SNPMiner Trials (Home Page)
Report for Mutation G12D
Developed by Shray Alag, 2020.
SNP Clinical Trial Gene
There are 11 clinical trials
Clinical Trials
1 Pilot Study Of Safety And Feasibility Of GI-4000, An Inactivated Recombinant Saccharomyces Cerevisiae Expressing Mutant Ras Protein Combined With Adoptive Transfer And Chemoradiation in Locally Advanced Pancreatic Cancer
The purpose of this study is to determine if it is safe to add multiple immunotherapies to standard chemotherapy and radiation for treating pancreatic cancer tumors that cannot be completely removed by surgery. 1. GI-4000 Vaccination: The first involves a "vaccine," which is an injection (shot) that teaches your immune system to attack foreign invaders. The vaccine we will use is called "GI-4000" - a vaccine composed of yeast that is made to carry the same proteins (called "mutated Ras proteins") found in some pancreatic cancer cells. 2. Adoptive T-cell Transfer: The second type of immunotherapy in this study is called "adoptive T-cell transfer." This involves collecting a specific type of white blood cells from you (called "T-cells")and growing T-cells grown in a lab which may help the research participants' immune systems recover more quickly after chemotherapy, and possibly improved response to other immunotherapies. We hope that studying these agents together will teach us how to help the immune system fight pancreatic cancer.
NCT00837135 Pancreatic Cancer Other: Screening Biological: GI-4000 Vaccine Biological: GI-4000 Vaccine + Activated T Cells Biological: Surgical Evaluation after Vaccine #4 MeSH:Pancreatic Neoplasms
HPO:Neoplasm of the pancreas
1. Histologically-confirmed pancreatic adenocarcinoma that expresses one of the GI-4000-related k-ras oncoproteins (G12V, G12C, G12D, Q61L, or Q61R) 2. Locally advanced disease, (stages I-III, i.e no evidence of metastasis outside the pancreas and its regional lymph nodes). --- G12V --- --- G12C --- --- G12D ---
Primary Outcomes
Measure: To evaluate the feasibility of incorporating GI-4000 vaccine and activated T-cell infusion into a regimen of chemotherapy, radiation, and surgical resection to treat locally advanced pancreatic cancer. Time: 1 year2 Phase I - Escalating Dose Study of siG12D LODER (Local Drug EluteR) in Patients With Locally Advanced Adenocarcinoma of the Pancreas, and a Single Dose Study of siG12D LODER (Local Drug EluteR) in Patients With Non-operable Adenocarcinoma of the Pancreas
Phase 0 - Open label, Single dose study of siG12D LODER in Patients with operable adenocarcinoma of the pancreas. The primary endpoint: To assess efficacy and local distribution of siRNA out of eight high dose siG12D LODERs in patients diagnosed with operable adenocarcinoma of the pancreas. The Secondary endpoint: Short term tolerability and safety assessment Phase I - This study is designed to investigate the safety of siG12D LODER (Local Drug EluteR) in patients diagnosed with adenocarcinoma of the pancreas. The primary endpoint: To asses efficacy of siG12D LODER and local distribution in non-operable patients by histopathology measurements, local distribution by RNA analysis. To define the dose-limiting toxicities (DLT) The Secondary endpoint 1. To determine the recommended Phase II dose (RP2D) 2. To define and maximum tolerated dose (MTD) 3. In the event of surgery, assessment of siG12D LODER local distribution and efficacy will be based on histopathology measurements and RNA analysis. 4. Progression free survival - only by long term follow-up
NCT01188785 Pancreatic Ductal Adenocarcinoma Pancreatic Cancer Drug: siG12D LODER MeSH:Adenocarcinoma Pancreatic Neoplasms
HPO:Neoplasm of the pancreas
The majority of pancreatic ductal adenocarcinomas involve mutations in the KRAS oncogene (the most common is G12D), therefore stable administration of KRASG12D siRNA has the potential to silence and lead to apoptosis of such cancer cells and thereby slow and even halt the tumor growth. --- G12D ---
Primary Outcomes
Measure: Number of Participants with Adverse Events Time: Phase 0 - 6 weeks, Phase I - 2 months3 A Phase 2 Trial of Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never Smokers or Those With KRAS G12D
The purpose of this study is to test the drug Bortezomib to see how well it works. The investigators want to find out what effects, good or bad, it has on patients with a limited smoking history or who have a specific mutation associated with their lung cancer.
