN(s)

Time: up to 12months

Secondary Outcomes

Description: Avoidance rate of subsequent surgeries or radiation treatments for GGN(s) within one year since the initiation of osimertinib treatment: Defined as the number (percent) of patients who do not require subsequent anticancer treatments including surgeries or radiation for remaining GGN(s) within one year since the initiation of osimertinib treatment

Measure: To assess the efficacy of osimertinib in avoidance of subsequent anticancer treatments including surgery or radiation for GGN(s)

Time: up to 12months

Description: Time to regression: Defined as the length of time from the date of initiation of osimertinib treatment to the first date of GGN regression

Measure: To evaluate when GGN(s) will regress after osimertinib treatment

Time: up to 12months

Description: Incidence of regrowth and reappearance of remaining GGN(s) within one year since the initiation of osimertinib treatment

Measure: To evaluate the rate of treatment failure

Time: up to 12months

Description: Number of patients who would have growing new nodules (either ground glass nodules or solid nodules) with high suggestion of lung cancer by lung-special radiologists within one year since the initiation of Osimertinib treatment

Measure: To evaluate the number of patients with new nodules

Time: up to 12months

Description: Incidence of adverse events and grades based on CTCAE (Common Terminology Criteria for Adverse Events) version 5.0.

Measure: To assess the incidence of treatment-emergent adverse events of osimertinib

Time: up to 12months

322 A Multi-centre Phase II, Double-Blind, Randomised Study of Savolitinib in Combination With Osimertinib vs Savolitinib in Combination With Placebo in Patients With EGFRm+ and MET Amplified Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Progressed Following Treatment With Osimertinib

This study will compare the activity of the combination of savolitinib and osimertinib against the combination of savolitinib with placebo to osimertinib in patients with Epidermal Growth Factor Receptor Mutation Positive and MET amplified, locally advanced or metastatic non-small cell lung cancer who have progressed following treatment with osimertinib.

NCT04606771
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib + Savolitinib
  2. Drug: Savolitinib + Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

All genders are permitted - Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity and that is permitted in the osimertinib national label (such as exon 19 deletion and/or L858R), which is not amenable to curative therapy. --- L858R ---

Primary Outcomes

Description: ORR will be performed based on Investigator assessment of disease progression by RECIST 1.1.

Measure: Objective Response Rate (ORR)

Time: The primary analysis will occur 6 months after the last patient is randomised.

Secondary Outcomes

Description: PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by the investigator or death due to any cause.

Measure: Progression-free Survival (PFS)

Time: The primary analysis will occur 6 months after the last patient is randomised.

Description: DoR is defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by the investigator or death in the absence of disease progression.

Measure: Duration of Response (DoR)

Time: The primary analysis will occur 6 months after the last patient is randomised.

Description: TSA is defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator.

Measure: Tumour Size Assessment (TSA)

Time: The primary analysis will occur 6 months after the last patient is randomised.

Description: OS is defined as time from randomisation until the date of death due to any cause.

Measure: Overall Survival (OS)

Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.

Description: Objective response rate in patients who cross over after progression on savolitinib plus placebo, defined as the proportion of patients with measurable disease who have a CR or PR as determined by the investigator at the local site per RECIST 1.1.

Measure: Objective Response Rate (ORR)

Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.

Description: Progression free survival in patients who cross over after progression on savolitinib plus placebo, defined as time from the first dose in the cross over period until progression per RECIST 1.1 as assessed by the investigator or death due to any cause.

Measure: Progression Free Survival

Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.

Description: Duration of response in patients who cross over after progression on savolitinib plus placebo, defined as the time from the date of first documented response during the cross-over period until date of documented progression per RECIST 1.1 as assessed by the investigator or death in the absence of disease progression.

Measure: Duration of Response

Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.

Description: Tumour size assessment in patients who cross over after progression on savolitinib plus placebo, defined as the percentage change from baseline in TLs at 12 weeks per RECIST 1.1 as assessed by the investigator.

Measure: Tumour Size Assessment

Time: The primary analysis will occur 6 months after the last patient is randomised. the final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.

Description: To determine the prevalence of ctDNA clearance after savolitinib plus osimertinib or savolitinib plus placebo treatment in this patient population

Measure: Total clearance in EGFR mutations at 6-weeks after therapy initiation (percentage and absolute change from baseline in EGFR mutation allele frequencies).

Time: The primary analysis will occur 6 months after the last patient is randomised.

Description: To evaluate the PK of savolitinib and osimertinib.

Measure: Plasma concentrations of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib)

Time: Cycle 1, Day 1: Pre-dose and 1 and 3 hours post-dose; Cycle 2, Day 1: Pre-dose and 1 and 3 hours post-dose; Cycle 3, Day 1: Pre dose and 1, 3, 4, and 6 hours post-dose; Cycles 6 and 11, Day 1: Pre-dose only. (Each Cycle is 28 days).

Description: To evaluate the PK of savolitinib and osimertinib.

Measure: Time dependency of the PK of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib)

Time: C3h Cycle 2 Day 1/C3h Cycle 1 Day 1; Cpre-dose Cycle 3 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 6 Day 1/Cpre-dose Cycle 2 Day 1; Cpre-dose Cycle 11 Day 1/Cpre-dose Cycle 2 Day 1. (Each Cycle is 28 days)

Description: To evaluate the PK of savolitinib and osimertinib.

Measure: AUCss of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib)

Time: Cycle 3, Day 1 (Each Cycle is 28 days)

Description: To evaluate the PK of savolitinib and osimertinib.

Measure: Cssmax of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib)

Time: Cycle 3, Day 1 (Each Cycle is 28 days)

Description: To evaluate the PK of savolitinib and osimertinib.

Measure: Tssmax of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib)

Time: Cycle 3, Day 1 (Each Cycle is 28 days)

Description: To evaluate the PK of savolitinib and osimertinib.

