There are 18 clinical trials

Clinical Trials

1 Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions, Including the D842V Mutation, in the PDGFRA Gene

This Phase II study is designed to evaluate the antitumor efficacy and pharmacokinetics of crenolanib (CP-868,596) in patients with D842-related mutant metastatic GIST.

NCT01243346 D842-related Mutant GIST Drug: Crenolanib besylate (CP-868,596-26), Dose: 140mg BID

MeSH:Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions, Including the D842V Mutation, in the PDGFRA Gene. --- D842V ---

To determine the response rate of patients with advanced D842V mutant GIST, when treated with Crenolanib (CP-868,596). --- D842V ---

To determine the progression free survival rate at 6 months in patients with advanced GIST with the D842V mutation in the PDGFRA gene, when treated with CP-868,596 (crenolanib).. Obtain toxicity information. --- D842V ---

To obtain additional toxicity information in patients with advanced GIST with the D842V mutation in the PDGFRA gene.. PKPD analysis. --- D842V ---

To obtain additional PK, pharmacodynamic and plasma inhibitory assay information in patients with advanced GIST with the D842V mutation in the PDGFRA gene.. Inclusion Criteria - Male or female, of any racial or ethnic group - Age 18 years or older - Life expectancy of greater than 12 weeks - Patient able and willing to provide informed consent - Normal liver function, defined as AST and ALT ≤2.5x ULN, and Total Bilirubin ≤ 2x ULN. - Total creatinine ≤ 1.5x ULN - ECOG Performance Status 0 - 2 (Appendix II) - Patients must have histologically or cytologically confirmed GIST with a D842-related mutation or deletion on the PDGFRA gene - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan. --- D842V ---

In preclinical models of cell lines with the D842V mutation in the PDGFRA gene, crenolanib (CP-868,596) blocked phosphorylation of PDGFRα at nanomolar concentrations, suggesting that it may provide a clinical benefit to patients with D842V mutant GIST. --- D842V ---

In preclinical models of cell lines with the D842V mutation in the PDGFRA gene, crenolanib (CP-868,596) blocked phosphorylation of PDGFRα at nanomolar concentrations, suggesting that it may provide a clinical benefit to patients with D842V mutant GIST. --- D842V --- --- D842V ---

In addition, crenolanib was also active in inhibiting phosphorylation of cell lines with two point mutations (double mutants) PDGFRA V561D + D842V and PDGFRA T674I + D842V. --- V561D --- --- D842V ---

In addition, crenolanib was also active in inhibiting phosphorylation of cell lines with two point mutations (double mutants) PDGFRA V561D + D842V and PDGFRA T674I + D842V. --- V561D --- --- D842V --- --- T674I --- --- D842V ---

2 A Randomized Multicenter Phase III Trial Evaluating the Interest of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)

This is a 2 arms study concerning patients with primary GIST who followed an Imatinib adjuvant treatment for 3 years after surgery and who have a high risk of recurrence. In the first arm, patients will continue Imatinib treatment for 3 more years, allowing to determine if the continuation of this treatment is efficient for disease control, in terms of Disease Free Survival improvement. In the second arm, patients will discontinue the Imatinib treatment, as standard practice. This arm will allow to determine if the re-introduction of Imatinib at relapse is still an efficient treatment for the control of disease.

NCT02260505 Gastrointestinal Stromal Tumors Resected Gastrointestinal Stromal Tumors Non-metastatic High Risk of Recurrence KIT Gene Mutation Drug: Imatinib maintenance

MeSH:Gastrointestinal Stromal Tumors Recurrence Neoplasms

HPO:Gastrointestinal stroma tumor Neoplasm

Exclusion Criteria: - Pregnant or breastfeeding women - Patient concurrently using other approved or investigational antineoplastic agents - Any contra-indication to imatinib treatment as per Glivec® SPC - Patient with GIST harboring the mutation D842V in PDGFRA - Major concurrent disease affecting cardiovascular system, liver, kidneys, haematopoietic system or else considered as clinically important by the investigator and that could be incompatible with patient's participation in this trial or would likely interfere with study procedures or results. --- D842V ---

3 Phase II Study of Ponatinib for Advanced Cancers With Genomic Alterations in Fibroblastic Growth Factor Receptor (FGFR) and Other Genomic Targets (KIT, PDGFRá, RET FLT3, ABL1)

This phase II trial studies how well ponatinib hydrochloride works in treating patients with cancer that has spread to other parts of the body (metastatic), has failed previous treatment (refractory), and has one of several alterations, or mutations, in its deoxyribonucleic acid (DNA) sequence. Ponatinib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether a patient's genetic alterations may affect how well ponatinib hydrochloride works.