NCT01833143 Non-Small Cell Lung Cancer Drug: Bortezomib Drug: Acyclovir MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma
A Phase 2 Trial of Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never Smokers or Those With KRAS G12D. --- G12D ---
Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never Smokers or Those With KRAS G12D The purpose of this study is to test the drug Bortezomib to see how well it works. --- G12D ---
Inclusion Criteria: - Pathologic or cytologic evidence of non-small cell lung cancer (NSCLC) - Documented KRAS mutation - History of smoking < 100 cigarettes (never-smoker) OR patient with a KRAS G12D mutation regardless of smoking history - Clinical stage IIIB/IV or recurrent/medically inoperable NSCLC - Age ≥ 18 years - Three (3) weeks since last chemotherapy, and three (3) weeks since prior radiation therapy and recovered from treatment - Karnofsky performance status ≥ 70% - Adequate hematologic, and/or hepatic function WBC ≥ 3,000/ul or absolute neutrophil count ≥ 1,000/ul Hemoglobin ≥ 9.0 g/dl Platelet count ≥ 100,000/ul AST ≤ 2.0 X ULN (upper limit of normal) - Total bilirubin ≤1.5 x ULN Measurable indicator lesions by RECIST v1.1 criteria. --- G12D ---
- No active concurrent malignancy, with the exception of in-situ malignancy completely resected basal cell carcinoma or squamous cell carcinomas of the skin low-risk prostate cancer after curative therapy - Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial Inclusion Criteria: - Pathologic or cytologic evidence of non-small cell lung cancer (NSCLC) - Documented KRAS mutation - History of smoking < 100 cigarettes (never-smoker) OR patient with a KRAS G12D mutation regardless of smoking history - Clinical stage IIIB/IV or recurrent/medically inoperable NSCLC - Age ≥ 18 years - Three (3) weeks since last chemotherapy, and three (3) weeks since prior radiation therapy and recovered from treatment - Karnofsky performance status ≥ 70% - Adequate hematologic, and/or hepatic function WBC ≥ 3,000/ul or absolute neutrophil count ≥ 1,000/ul Hemoglobin ≥ 9.0 g/dl Platelet count ≥ 100,000/ul AST ≤ 2.0 X ULN (upper limit of normal) - Total bilirubin ≤1.5 x ULN Measurable indicator lesions by RECIST v1.1 criteria. --- G12D ---
Primary Outcomes
Description: The following evaluations will be conducted to assess the efficacy of bortezomib - radiographic response rate by RECIST v1.1. 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; Overall Response (OR) = CR + PR
Measure: Radiographic Response Rate Time: 2 yearsSecondary Outcomes
Description: Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as 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
Measure: Progression Free Survival Time: 2 yearsDescription: Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE v4.0,).
Measure: Participants Evaluated for Toxicity Time: 2 yearsMeasure: Overall Survival Time: 2 years
4 Chemotherapy in KRAS Mutated Chemotherapy Naive Non-small Cell Lung Cancer Patients: a Phase III Study Comparing Cisplatin-pemetrexed With Carboplatin-paclitaxel-bevacizumab: NVALT 22
The purpose of this study is to determine whether carboplatin-paclitaxel-bevacizumab results in a prolonged progression free survival compared to cisplatin-pemetrexed as first line treatment in patients with KRAS mutated non-small cell lung cancer.
NCT02743923 Carcinoma, Non-Small Cell Lung Drug: carboplatin Drug: paclitaxel Drug: Bevacizumab Drug: Pemetrexed Drug: cisplatin MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma
The two most common KRAS types are G12C in about 40% of cases, G12V in 18% and G12D in 15% of cases. --- G12C --- --- G12V --- --- G12D ---
Primary Outcomes
Measure: progression free survival Time: Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 monthsSecondary Outcomes
Measure: disease control rate Time: Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months.Description: Stratification for KRAS mutation (G12V versus G12C versus other)
Measure: overall survival Time: date of randomization to the date of death from any cause, assessed up to 60 months.Description: The two most common KRAS types are G12C in about 40% of cases, G12V in 18% and G12D in 15% of cases. Subgroup analyses are planned to explore treatment effect in these different KRAS mutations groups. At baseline the metastatic patterns of these subgroups will be described. KRAS mutations in NSCLC occur mainly in codon 12 and 13. Stratification for KRAS mutation (G12V versus G12C versus other) at randomization.