Measure: CLss/F of savolitinib, osimertinib and their metabolites, (M2 and M3 for savolitinib; AZ5104 for osimertinib)

Time: Cycle 3, Day 1 (Each Cycle is 28 days)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number and percentage of subjects with adverse events (AEs) in different categories: All AEs

Time: Continuous collection from First dose until study termination, on average 12 months

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Serious AEs

Time: Continuous collection from First dose until study termination, on average 12 months

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Causally related AEs

Time: Continuous collection from First dose until study termination, on average 12 months

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Discontinuations due to AEs

Time: Continuous collection from First dose until study termination, on average 12 months

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number and percentage of subjects with adverse events (AEs) in different categories: Deaths

Time: Continuous collection from First dose until study termination, on average 12 months

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Albumin

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Alkaline phosphatase

Time: Screening, weekly for first 5, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in ALT

Time: Screening, weekly for first 10, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Amylase

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in AST

Time: Screening, weekly for first 10 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation(an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Total bilirubin

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Total Calcium

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Creatinine

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Glucose

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation(an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Magnesium

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Sodium

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Potassium

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Total Protein

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in BUN or urea

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Lactate dehydrogenase

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Haematocrit

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Haemoglobin

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Leucocyte cell count

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Platelet count

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Red blood cell count

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Reticulocytes

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Neutrophil count

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Lymphocyte count

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Description: To evaluate the safety and tolerability of savolitinib plus osimertinib or savolitinib plus placebo.

Measure: Number of subjects with at least one treatment emergent change in laboratory parameters in Eosinophil count

Time: Screening, weekly for first 5 weeks, then Day 1 of every cycle (each Cycle is 28 days) until treatment discontinuation (an average of 1 year)

Other Outcomes

Description: To collect and store germline DNA for exploration of the role of HLA alleles in developmental toxicity.

Measure: HLA alleles associated with susceptibility to drug related AEs (such as but not limited to hypersensitivity).

Time: On Cycle 1 Day 1 only (each cycle is 28 days)

Description: Defined as time from randomisation until the date of death due to any cause

Measure: Overall survival, in patients who cross over after progression on savolitinib plus placebo

Time: The primary analysis will occur 6 months after the last patient is randomised. The final analysis will occur at the earlier of 18 months after the last patient is randomised or when 70% of patients have progressed or died.

323 Real World Utilization and Outcomes With Dacomitinib First Line Treatment for EGFR Mutation-positive Advanced Non Small Cell Lung Cancer Among Asian Patients - A Multi Center Chart Review

This is a longitudinal, consecutive case-series, multi-center study with mixed prospective and retrospective data collection. Data will be collected from eligible adults with EGFR mutation-positive advanced NSCLC treated with dacomitinib as first-line therapy from the date of advanced NSCLC diagnosis to the date of death, lost to follow-up, withdrawal of consent or end of study, whichever occurs first.

NCT04609319
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - Adult (aged ≥18 years) with histology-confirmed advanced NSCLC (TNM stage IIIB-IV); - Presence of any EGFR-activating mutation (exon 19 deletion or exon 21 L858R substitution) or other uncommon EGFR mutations prior to anti-cancer treatment; - Initiating dacomitinib as first-line treatment after confirmation of EGFR-mutation status (ie, no prior treatment with other EGFR TKI or systemic therapy); Exclusion Criteria: - Enrolled in any interventional clinical study or trial (however, patients enrolled in non-interventional, real world study may still be included). --- L858R ---

Primary Outcomes

Measure: Proportion of patients who initiated dacomitinib at 45mg, 30mg and 15mg dose respectively

Time: Uo to 3 years

Measure: Proportion of patients that experience dose modification

Time: Up to 3 years

Measure: Proportion of patients that experience dose interruption

Time: Up to 3 years

Measure: Proportion of patients that experience dose discontinuation

Time: Up to 3 years

Secondary Outcomes

Measure: Real world progression-free survival

Time: Up to 3 years

Measure: Overall response rate

Time: Up to 3 years

324 HERTHENA-Lung01: A Phase 2 Randomized Open-Label Study of Patritumab Deruxtecan (U3-1402) in Subjects With Previously Treated Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer (NSCLC)

This study is designed to evaluate the antitumor activity of patritumab deruxtecan in participants with metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R) who have received and progressed on or after at least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen.

NCT04619004
Conditions
  1. Non-Small Cell Lung Cancer Metastatic
  2. Non-Small Cell Lung Cancer With Mutation in Epidermal Growth Factor Receptor
Interventions
  1. Drug: Patritumab Deruxtecan (Fixed dose)
  2. Drug: Patritumab Deruxtecan (Up-Titration)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer This study is designed to evaluate the antitumor activity of patritumab deruxtecan in participants with metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R) who have received and progressed on or after at least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen. --- L858R ---

- Documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: exon 19 deletion or L858R. --- L858R ---

Primary Outcomes

Description: ORR is defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) as assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Measure: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Secondary Outcomes

Description: DoR is defined as the time from the first documented confirmed response (CR or PR) to the date of progression or death due to any cause as assessed by BICR and Investigator per RECIST v1.1, respectively.

Measure: Duration of Response (DoR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: PFS is defined as the time from the start of study treatment to the earlier of the dates of the first documentation of objective progressive disease (PD) per RECIST v1.1 or death due to any cause. PFS will be determined by BICR and by Investigator, respectively.

Measure: Progression-free Survival (PFS)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: ORR is defined as the proportion of participants with a BOR of confirmed CR or confirmed PR as assessed by the Investigator per RECIST v1.1.

Measure: Objective Response Rate (ORR) as Assessed by the Investigator

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: DCR is defined as the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD) as assessed by BICR and by the Investigator per RECIST v1.1, respectively.

Measure: Disease Control Rate (DCR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: TTR is defined as the time from the start of study treatment to the date of the first documentation of confirmed response (CR or PR) as assessed by BICR and Investigator per RECIST v1.1, respectively.

Measure: Time to Tumor Response (TTR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: The best percentage change in the SoD of measurable tumors is defined as the percentage change in the smallest SoD from all post-baseline tumor assessments, taking as reference the baseline SoD.

Measure: Best percentage change in the sum of diameters (SoD) of measurable tumors

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: OS defined as the time from the start of study treatment to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: Death date is collected until the participant discontinues the study or up to approximately 26 months

Description: A TEAE is defined as an adverse event (AE) with a start or worsening date during the on-treatment period. A serious AE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event, or may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes noted. AESIs will also be assessed. Adverse events will be coded using MedDRA and will be graded using NCI-CTCAE v5.0.