NCT02272998 Malignant Neoplasm Drug: ponatinib hydrochloride Other: laboratory biomarker analysis

MeSH:Neoplasms

HPO:Neoplasm

- Patients with known ponatinib-resistant gene alterations - PDGFRA D842V mutation - cKIT D816V mutation - FLT3 D835V/Y/H/F or Y842C mutations - FGFR3 K652E mutation - Major surgery (e.g. --- D842V ---

4 A Randomised Phase II Trial of Imatinib Alternating With Regorafenib Compared to Imatinib Alone for the First Line Treatment of Advanced Gastrointestinal Stromal Tumour (GIST)

An open label randomised trial for adults with histologically confirmed measurable metastatic GIST who have received no other treatment for metastatic disease. The study aims to determine if an alternating regimen of imatinib and regorafenib has sufficient activity and safety in comparison to imatinib alone to warrant further evaluation as a first line treatment for metastatic GIST.

NCT02365441 Gastrointestinal Stromal Tumour Drug: Regorafenib Drug: imatinib

MeSH:Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

- The presence of PDGFR D842V mutation or other mutation known to cause imatinib resistance. --- D842V ---

5 Three Versus Five Years of Adjuvant Imatinib as Treatment of Patients With Operable GIST With a High Risk for Recurrence: A Randomised Phase III Study

In this study, patients who have been diagnosed with gastrointestinal stromal tumor (GIST) and have been treated with adjuvant imatinib for 3 years after surgery will be randomly allocated in a 1:1 ratio to receive imatinib (Gleevec) for 2 more years (Arm A) or to stop imatinib (Arm B). The study participants are required to have histologically verified GIST with a high risk of GIST recurrence despite removal of all macroscopic GIST tissue at surgery and 3 years of adjuvant imatinib. The high risk of GIST recurrence is defined as one of the following: gastric GIST with mitotic count >10/50 high power fields (HPFs) of the microscope, non-gastric GIST with mitotic count >5/50 HPFs, or tumor rupture. Study participants allocated to Arm A will receive imatinib 400 mg/day for 24 months after the date of randomization. All study participants will be followed up using blood tests and computerized tomography (or MRI) of the abdomen. The computerized tomography examinations will be performed at 6 month intervals. A total of 300 patients will be entered to the study. The study hypothesis is that adjuvant imatinib given for a total of 5 years may prevent some of the GISTs to recur as compared to patients who receive adjuvant imatinib for 3 years, and there may be a difference in the rate of GIST recurrence between the two groups.

NCT02413736 Sarcoma Drug: Imatinib

MeSH:Sarcoma

HPO:Sarcoma Soft tissue sarcoma

- Presence of a substitution mutation at PDGFRA codon D842 (usually D842V). --- D842V ---

6 A Phase 1 Study of BLU-285 in Patients With Gastrointestinal Stromal Tumors (GIST) and Other Relapsed and Refractory Solid Tumors

This is a Phase 1, open-label, first-in-human (FIH) study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antineoplastic activity of avapritinib (formerly BLU-285), administered orally (PO), in adult patients with unresectable GIST or other relapsed or refractory solid tumors. The study consists of 2 parts, a dose-escalation part (Part 1) and an expansion part (Part 2).

NCT02508532 Gastrointestinal Stromal Tumors (GIST) Oth Other Relapsed or Refractory Solid Tumors Drug: Avapritinib

MeSH:Gastrointestinal Stromal Tumors Neoplasms

HPO:Gastrointestinal stroma tumor Neoplasm

OR For Part 2: - Group 1: Patients must have a confirmed diagnosis of unresectable GIST that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib, or an experimental kinase-inhibitor agent, and the patient does not have a D842V mutation in PDGFRα. --- D842V ---

- Group 2: Patients must have a confirmed diagnosis of unresectable GIST with a D842V mutation in the PDGFRα gene. --- D842V ---

Patients must not have a known D842V mutation in PDGFRα. --- D842V ---

7 A Multicenter Phase 1, Open-Label Study of DCC-2618 to Assess Safety, Tolerability, and Pharmacokinetics in Patients With Advanced Malignancies

This is a Phase 1, open-label, first-in-human (FIH) dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of DCC-2618, administered orally (PO), in adult patients with advanced malignancies. The study consists of 2 parts, a dose-escalation phase and an expansion phase.

NCT02571036 Gastrointestinal Stromal Tumors Advanced Systemic Mastocytosis Advanced Cancers Drug: DCC-2618 Drug: DCC-2618

MeSH:Gastrointestinal Stromal Tumors Mastocytosis Mastocytosis, Systemic

HPO:Gastrointestinal stroma tumor Mastocytosis

Patients with de novo imatinib resistant mutations, such as but not limited to KIT D816V or PDGFRA D842V, are eligible without prior imatinib therapy. --- D816V --- --- D842V ---

8 Efficacy of Adjuvant Imatinib in Patients With Intermediate-risk Gastrointestinal Stromal Tumor With a High-risk Genomic Grade Index. Multicenter, Prospective, Randomized Study. Etude Multicentrique, Prospective, randomisée