Measure: outcome between G12V versus G12C versus other subtypes of KRAS mutations (mutational analysis on plasma and blood platelets). Time: date of randomization to the date of death from any cause, assessed up to 60 months.Measure: response by Crabb criteria (if applicable) Time: Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months
5 Comparison of KRAS/BRAF Mutational Status Between Tumor Tissue Section Analysis With Conventional Techniques and Plasma Samples Analysis (KPLEX2)
The goal of this multicenter prospective study is to validate, and ultimately translate in routine clinical practice, the use of plasma analysis of ccfDNA for the determination of KRAS mutation status in mCRC patients.
NCT02784639 Colorectal Cancer Other: Plasma Analysis of circulating cell free DNA Other: Tumor tissue analysis of circulating cell free DNA MeSH:Colorectal Neoplasms
HPO:Neoplasm of the large intestine
As a consequence, the method was adapted to detect the six more frequent KRAS mutations in CRC (G12D, G12V, G13D, G12S, G12C, G12A) and the BRAF V600E. --- G12D ---
Primary Outcomes
Description: Area under the ROC curve of the mutation percentage obtained from plasma ccfDNA analysis
Measure: Area under ROC curve Time: 12 month6 Pilot Study of Mature Dendritic Cell Vaccination Against Mutated KRAS in Patients With Resectable Pancreatic Cancer
This research study is designed to evaluate the effects of a dendritic cell (kind of white blood cell) vaccine for pancreatic cancer.
NCT03592888 Pancreatic Ductal Adenocarcinoma Drug: mDC3/8-KRAS Vaccine MeSH:Adenocarcinoma
Inclusion Criteria: - Pathologically-confirmed KRAS(G12D-), KRAS(G12V-), KRAS(G12R-) or KRAS(G12C-mutated) pancreatic ductal adenocarcinoma who are at high risk of relapse and have no evidence of disease. --- G12D ---
Primary Outcomes
Measure: Safety and side effects of vaccine per CTCAE 4.0 Time: At time of consent through 30 days after the subject's last DC vaccineSecondary Outcomes
Measure: Immune response measuring increased numbers of peptide specific T cells as calculated by the peptide-MHC multimer assay. Time: Day 1 through week 12Measure: Disease Free Survival Time: 30 days following second vaccine through study completion approximately 12 months after the first DC vaccine
7 A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients
Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-70 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: - Get 2 chemotherapy medicines by IV over 5 days. - Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. - Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.
NCT03745326 Gastrointestinal Cancer Pancreatic Cancer Gastric Cancer Colon Cancer Rectal Cancer Drug: Cyclophosphamide Drug: Fludarabine Drug: Aldesleukin Biological: anti-KRAS G12D mTCR PBL MeSH:Gastrointestinal Neoplasms
HPO:Malignant gastrointestinal tract tumors Neoplasm of the gastrointestinal tract
A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients. --- G12D ---
Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. --- G12D ---
It is called gene transfer using anti-KRAS G12D mTCR cells. --- G12D ---
Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. --- G12D ---
-INCLUSION CRITIERIA: 1. Measurable (per RECIST v1.1 criteria), metastatic, or unresectable malignancy expressing G12D mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on resected tissue. --- G12D ---
Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D ---
Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D --- --- G12D ---
Gastrointestinal Cancer Pancreatic Cancer Gastric Cancer Colon Cancer Rectal Cancer Gastrointestinal Neoplasms Background: - We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12D-mutated variant of KRAS (and other RAS family genes) expressed by many human cancers and constructed a single retroviral vector that contains alpha and beta chains that confer recognition of this antigen when transduced into PBL. --- G12D ---
Objectives: -Primary objectives: - Phase I: Determine the safety of administering PBL transduced with anti-KRAS G12D mTCR in concert with preparative lymphodepletion and high-dose interleukin-2 (IL-2; aldesleukin). --- G12D ---
- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D ---
- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D --- --- G12D ---