Measure: Incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs)

Time: From baseline up to Day 47 post last dose


HPO Nodes


HP:0002664: Neoplasm
Genes 1537
H19 RPS19 WT1 GPR101 CHEK2 MYD88 VEGFC PGM3 CTNNB1 PDGFRA IRF1 RHBDF2 PICALM FANCC GDNF RET PRKAR1A NELFA BCL10 KRT10 BLK TINF2 SMARCD2 NSD2 BRCA1 KRAS TRIP13 KCNH1 PERP CDH23 IKBKG MCC JAK2 MET GTF2E2 FOXC2 NF1 RAD51 TP53 ERCC4 WNT10A ASXL1 CTLA4 FLT4 DVL3 BRCA1 MLH3 NSD1 ERCC2 TSC2 FANCL RPS14 CDC73 TNFRSF4 STAG3 MSTO1 AIP EVC RET PLCD1 SDHB NEK1 POLH ASXL1 BRAF IL7 MAP2K1 ARSA BRAF COL4A5 CYLD KRT14 MLLT10 RASGRP1 H19 XIAP NTHL1 FGFR2 IGH DNAJC21 LETM1 MCM4 MYF6 CD70 FAM149B1 FGFR3 TERF2IP TNFRSF13C GLI3 DDX41 RPL26 PRLR SBDS LIG4 MGMT RERE KLLN FANCM WT1 PHB AXIN2 KIT PTEN TGFBR2 GJA1 PDGFRL STAT6 TYR CPLANE1 IFNG SIX6 JAG1 PALB2 SSX1 FANCG KIT MYO1H ELANE RPS19 H19-ICR KRT6B IDH2 PLCB4 FGFR1 BAP1 MINPP1 MST1 SMARCB1 PDGFRB RB1 FAT4 NF1 HFE SDHD WT1 TET2 BMPR1A RAF1 POLR1D CBFB SKIV2L IRF1 COL18A1 HMBS RET MMEL1 IGF2R JAK2 SEC23A BUB1B XPC ING1 AXIN2 KIT PALB2 MAGT1 STAC3 ALK SLC25A13 TMEM231 SHOX TDGF1 REST SMO SMARCA4 DNM2 TSR2 LIN28B GNAS WT1 CDKN1A DNAJC21 DKC1 BAP1 SRGAP1 ALX1 PTPN11 CBL APC SCN11A MAP3K1 RPL10 KLF6 PAX7 APC C1S NRTN BUB3 KRT5 LIG4 CARD14 GNAS MLH1 CDKN2A GNA11 TMEM127 ESR1 IL2RG KRT1 MET NF2 SDHAF2 SDHD WT1 MAP3K8 STAT1 PHOX2B PTPRJ PTCH2 CHD7 TERT LMNA ERCC6 EDNRB XPA PDGFRA OFD1 VHL SAMD9L SF3B1 FERMT1 BRCA1 GDF2 CASP8 TP53 LAMC2 GFI1B FANCD2 PYGL CR2 AR REST APPL1 APC CYP2A6 SEMA3C WT1 CDKN2A CTSA LRRC8A PHOX2B SMARCB1 NAGS FLI1 SOX2 RAD21 TMEM127 APC FGF3 BAP1 BUB1 RAD51 DKC1 RAD54B VHL EPCAM ASXL1 SRC HRAS BMP2 SLC25A11 PTH1R KRAS MYD88 NPM1 PTEN SH3GL1 PHOX2B TP53 SMAD4 XPA GATA4 MLH1 PMS2 STK11 FANCC DHCR7 PTCH1 CDC73 CYLD MEN1 CLCNKB CHEK2 RNF139 HABP2 POLE H19-ICR MMP1 RPL27 CC2D2A PIK3CA GPC3 ABL1 PALLD WASHC5 INTU ERCC5 DYNC2LI1 SLC22A18 TP53 CDH1 SHH MPL AKT1 NFKB2 NRAS PIGL CASP8 MYC KCNE3 DLST TAF15 TNFRSF13B GDNF EYA1 APC2 TNFRSF1B TCTN3 PPOX PNP PKHD1 BLM ODC1 IL12A TERT STK11 KRT17 IDH1 CIB1 RPL18 DVL1 ARHGAP26 PHOX2B CASP8 RPGRIP1L KRT6A SDHB FGFR2 VAMP7 JAK2 SRY DNMT3A EPAS1 KCNQ1OT1 MSH6 KRAS SDHB WNT5A DNMT3A RUNX1 TRIM28 DHCR24 USB1 VANGL2 GCM2 LIG4 KRAS SDHB ENG SEMA3D TRNS2 MINPP1 CASP10 NTHL1 LMOD1 SUFU FOXH1 CD81 ALX4 F13B BMPR1B RB1 CACNA1S CHIC2 VHL HRAS KIF11 KCNJ11 WRN SLC37A4 GNAQ LZTR1 CCND1 CPLX1 NR4A3 RYR1 NBEAL2 GATA2 TP63 APC KRAS HNF1B SUFU GNB1 MSX2 GPC3 CEL TCTN3 OCA2 MDM4 RB1 TMC6 ASCL1 AR BRIP1 CHEK2 AAGAB TSC1 TXNRD2 POLD1 CARMIL2 APC PIK3CA AKT1 POLE FAN1 RAD21 G6PC BRD4 PTCH2 MSH2 DHH EWSR1 SPRTN SDHC PTCH1 ALX3 CD79A TMEM67 INPP5E CCBE1 KRT6B BRCA2 ITK GINS1 HLA-DRB1 SNAI2 NBN PHOX2B BRAF CDH1 FANCE TYR GPC4 NF1 CD19 MVD AIP AR NBN TMEM107 BRIP1 ATRX BCHE MITF WRN BCR BCR NF2 SERPINA1 SDHB RABL3 PARN ANTXR2 TERT DPM1 IFIH1 GDF5 ZAP70 MEN1 TP53 GNAS BRCA2 TMC8 NODAL LETM1 VANGL1 TBXT BRCA1 FIBP FLT4 IL1B