Eligibility: - Patients must be/have: - Age greater than or equal to 18 years and less than or eqaul to 70 years - HLA-A*11:01 positive - Metastatic or unresectable RAS G12D-expressing cancer which has progressed after standard therapy (if available). --- G12D ---
Design: - This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. - PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D ---
Design: - This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. - PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D --- --- G12D ---
- Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12D mTCR. --- G12D ---
- On Day 0, patients will receive PBL transduced with the anti-KRAS G12D mTCR and will then begin high-dose aldesleukin. --- G12D ---
- The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. --- G12D ---
- The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. --- G12D --- --- G12D ---
Primary Outcomes
Description: Grade and type of toxicity per dose level; fraction of patients who experience a DLT at a given dose level, and number and grade of each type of DLT
Measure: Frequency and severity of treatment-related adverse events Time: From time of cell infusion to two weeks after cell infusionDescription: Percentage of patients who have a clinical response (PR + CR) to treatment (objective tumor regression)
Measure: Response rate Time: 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per PI discretion8 A Phase 1, Open-Label, Multicenter Study to Assess the Safety and Tolerability of mRNA-5671/V941 as a Monotherapy and in Combination With Pembrolizumab in Participants With KRAS Mutant Advanced or Metastatic Non-Small Cell Lung Cancer, Colorectal Cancer or Pancreatic Adenocarcinoma
This study will determine the safety and tolerability and establish a preliminary recommended Phase 2 dose of V941(mRNA-5671/V941) as a monotherapy and in combination with pembrolizumab infusion.
NCT03948763 Neoplasms Carcinoma, Non-Small-Cell Lung Pancreatic Neoplasms Colorectal Neoplasms Biological: V941 Biological: Pembrolizumab MeSH:Carcinoma, Non-Small-Cell Lung Colorectal Neoplasms Pancreatic Neoplasms Neoplasms
HPO:Neoplasm Neoplasm of the large intestine Neoplasm of the pancreas Non-small cell lung carcinoma
All - Has a histologically confirmed advanced or metastatic KRAS 4MUT+ (G12D, G12V, G13D or G12C) (4 prevalent KRAS mutant antigens in solid tumors) solid tumor identified by local laboratory testing, and who have received, or been intolerant to, or ineligible for all treatment known to confer clinical benefit. --- G12D ---
Primary Outcomes
Description: The following toxicities graded for severity using NCI Common Terminology for Adverse Events (CTCAE), Version 4.0 will be considered a DLT if judged by the investigator to be possibly related to study investigational products: 1) Grade 4 nonhematologic toxicity (ie. not a laboratory finding). 2) Grade 4 hematologic toxicity lasting ≥ 7 days, except thrombocytopenia: 3) Grade 4 thrombocytopenia of any duration 4) Grade 3 thrombocytopenia associated with clinically significant bleeding 5) Any nonhematologic AE ≥ Grade 3 in severity, with some exceptions 6) Any Grade 3 or Grade 4 nonhematologic laboratory value that meets one of the study criteria 7) Febrile neutropenia Grade 3 or Grade 4 8) Prolonged delay (> 2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 9) Any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1. 10) Grade 5 toxicity 11) Any other clinically significant toxicity judged to be a DLT by the investigator.
Measure: Dose-Limiting Toxicities (DLTs) Time: Cycle 1 (Up to 21 days)Description: Number of participants who experienced an AE. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Measure: Adverse Events (AEs) Time: Up to approximately 25 monthsDescription: Number of participants who discontinued from study due to an AE. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Measure: Discontinuations Time: Up to approximately 24 monthsSecondary Outcomes
Description: ORR is assessed by the investigator based on Response Rate Assessed by Modified Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and RECIST for immune-based therapeutics (iRECIST) following administration of V941 in combination with pembrolizumab. Objective response is a confirmed complete response (CR) or partial response (PR).
Measure: Objective Response Rate (ORR) Time: Up to approximately 24 monthsDescription: Presence of and changes in the quantity of mutant KRAS specific T cells in the blood.
Measure: Mutant KRAS Specific T cells Time: Up to approximately 24 monthsOther Outcomes
Description: T-cell receptor (TCR) clonality and diversity in the periphery and tumor.
Measure: T-cell receptor (TCR) Time: Up to approximately 24 months9 Clinical Trial Evaluating the Safety and Activity of Mutant KRAS G12V-specific TCR Transduced T Cell Therapy for Advanced Pancreatic Cancer
This clinical trial will evaluate the safety and activity of mutant KRAS G12V-specific TCR transduced T cell therapy for advanced pancreatic cancer patients who express the KRAS G12V mutation and HLA-A*11:01 allele. The theoretical basis of this study is that mutant KRAS antigen-specific TCR transduced autologous Tcells will target and kill HLA-matched mutant KRAS cancer cells but not normal cells.
NCT04146298 Pancreatic Cancer Pancreatic Neoplasms Pancreatic Ductal Adenocarcinoma Advanced Cancer Drug: Cyclophosphamide Drug: Fludarabine Biological: Mutant KRAS G12V-specific TCR transduced autologous T cells Drug: Anti-PD-1 monoclonal antibody MeSH:Pancreatic Neoplasms
HPO:Neoplasm of the pancreas
For example, TCRs that target mutant KRAS G12D peptides presented by HLA-C*08:02, and a TCR that targets a KRAS G12V peptide presented by HLA-A*11:01 have been identified. --- G12D ---
Mutant KRAS-reactive T cells appear capable of inducing tumor regression as highlighted in a patient with metastatic colorectal cancer who experienced regression of metastatic tumors after infusion of HLA-C*08:02-restricted KRAS-G12D reactive tumor-infiltrating lymphocytes (TIL). --- G12D ---
Primary Outcomes
Description: Aggregate of all adverse events, as well as their frequency and severity
Measure: Frequency and severity of treatment-related adverse events Time: 2 years following cell infusionDescription: Percentage of patients who have a clinical response to treatment (objective tumor regression)
Measure: Objective response rate Time: From the date of cell infusion to disease progression (up to 24 months after cell infusion).Secondary Outcomes
Description: The percentage of TCR transduced T cells in peripheral blood will be detected with an established flow cytometric assay.
Measure: The percentage of TCR transduced T cells in peripheral blood Time: 2, 6 and 12 weeks after cell infusion, then every 3 months, and up to 24 months after cell infusion.Description: The time between cell infusion and the death of patients
Measure: Overall survival Time: From date of cell infusion until the date of death from any cause, whichever came first, assessed up to 24 months after cell infusion.10 A Phase 1, Open Label, Dose Escalation Study of RLY-1971 in Subjects With Advanced or Metastatic Solid Tumors
This study is a multi-center, open-label, dose escalation study of RLY-1971 in subjects with advanced or metastatic solid tumors.
NCT04252339 Solid Tumor, Unspecified, Adult Drug: RLY-1971 MeSH:Neoplasms
HPO:Neoplasm
Male and female subjects of child-bearing potential are willing to use medically acceptable methods of birth control from the screening visit through 30 days after the last dose of study medication Exclusion Criteria: 1. Subjects with documented history of tumor mutations that may not be amenable to treatment with RLY-1971, including 1. KRAS mutations: G12D, G12V, G13X, and Q61X 2. BRAF V600E mutation 3. MEK mutations 2. Subjects with prior antineoplastic therapy within 3 weeks of Study Day 1, or 5 half-lives, whichever is shorter 3. Subjects with prior palliative radiotherapy within 1 week of Study Day 1 4. Subjects who have had major surgery or trauma, or incomplete recovery from surgery or trauma, within 4 weeks of Study Day 1 5. Subjects with known central nervous system (CNS) primary tumor, uncontrolled CNS metastases, or carcinomatous meningitis. --- G12D ---
Primary Outcomes
Measure: Maximum Tolerated Dose (MTD) Time: Escalation Phase - 18 month EnrollmentMeasure: Recommended Phase 2 Dose (RP2D) Time: Escalation Phase - 18 month Enrollment
Secondary Outcomes
Description: Blood samples may be taken at pre-dose, 0.5, 1, 2, 4, 6, and 8hrs on Cycle I Day 1 and 15, 24 hrs post dose on Cycle 1 Day 2, 48hrs post dose on Cycle 1 Day 3, and post dose on Cycle 2 Day 1
Measure: Plasma concentration levels of RLY-1971 Time: At the beginning of Cycle 1 & Cycle 2 (Each Cycle is 21 days)Description: Evaluation by RECIST 1.1; ORR is defined as the proportion of subjects in the response evaluable population who achieve the best overall response (BOR) of CR or PR
Measure: Objective Response Rate (ORR) Time: Through study completion (an average of one year)Description: DCR is defined as the percentage of response evaluable subjects who achieve a BOR of CR, PR or SD for at least 3 months
Measure: Disease Control Rate (DCR) Time: Through study completion (an average of one year)Other Outcomes
Description: Blood will be collected at pre-dose at baseline on Cycle 1, Day 1 (C1D1) and at 3 time points (pre-dose, 2 hours post-dose, and 4 hours post-dose) on Cycle 1, Day 15 (C1D15) to assess the extent of target engagement.