CCL2 FGFR3 SUFU MTAP ELANE CD19 HNF4A SAMD9 BUB1B KLHDC8B SLC26A2 FGFR3 FOXP1 PUF60 RUNX1 PTCH2 TRNK FLT4 TYROBP MPL KRAS RAD54L PIK3CA FAH CHEK2 CPLANE1 FAM20C CXCR4 DDR2 POU6F2 TMC6 SEC23B RET TRNP TFE3 TP53 NAB2 ANTXR1 MYSM1 SDHAF2 BTK TNFRSF10B DCLRE1C L2HGDH CDKN2A CYP11B2 BRCA2 SDHD TET2 TMEM216 BRAF PTCH2 TCF3 RPL11 NNT FLT3 BAX HAX1 IGF2 AKT1 FGFR3 MLH3 PLA2G2A TCF4 MLH3 NOTCH1 ERCC4 RRAS2 GPC4 DICER1 LZTS1 DOCK8 CASP10 GREM1 HPGD COL1A1 DCLRE1C IDH1 XRCC3 SUFU DNAJC21 PDGFRB TP53 NLRP1 WWOX TSC1 CTSC USP9X PDCD10 MEN1 ASCL1 RNF43 TNFRSF13C ESCO2 ZFPM2 AP2S1 PRCC HMBS ADA2 GANAB WT1 RNF43 HRAS KRAS SETD2 ATP6V1B2 FLT3 TJP2 BMPR1A PDGFB KIAA0753 PTEN STK4 NFKB1 BAP1 PMS1 MSR1 SLC26A2 RECQL4 MSH2 JAK2 ATRX FH RECQL4 FCN3 CD28 ASPSCR1 ADAR WHCR NOTCH3 GATA2 SMARCE1 CDKN2A RET ESCO2 EXT1 ERCC5 TET2 MBTPS2 NF1 OFD1 AGGF1 MVK KIT MUTYH HRAS KRIT1 FGFR1 TRIM28 CHEK2 CD79B GNAS BRCA2 KDSR BAX HACE1 MAP2K2 EDN3 ERCC2 CTNNB1 IL6 IGH PIK3CA MSH3 FZD2 SMPD1 SNAI2 PHOX2B SLC26A2 OFD1 PAX4 RB1 TRIP13 EWSR1 SCN9A PIK3R1 GBA EP300 PIK3CA HMMR KIT PDE6D ZSWIM6 SH3KBP1 SRP54 FUZ USP8 WT1 TERT MAFA FOXO1 GJB3 RAD51D POT1 SDHC PRKAR1A CREB1 SH2D1A WIPF1 WWOX PIK3CA NF2 HNF4A FAS RNASEH2A CD27 ATRX SPRED1 RPS14 FDPS RNR1 PALB2 NF1 MN1 TET2 GPC4 KDR SOX9 RAD51 MAX MYLK EP300 SHOX FOXE1 TCOF1 ESCO2 MYH11 HSPA9 MAD2L2 KRT9 CYP2D6 RFWD3 FANCE KRAS CCND1 LMO1 PTCH1 PORCN EDN3 PDGFRA DICER1 FANCA TERC CTBP1 SDHD ANTXR1 CXCR4 RAD50 BRCA2 MC1R MPL SLC22A18 MMP1 KRT16 F13A1 TSC2 ENG SETBP1 WT1 TET2 SDHC SMAD4 ZFHX3 GFI1 RNF113A STK11 KARS1 FOXE1 CDKN2B WT1 ERBB3 SMARCAD1 PDGFRL DMPK GTF2H5 NF2 CEBPA RPS28 PMS1 AKT1 PRDM16 NBN GCK SPINK1 ERBB2 JAK2 KIT DKC1 EXT1 JAK2 COL7A1 AXIN1 SLC22A18 NRAS ECM1 GNPTAB ABCA5 CDH1 NRAS ERCC6 VANGL1 RAD51C MYCN HBB TP53 SRY FANCI AKT1 MITF LEMD3 TARS1 TET2 NSD2 DAXX DYNC2LI1 OGG1 EXT1 TNFSF15 TERT ERCC6 DMRT3 SLC25A11 CTNNB1 VHL KLLN MLH3 EIF2AK4 GJB6 BARD1 OCRL GPR35 MYC DLST KRAS MSH3 RMRP PRKCD KLF6 NEUROD1 FANCG SLC17A9 BMPER FLCN SDHC SF3B1 STS GNA14 TERC MNX1 CAT TCF4 TUBB TRNQ BRCA2 IL12RB1 PDX1 CDKN2A SLC26A4 SDHC PPM1D NRAS PRKAR1A NRAS TAL1 KIF1B DNMT3A PDGFB MRAP ERCC3 CDC73 PRF1 RFWD3 PMVK RPL15 FGFR1 TP53 BICC1 HNF1A GATA1 RTEL1 RPS15A ERCC4 WRAP53 NR0B1 BCR FGFR2 SEC23A KRT17 NR5A1 VHL BLM BRAF ICOS POLD1 RPS27 FASLG CYSLTR2 PTEN PRKN THPO KIF7 NRAS TAL2 BRAF WDPCP DCC MSH6 NOP10 WNT10A PSAP ERCC2 CALR ACD SLX4 ACAN HABP2 GJB4 TET2 PHF21A ERCC3 MDH2 APC PALB2 RPL10 KRT17 PGM3 IL7R ARL6IP6 APC TCIRG1 NF1 SMAD4 PTPN3 PIK3CA ABCA5 FGFR2 TGFBR2 BRCA2 HNF1A RNASEH2C PAX6 IGH TTC37 DICER1 SRY GPC6 TOP2A KIT OFD1 PALB2 NRAS MC1R SDHD TFAP2A FGFR3 TNFRSF1B REST PTEN MST1R SCN4A BRCA2 CDKN2A FGFR2 ZIC2 EFL1 ECE1 NUP214 DDB2 GPC3 KCNQ1 PTEN HNF1B FN1 ASCC1 SPIB SRP72 PTEN FANCB KCNJ10 AKT1 KRAS KEAP1 INS DISP1 PTEN SASH1 CDKN1C ACTB TNFRSF13B MYH8 EDN1 IVNS1ABP NSUN2 TSC1 RAD51C MSH3 ATP7B RET PTPN12 STIM1 DHCR7 