Measure: Changes in phospho-ERK levels Time: At the beginning of Cycle 1 Day 1 post and preDescription: Blood will be collected at screening and at End of Treatment on all patients
Measure: Tumor mutations by sequencing circulating tumor DNA (ctDNA) Time: At the beginning of Cycle 1 Day 1Description: DOR is defined as the time from the participant's initial objective response (CR or PR) to RLY-1971, to disease progression or death due to any cause, whichever occurs first
Measure: Duration of Response (DOR) Time: Through study completion (an average of one year)Description: TTR is defined as the period of time from the date of first the dose of RLY-1971 administration until the first objective documentation of response.
Measure: Time to Response (TTR) Time: Through study completion (an average of one year)Description: TTP is defined as the interval between the first dose of RLY-1971 until disease progression
Measure: Time to Progression (TTP) Time: Through study completion (an average of one year)Description: PFS is defined as the time from the start of study treatment to the first documented disease progression per RECIST v1.1, or death due to any cause, whichever occurs first
Measure: Progression-free Survival (PFS). Time: Through study completion (an average of one year)11 First-in-Human, Phase 1/1b, Open-label, Multicenter Study of Bifunctional EGFR/TGFβ Fusion Protein BCA101 Alone and in Combination With Pembrolizumab in Patients With EGFR-Driven Advanced Solid Tumors
The investigational drug to be studied in this protocol, BCA101, is a first-in-class compound that targets both EGFR with TGFβ. Based on preclinical data, this bifunctional antibody may exert synergistic activity in patients with EGFR-driven tumors.
NCT04429542 TNBC - Triple-Negative Breast Cancer Head and Neck Squamous Cell Carcinoma Squamous Cell Carcinoma of Anal Canal Uveal Melanoma Glioblastoma Colorectal Cancer Chordoma Squamous Cell Carcinoma of the Lung KRAS G12D KRAS G13D EGFR Amplification Epithelial Ovarian Cancer Hepatocellular Carcinoma Anaplastic Thyroid Cancer Pancreas Cancer Drug: BCA101 Drug: Pembrolizumab MeSH:Carcinoma Carcinoma, Squamous Cell Glioblastoma Triple Negative Breast Neoplasms Squamous Cell Carcinoma of Head and Neck Carcinoma, Ovarian Epithelial Pancreatic Neoplasms Chordoma Thyroid Carcinoma, Anaplastic Lung Neoplasms
HPO:Anaplastic thyroid carcinoma Carcinoma Chordoma Glioblastoma multiforme Neoplasm of the lung Neoplasm of the pancreas Squamous cell carcinoma
i Single agent BCA101 - patients with the following tumor types will be eligible: 1) Squamous Cell Lung Cancer (SqCLC) 2) Squamous Cell Carcinoma of the Head and Neck (HNSCC) 3) RAS wild-type microsatellite stable Colorectal Carcinoma (RAS WT MSS CRC) 4) Triple Negative Breast Cancer (TNBC) 5) Chordoma 6) Squamous Cell Carcinoma of the Anal Canal (SCCAC) 7) Uveal Melanoma 8) Glioblastoma (GBM) 9) Gastric Cancer 10) Any solid tumor with a KRAS G12D or G13D mutation 11) Any solid tumor with EGFR amplification 12) Epithelial Ovarian Cancer 13) Hepatocellular Carcinoma (HCC) 14) Anaplastic Thyroid Cancer (ATC) 15) Pancreatic Cancer 16) Other EGFR-driven advanced solid tumors (if there is compelling data or evidence to enroll a patient with a tumor type other than those listed in 1 - 15, the treating physician may discuss the patient with the Sponsor to determine eligibility). --- G12D ---