KRAS SFTPC BMPR1A XPC TMC8 KCNJ10 KDM6B STK11 KRAS GNAQ KRAS HFE HOXD13 B3GALT6 RPL5 KAT6B GATA2 MUC5B PIK3CA USP8 GDNF SMAD4 MVK RHBDF2 SSX2 CEP57 RAD51C NEK9 JAK2 PDGFB NRAS KRT1 PIK3CA MFN2 DOCK8 PTEN IL7 SDHC ATM AKT1 BRCA1 RELA GCDH PIK3CA IDH2 HRAS CTLA4 GPR143 ERCC2 GATA2 PTPN11 IGF2 SMAD4 NDUFAF6 CDH23 RPS7 RAD54B TP53 MUTYH GLI3 PTPN11 BRIP1 CDKN1B SF3B1 PTCH1 CIB1 ERCC3 PTPN11 TRPV3 GDNF IGLL1 PRKCD CTNNB1 PIK3CA PTPN11 SLCO2A1 FAH BRCA1 ETV6 BRCA2 EPCAM TP53 EXT1 BCL10 TRPS1 BMPR1A ATM MPL KRT17 MAX SLC12A3 ADA TERT UBE2T TSC2 TCTN3 MSH2 BDNF BTK SKI RPS20 NRAS RUNX1 DCC MSH2 RPS24 WT1 TRNF TFAP2A RPL35 RPS17 SDHA RARA CDC73 SBDS POLH BRAF LAMB3 RNF6 PIEZO2 KCNQ1OT1 CCM2 PHKA2 POU2AF1 TP53 TREM2 ABCC8 EXT2 ALK PHKG2 NUTM1 SLC26A4 PTCH1 MUTYH PALLD NBN FANCA SQSTM1 ELMO2 ACP5 TWIST1 TRIM37 RPL31 HFE RET DLC1 SDHB EP300 TREX1 HSPG2 ATP7A MSH6 C2CD3 CHRNG SRP54 TINF2 BUB1 PSENEN SMAD4 NF1 ERCC3 ARID1B RMRP WAS GATA2 MAPK1 BIN1 COL7A1 EDN3 PIK3CA IGF2 H19-ICR TUBB FH MLH1 TNFSF12 PIK3R1 RASA1 F5 SH2B3 CTNNB1 FOXI1 SUFU TLR2 SRSF2 CDKN1B GJC2 OPCML LEMD3 FIBP TRNS1 HNF1A VHL PTEN PRKAR1A MSH2 CYLD CTHRC1 COL7A1 DDB2 SDHC GJB2 LIG4 MDM2 LAMA3 CHEK2 MTOR CDON SMARCE1 TAF1 GNAQ TP53 RAD54L WWOX BMPR1A CCND1 GFI1 BCL10 PTEN CTNNB1 DHX37 SLX4 FGF8 XRCC4 TRIP13 CDC73 BIRC3 NOTCH3 DIS3L2 PKD2 KIF1B GNA11 ARMC5 CREBBP DIS3L2 HRAS LMX1B BAP1 BRCA2 POT1 ABCB11 AURKA RASA1 SMARCB1 ALX4 GPC3 MGAT2 PAX3 IGHM LMNA TCF4 GATA1 TRNK IDH1 LRP5 CALR FH RET SEC23B APC TET2 SETBP1 WT1 PMS2 POLR1C SIX3 EPHB2 RPL35A RET TINF2 CD28 CYP26C1 MNX1 ALX3 KIT CPOX GJB2 DLL1 MSTO1 RSPO1 TEK EXT2 ABCC6 COL2A1 GNAS FH FASLG BAP1 COL14A1 YY1 RAG2 RB1CC1 MAP2K1 RHOH STAR CREBBP RECQL4 EVC2 HBB ERBB2 ABL1 NDP SUFU NF2 MSH6 ATP7A TSC1 FAS SLC6A17 MS4A1 NQO2 FLCN EXTL3 SOS1 RNASEL NPM1 KIT GNAI3 TRNH RAG1 HRAS BUB1B IGF2 PLAG1 FANCD2 BCL2 NEK1 KIT ATP7A PIK3CA SMARCB1 PCGF2 LIG4 BCL6 NUP214 FLNA IRF5 ACVR1 GAS1 DYNC2H1 RSPRY1 TRAF7 RNASEH2B REST RPS29 TGIF1 TERT PIGA TP53 CDK4 GPR101 ACVRL1 SAMHD1 MSL3 MAPRE2 SLC45A2 CTNNB1 ADA KLF11 NKX2-1 GLI2 PKD1 MAP3K1 SRP54 TNFSF12 ND5 CRKL RASGRP1 BCL10 RPS26 GLI3 TRNL1 AR SDHA RB1 MLH1 MC2R TGFBR1 KIT CYP11B1 AXIN2 EGFR PIK3CA RECQL4 EXOC6B SMO SFTPA2 NRAS CDKN1B TP53 PIK3CA MSH6 ACTG2 POT1 SDHB RNF6 CALR KCNN3 C11ORF95 TSC2 CD96 SOS1 COL2A1 SMAD7 GLI1 FANCF MPL CDH1 BRCA2 BRAF ATR SDHA FLCN DICER1 IL1RN ICOS AIP RSPO1 DICER1 GCM2 XRCC2 DNASE1L3 PPP2R1B TGFBR2 MTM1 CDKN2C SIX1 MEN1 POU6F2 SRD5A3 STAT3 ERCC3 TG ASXL1 CDKN2B CYLD NHP2 CCDC22 TBC1D24 BLNK DIS3L2 SH2B3 MPLKIP AHCY PCNA EXT2 EXT2 MEN1 PARN WRAP53 TP53 HBB GABRD NUMA1 APC ZSWIM6 BRCA1 GJB2 KCNAB2 AIP USF3 RUNX1 H19 HDAC4 SDHD UROD PDGFRB CR2 HRAS CDH1 ERBB2 TNPO3 LPP SDHD IL2RG ATM BARD1 TREX1 POLE C2CD3 ERCC4 SLC25A13 PNP KRAS SRSF2 SDHB FGFR3 CASR CASP10 TET2 CTC1 ENPP1 SOX6 PIK3CA BMPR1A ERCC2 TERC CBL ADAMTS3 PIGL BCR SAMD9L NOD2 CBL TGFBR2 MALT1 SEMA4A ANTXR2 SLC37A4 TBX2 DHH STS SDHB TERT KRT16 DZIP1L RTEL1 SDHD CCND1 AKT1 FOXI1 CDK4 NSD1 MLH1 FLCN DLEC1 FGFRL1 MTMR14 GCGR TBX18 CREBBP MXI1 APC BCL10 COL11A2 TERT MC1R SCN10A RPS10 SMO BRCA2 KIT ATM PRKN MRE11 KIF1B KCNH1 VHL GPR101 GNAS PMS2 ACD WDPCP MAD1L1
HP:0002088: Abnormal lung morphology
Genes 1393
CDC45 SMARCA4 TBC1D24 ELN SNX10 SLC1A4 GRHL3 CFAP298 RSPH4A EDNRB TMEM94 CARD11 LPIN2 CD3E COG4 PGM3 ECM1 GNPTAB LIMK1 HLA-DRB1 CFTR CD247 PDGFRA LMNA FBN1 NTRK1 SOS2 PSAT1 ZBTB24 GP1BB MANBA CLEC7A IL2RG TARS1 DNAAF2 NSD2 SEC24C DNAJB13 DNAAF3 EXOSC9 DYNC2LI1 NELFA EDARADD NPHP3 STING1 GDF1 COL2A1 MAP3K20 CTRC HLA-DPB1 OFD1 SMARCD2 ABCA12 ERCC6 FGF20 LZTR1 SCNN1G SLC25A24 BLNK NKX2-5 TRIP13 SOX10 GAS2L2 TYK2 HELLS TTC21B FOXH1 DNAAF6 INPPL1 ITGA8 PERP EIF2AK4 OCRL GPR35 GTF2E2 NEB FOXC2 MASP2 STAT5B COL11A2 FBXW11 MYO5A CTLA4 LBR FCGR2A PRKCD RANBP2 HYLS1 IL21R DGCR8 BMPER GATA4 NSD1 TSC2 FLCN LTBP3 CYBA SPINK5 ATP5F1A CTLA4 FLT4 TERC KCNJ6 FOXH1 TCF4 NAGLU GUSB SHROOM4 EVC LIPN RNU4ATAC TPM3 PTPN11 CDT1 MUSK HERC2 NEK1 FLNB EPG5 GAS1 FBLN5 NRAS ACP5 MCIDAS MAN2B1 TIMM8A COL13A1 BCOR MYLK PTPN22 SLC35A1 SLC46A1 HGSNAT RASGRP1 LYST ZNF341 XIAP LRRC56 FGFR1 IGH NODAL WDR19 LETM1 TRIP4 EFEMP2 NCF1 MCM4 SFTPC SOS1 STRA6 RSPH4A IL2RB RAG2 RAC1 DISP1 PHGDH WRAP53 PSMC3IP RBM10 PANK2 PEX1 TNFRSF13C GLI3 WNT3 ARID2 SBDS NPAP1 ACTA1 BLM CD40LG BRAF ICOS FASLG PRKN CCDC103 SNORD116-1 FOXP3 MEFV PTEN TDGF1 IL6R CIITA SLC2A10 CYTB ENG GLI2 FGF8 DNAJB13 CCDC39 STAT6 INVS IDUA GATA4 RPS15A NOP10 IFNG HLA-DRB1 FLNA JAG1 HABP2 VANGL1 GNPTAB MYBPC3 TBX6 MKRN3 SNORD115-1 LACC1 ELANE SMN1 DYNC2H1 KIF20A RPL10 ARHGAP31 PGM3 PEX13 CDON IL7R RAF1 SCNN1A STAG2 PLEC FLI1 CITED2 SIX3 TCIRG1 ETFA MITF MST1 ZNHIT3 LAMA2 IFT81 PDGFRB CYP4F22 DNAAF4 HLA-B FAT4 ZIC2 CALCRL KMT2E HFE CSF2RB CD55 IGH TTC37 DICER1 NFKB2 PEPD GPC6 TNFRSF13B FGF8 RAF1 ABCA3 STK36 RFX5 DPP9 RYR1 SFTPA1 SHH SKIV2L IRF1 LAT DCLRE1C SON SLC25A22 TLL1 AP3D1 TGFBR1 NODAL AGT ZMYND10 SOX18 NOS1 TPM2 BUB1B TRIP11 ERAP1 TNFRSF1B REST ZIC2 CTCF RAC2 CTLA4 PLP1 GAS1 EFL1 FMO3 TRIP4 RYR1 CIITA DLL3 AP3B1 PRTN3 PIGN TBX1 ABCA3 EFEMP2 AGA CHRND PCNT PKHD1 RSPH1 ZAP70 PAX3 NDN CHRNG NHLRC1 ACE DNAH1 KRAS IL12A KEAP1 ALDH18A1 SCNN1G ACADVL DCTN4 IRF5 TRAPPC4 CCN2 PTCH1 DKC1 GMNN TNFRSF13B GLI2 MCIDAS SCN11A ROR2 IVNS1ABP TRPV4 TSC1 FANCB ZEB2 RPL10 ODAD1 MESP2 CHST14 IL23R SLC12A6 MGP CFAP300 SMAD3 RSPH9 UMPS DHCR7 KRAS SFTPC COL13A1 SNRPN BUB3 FAM13A GAS8 WDR35 MFAP5 CACNA1B ZCCHC8 NTNG1 FLCN AK2 INPPL1 CHAT CCDC40 IL2RG CDC42 DYNC2H1 CD3G TASP1 SLC18A3 DGCR6 HOXD13 SCNN1G WT1 KAT6B WT1 MAP3K8 STAT1 ACTA1 TGFB3 MUC5B PRKAG2 SMN1 TAP1 SMAD4 ABL1 MED25 CHD7 TERT COG4 LMNA SULT2B1 GBA SPEF2 RREB1 SDR9C7 CEP57 CFI IDUA FUCA1 FLCN TBX1 HPS4 PIGT SAMD9L FLNC ESS2 NCF4 LRBA DRC1 DYNC2I2 RFXAP KIAA0586 DNAH5 DOCK8 PTEN MAN2B1 ZMPSTE24 TP53 ATM LAMC2 ACTL6A TRAF3IP2 POLR3H RELA TBX5 PARN CR2 IRF5 MED13 NUP88 