i Single agent BCA101 - patients with the following tumor types will be eligible: 1. PD-L1 negative, EGFR-amplified SqCLC 2. RAS WT MSS CRC 3. EGFR-amplified TNBC 4. Any solid tumor with a KRAS G12D or G13D mutation ii. --- G12D ---
TNBC - Triple-Negative Breast Cancer Head and Neck Squamous Cell Carcinoma Squamous Cell Carcinoma of Anal Canal Uveal Melanoma Glioblastoma Colorectal Cancer Chordoma Squamous Cell Carcinoma of the Lung KRAS G12D KRAS G13D EGFR Amplification Epithelial Ovarian Cancer Hepatocellular Carcinoma Anaplastic Thyroid Cancer Pancreas Cancer Carcinoma Carcinoma, Squamous Cell Glioblastoma Triple Negative Breast Neoplasms Squamous Cell Carcinoma of Head and Neck Carcinoma, Ovarian Epithelial Pancreatic Neoplasms Chordoma Thyroid Carcinoma, Anaplastic Lung Neoplasms This is a Phase 1/1b, open-label study, which consists of dose escalation parts (Part A) followed by expansion cohorts (Part B) for both single agent BCA101 and combination BCA101 plus pembrolizumab. --- G12D ---
Planned expansion cohorts for single agent BCA101 include 1) PD-L1 negative, EGFR-amplified Squamous Cell Lung Cancer (SqCLC); 2) RAS wild-type, microsatellite stable Colorectal Carcinoma (RAS wt, MSS CRC); 3) EGFR-amplified Triple Negative Breast Cancer; and 4) any solid tumor with either a KRAS G12D or G13D mutation. --- G12D ---
Primary Outcomes
Description: Incidence and severity of AEs and SAEs
Measure: Safety of BCA101 alone and BCA101 in combination with pembrolizumab: Incidence and severity of AEs and SAEs Time: 24 monthsDescription: Incidence and severity of AEs and SAEs
Measure: Tolerability of BCA101 alone and BCA101 in combination with pembrolizumab: Incidence and severity of AEs and SAEs Time: 24 monthsDescription: Incidence of DLTs during the first cycle of treatment with BCA101 monotherapy or the combination of BCA101 and pembrolizumab.
Measure: Incidence of Dose Limiting Toxicities (DLTs) Time: 21 daysSecondary Outcomes
Description: Determine objective response rate in each part of the study, per RECIST v1.1 and iRECIST
Measure: Objective Response Rate Time: 24 monthsDescription: Determine clinical benefit rate in each part of the study, per RECIST v1.1 and iRECIST
Measure: Clinical Benefit Rate Time: 24 monthsDescription: Determine PFS in each part of the study, per RECIST v1.1 and iRECIST
Measure: Progression free survival Time: 24 monthsDescription: Determine duration of response in each part of the study, per RECIST v1.1 and iRECIST
Measure: Duration of Response Time: 24 monthsDescription: Determine survival rates in each part of the study.
Measure: Overall Survival Time: 24 monthsDescription: AUC
Measure: AUC of BCA101 and pembrolizumab Time: 24 monthsDescription: Cmax
Measure: Cmax of BCA101 and pembrolizumab Time: 24 monthsDescription: Tmax
Measure: Tmax of BCA101 and pembrolizumab Time: 24 monthsDescription: Ctrough
Measure: Concentration vs time profile of BCA101 and pembrolizumab Time: 24 monthsDescription: Half-life
Measure: Half-life of BCA101 and pembrolizumab Time: 24 monthsDescription: Incidence and titer of anti-drug-antibodies
Measure: Immunogenicity of BCA101 and pembrolizumab Time: 24 months