GALNS TAP2 AFF4 UNG DNAAF4 RFC2 BCL11B NCF1 HPS1 CD3D RELB PTPN11 ODAD4 TDGF1 KAT6B PMM2 CYP2A6 RUNX2 POLA1 SGSH RIPPLY2 SERPINA1 WAS NDUFAF6 MMP21 SPP1 GLDN NSDHL ZFPM2 IL17F IL6ST IRAK4 KAT6B ACTL6B LRRC8A TAPBP CCNO GLI3 PLCG2 HK1 BMP15 TMEM260 MYL2 LEP ERCC3 TRPV3 IGLL1 EPM2A CCDC65 PRKCD SLC18A3 TAPT1 BMPR2 CD79B SLC7A7 FLNA FAM20C HLA-DRB1 SLCO2A1 CD46 XIAP DKC1 CYBB MYT1L CD3E AFF4 MESP2 VHL POLE BCOR FOXH1 BMP2 HYDIN TNNI3 RARA MAT2A EOGT NFIX MEFV DVL3 PTH1R BCL10 RNF168 CBL ITGA8 NEU1 KRAS CEP55 MYD88 NPM1 IGLL1 TP53 RSPO2 RRAS TRIP11 TGIF1 WAC ADA PKD1L1 UNC119 ACTA2 PSMD12 ACTA1 STRA6 PIGN GAA CD8A BCOR NEK9 TERT DHCR7 IKZF1 TSC2 LEPR SLC35A1 MUSK ARSB COG6 VPS51 COLQ WDR1 RASA2 TTC7A LTBP4 BTK GPC3 STAT3 GAS1 RUNX1 TTC12 WASHC5 INTU CD3D WT1 STAT3 BPTF CRTAP SLC2A10 COL2A1 COMT CCDC40 ASAH1 LIFR MEFV ACVRL1 MYH3 FAT4 DNAI2 LAMB3 PIEZO2 FOXE3 GRIP1 NFKB2 PIGL PTCH1 TGFBR2 ATP6V1E1 COL6A3 IL1RN PAFAH1B1 FOXH1 TP53 CRELD1 MBTPS2 RYR1 TNFRSF13B GRIP1 TGIF1 CLCN7 SP110 CC2D2A COL6A1 STN1 APC2 ITPR1 TCTN3 SMARCC2 PNP SLC11A1 GLUL PKHD1 ALPL BLM ACP5 WDR19 ASCC1 TDGF1 TFRC MGP DLL1 WNT4 IFT140 CCN2 SHH SMAD3 TGIF1 PRKAR1A EHMT1 EP300 CASP8 TGFBR1 ITGA7 AARS2 ERF DNMT3B FGFR1 IRF2BP2 CHRNG HLA-DQB1 SPAG1 SRP54 UBE2A CCNQ TINF2 BUB1 LFNG CARD11 DHCR24 ARID1B SELENON RMRP WAS NEK10 MAPK1 GATA6 SCNN1B TRIM28 DHCR24 SYT2 DOCK6 USB1 B3GLCT DLL1 CCR1 POLR3A PRPS1 HIRA RSPH1 SLC26A2 TNFSF12 PIK3R1 IER3IP1 GSN TINF2 NME8 SVBP LIG4 IL7R ALB COL11A2 COL3A1 NHLRC2 KIAA0319L TGFB1 DLL1 IFNGR1 LAMTOR2 DNAAF5 NXN CTLA4 CEP57 HLA-DRB1 MINPP1 CASP10 PTPN22 TBX20 RAB3GAP2 ALOXE3 ZIC2 NUP107 HES7 LRRC56 HLA-DQA1 KIF1A GAS8 TERT PSAP DNAI2 NOTCH2 DPM2 CD81 NODAL DNAH9 NABP1 PRKAR1A NUMA1 TBC1D23 NFKB2 DLL4 ORC6 FANCB SMARCB1 FCGR2B SIX3 GBA GATA4 MDM2 LAMA3 DSP KIF11 MLXIPL HLA-DRB1 NOTCH2 ADGRG6 DNAH5 SLC26A2 DYNC2I1 ATP6V0A2 EGFR ZBTB24 LYST ODAD4 CACNA1C CYBB RNF125 DPF2 RIT1 CITED2 RLIM WDR35 DYNC2I2 GATA6 RTEL1 IRF8 DISP1 GAS1 ABCA12 TRIP13 GPC3 ODAD3 DNAAF2 MECP2 BIRC3 SFTPB ELN CFTR NOTCH3 SCNN1A KMT2D DIS3L2 MDM4 IL17RA EPHB4 CCDC39 FBLN5 SPIDR TCF20 KLHL41 WNT3 IL17RA FCGR3A JMJD1C VPS33A UFD1 ODAD1 IKBKB CHEK2 FADD RSPH3 ZMIZ1 CREBBP TNFSF11 SCNN1B FREM2 CCR6 AGA SCNN1A ADA RAG1 RAG1 LMNA BRCA2 TGM1 TSC1 DLL1 SIX3 CARMIL2 GTF2I AKT1 CCDC65 ARID1A FGF20 RIPK4 ALG9 CFB RAG2 SCNN1G APOE SOX4 RAB27A MUC5B EWSR1 NECTIN1 ZMYND10 SGCG DNAAF6 CDON TAF1 IGHM LMNA LAMB2 LEP CSF2RA CD79A CFTR HPS6 DOK7 RCBTB1 CCBE1 FIP1L1 COQ7 SERPINF2 PWAR1 RPGR VPS33A ELN SPECC1L TET2 BTK SCNN1A RLIM IL7R EPG5 HLA-DRB1 TGFB2 PIK3CD GLA NBN HYDIN PSMB8 VAMP1 SDCCAG8 TINF2 FCGR2A SHH ARHGAP31 RAC2 CD19 DSE DDX6 HLA-B SERPINH1 GLI2 FLNA MARS1 ALMS1 SCNN1B ITCH SPAG1 DISP1 DNAAF5 IDUA TGFB2 FGF8 MSN SMARCE1 CHST14 WRN BCR FGFR3 SERPINA1 WDFY3 RAG1 PRPS1 FASLG DNASE1 NIPBL KLHL40 RAG2 MRAS RHOH ZAP70 TK2 FGFR1 CREBBP MYRF ALOX12B NOD2 RFXANK MYH11 EVC2 DYNC2LI1 ZEB2 IFIH1 RARB GBA USP9X IKBKB ABCA3 MYOD1 GATA6 CCNO CSPP1 TBCE GBA RARB NAA10 TSC1 FAS WNT4 PLCG2 ETFDH G6PC3 MS4A1 SPINK1 CD19 UBAC2 FLCN EXTL3 GUSB DYNC2I2 ATP11A NGLY1 SAMD9 NME8 TRAIP RRAS2 PYROXD1 SIK1 SLC26A2 RAG1 MYOD1 ALMS1 NKX2-5 IL21 FOXP1 PUF60 LAMTOR2 BCL2 SMAD4 TBL1XR1 ACTC1 FOXJ1 ARID1B HELLPAR SCNN1B DGCR2 DOCK3 FSHR MIF CYBC1 SNAI2 CSPP1 CCBE1 SMARCD1 IRAK1 JAK3 STAG2 PCGF2 CXCR4 LEPR DDR2 BCL6 POLA1 TRMT1 PTCH1 RPGR GATA6 CSF2RB CHRNA1 ASAH1 ASAH1 RAG2 NAB2 TERT MYSM1 BTK FRAS1 DCLRE1C BTNL2 CFTR NOP10 KNSTRN FOXJ1 PEPD TERT NR5A1 CDON MARS1 BRAF TCF3 NKX2-1 ICOS ZMPSTE24 DNAH11 OSTM1 ALG12 KATNIP AGTR1 PPP1CB BMPR2 CAV1 TGFB1 KPTN ADA TPP2 MKRN3-AS1 SLC25A1 FARSB GPC4 FUZ MYH6 HLA-DPA1 FBLN5 SRP54 TNFSF12 IGHM NEK10 RSPH3 TTC12 CRKL RASGRP1 SELENON PTPN22 DLL3 CLPB DOCK8 GLI3 HPGD THOC2 LOX RBPJ PIGN SMC1A DCLRE1C DNAL1 RIPK1 ZBTB16 CFH BTNL2 GLE1 SFTPC FOXF1 KLRC4 CCND1 CD79A EGFR TNNT2 DNAJC21 IL12A-AS1 IFT80 TSC1 CTSC USP9X MKKS SFTPA2 PIK3R1 CHRNG CITED2 TNFRSF13C ELN ADAMTS2 NR2F2 RSPO2 CFTR SCARB2 NKX2-5 SOX18 ADNP DNMT3B CCR6 TCIRG1 PAX6 STAT4 SETD2 DRC1 CFAP221 C11ORF95 TSC2 IFT172 TNFRSF13C FBN1 ARVCF RNF168 NFKBIA NFKB1 BAP1 NEPRO SLC52A3 PRSS1 SLC26A2 CLIP2 MKS1 GLI1 CRELD1 FGFR3 SFTPC FCN3 NCF2 SIM1 CD28 BAZ1B P4HTM DNAAF3 GAS2L2 CCDC103 UGP2 CEP120 GATA2 ETFB DICER1 IL6 ICOS CDCA7 CDKN2A SIX3 JAGN1 SFTPB DNASE1L3 PPP2R1B MBTPS2 CLCA4 STX1A KIAA0586 AGGF1 BNC1 POU6F2 MYH3 PHGDH STAT3 HRAS SFTPA2 DNAH11 LRRC6 SLC35C1 CDON IL17RC ASXL1 TRIM28 COL3A1 CD79B KDM6A UBB NHP2 NAA10 NCF4 CCDC22 MAGEL2 TBC1D24 PARN NRAS MTHFD1 MYH7 MIR140 BLNK LCK NFE2L2 CSF2RA MYSM1 DNAI1 MYT1L RAG2 CAV1 ZIC2 PRKG1 HACD1 MPLKIP TLL1 PIK3CA NSMCE3 IL10 PRSS2 SMPD1 IFT80 NLRC4 COL6A2 FLNB OFD1 PARN RB1 SCN9A MCTP2 FGF8 MAGEL2 FANCF CORO1A PIK3R1 PRKDC CR2 GBA EP300 TGFBR2 PIK3CD CASP8 CRLF1 PLVAP RAPSN NOTCH1 H19 PTCH1 NCF2 SH3KBP1 CR2 ERBB2 DNAAF1 AGRN RFXANK TDGF1 LGI4 GLE1 IL2RA SOX11 IL2RG MEFV ATM STAT3 ODAD3 SERPINF2 CYBC1 SNAP25 SMPD1 TRPS1 REN SHH ELP1 GLI2 CHRM3 IL2RG PNP GREB1L BACH2 SRSF2 NPHP3 CREBBP RIT1 BGN SH2D1A WIPF1 GATA6 DDR2 CTC1 FAS DYNC2I1 KITLG TBX1 TGIF1 RFX5 DCLRE1C CFAP410 GTF2IRD1 GPKOW FAS DONSON CCNQ ELN FADD SLC5A7 GDF1 ERCC2 TERC CBL ADAMTS3 TBX20 ODAD2 STAT4 SLC29A3 FOXE1 CBL FBN1 DVL3 MALT1 IFT43 DSG1 TECPR2 RTEL1 IPW NGLY1 CYBA PIEZO1 NHP2 EP300 TNFRSF11A DZIP1L CCND1 TLR4 CD81 FAM111B LRRC6 RTEL1 BCORL1 PORCN RAG1 SLC34A2 COPA DICER1 FRAS1 DNAI1 TERC MYPN NFKB1 ODAD2 ITCH TBCD ELANE NPM1 CXCR4 PWRN1 TNFRSF1A FOXP1 MYO9A DNAAF1 TGFB1 RFXAP C4A PML RAG1 TREX1 SMPD1 CREBBP SLC22A18 ELN TSC2 A2ML1 FSHR SETBP1 USB1 NADK2 MS4A1 CHAMP1 TERT NKX2-1 PTPRC SCN10A NEK8 CEP120 SMO CFI LMOD3 ELP1 NAA10 POLR2A NODAL GFI1 PLG RNF113A HSPG2 TBL2 EMG1 SFTPB STK11 SLC7A7 RSPH9 MRPS22 TERC CFAP298 WT1 CD19 RET JAK3 AICDA GLB1 GTF2H5 NIPAL4 PLOD1 MESP2 DYNC2I1 RNU4ATAC ZEB2 TANC2 ITGA3 NBN GNS FOXN1 STAT1 DISP1 B2M