Following the ACOSOG Z9001trial, imatinib received market authorization in Europe for patients with GIST at significant risk of relapse in the adjuvant setting, according to the classifications of Miettinen and Joensuu. Thereafter, the SSG XVIII / AI trial proved the need to revise the recommendations of the European Society for Medical Oncology regarding the optimal duration of treatment, which is currently three years. Patients at low risk of recurrence should not receive adjuvant treatment with imatinib and recommendations cannot be made from the literature data as to the indication of adjuvant treatment for patients with an intermediate risk of relapse. The provision of prognostic molecular markers in this group of so-called intermediate-risk subjects would facilitate the identification of responders to imatinib and avoid overtreating some patients and undertreating others who would benefit from Imatinib. Recently, Lagarde et al. have shown that the Genomic Index (GI = A ² / C, where A is the total number of alterations gains or losses and C is the number of chromosomes involved in these alterations in Comparative Genomic Hybridization array(CGH array)) could have prognostic value in GIST, particularly in intermediate risk GISTs. More recent work by the same author in 100 cases of GISTs with intermediate prognosis according to the classification of Miettinem identified two prognostic groups based on GI. The rate of metastatic relapse at 2 years was 30.6% in the group with GI greater than 10 versus 5.4% in the group with GI less than 10 (manuscript under preparation). Thus, it is legitimate to set up a randomized trial to study the effectiveness of adjuvant treatment with imatinib in the GIST population at intermediate risk of relapse and with a high GI. This study is a prospective randomized clinical trial: a phase III, open-label, 2 parallel groups, multicenter study. The primary objective of this study is to assess the efficacy of adjuvant Imatinib on rate of metastatic relapse at 2 years in patients with intermediate-risk gastrointestinal stromal tumor presenting a high Genomic Grade Index. The second objectives of this study are to compare the two therapeutic approaches in terms of metastasis-free survival at 1 year, 2 years and 3 years, overall survival, clinical and biological tolerance, safety and Quality of life of patients and caregivers. The eligible subjects must meet all of the following criteria : subject with a gastrointestinal stromal tumor, intermediary risk from the Armed Forces Institute of Pathology classification [Miettenen 2006], subject with Genomic Grade Index higher than 10 determined by CGH array, subject with surgery for primary tumor performed from 2 weeks to 2 months before starting adjuvant Imatinib mesylate, subject with no evidence of residual macroscopic disease after surgery and with a medical decision to prescribe imatinib. Subjects meeting any of the following criteria must not be enrolled : subject who have experienced spontaneous tumor rupture before surgery, subject whose tumor has a PDGFRA D842V mutation evidenced by sequencing from tumor Block and subject whose mutational status meets the wild phenotype definition as evidenced by sequencing from tumor Block. The Standard Group will receive adjuvant imatinib at a dose of 400 mg per day for a period of 3 years. Patients will be assessed for metastases every three months for three years with thoraco-abdominal and pelvic CT scan. The Experimental Group will receive the same thoraco-abdominal and pelvic CT scan. The estimated proportion of subjects relapsing at 2 years will be 30% in the experimental group and 2.5% in the standard group: alpha risk, 5%, power 80%. A total of 80 subjects (40 in each arm) will be included. This is a trial combining two learned societies that already are taking part in many clinical trials in France (French Sarcoma Group and French Digestive Cancer Federation). The expected benefits for patients are : not treat subjects for whom this treatment would offer too little benefit weighed against the disadvantages and treat subjects in whom this treatment would provide a real benefit and reduce the cost of treatment in patients who would not benefit from being treated by imatinib. The originality of this study is that it will include molecular data in the therapeutic decision and demonstrate the concept of individualized treatment in this patient population. This could ultimately change the current recommendations.

NCT02576080 Gastrointestinal Stromal Tumor Drug: Imatinib Other: Surveillance

MeSH:Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

Subjects meeting any of the following criteria must not be enrolled : subject who have experienced spontaneous tumor rupture before surgery, subject whose tumor has a PDGFRA D842V mutation evidenced by sequencing from tumor Block and subject whose mutational status meets the wild phenotype definition as evidenced by sequencing from tumor Block. --- D842V ---

- Subject with a contraindication to Imatinib, a known hypersensitivity to the active substance or to any of the excipients (ambivalence clause); - Subject treated with medicinal products that induce CYP3A4; - Subject who have experienced spontaneous tumor rupture before surgery (risk of spread); - Subject whose tumor has a PDGFRA D842V mutation evidenced by sequencing from tumor block; - Subject whose mutational status meets the wild phenotype definition as evidenced by sequencing from tumor block Inclusion Criteria: - Man or woman 18 years old or over and PS:0-2 - No prior radiation therapy, no prior chemotherapy, no molecular targeted or biological therapy - Subject with a gastrointestinal stromal tumor, intermediary risk from the Armed Forces Institute of Pathology classification [Miettenen 2006] - Subject with Genomic Grade Index higher than 10 determined by CGH array; - Subject with surgery for primary tumor performed from 2 weeks to 2 months before starting adjuvant Imatinib mesylate; - Subject with no evidence of residual macroscopic disease after surgery (RO). --- D842V ---

- Subject with a contraindication to Imatinib, a known hypersensitivity to the active substance or to any of the excipients (ambivalence clause); - Subject treated with medicinal products that induce CYP3A4; - Subject who have experienced spontaneous tumor rupture before surgery (risk of spread); - Subject whose tumor has a PDGFRA D842V mutation evidenced by sequencing from tumor block; - Subject whose mutational status meets the wild phenotype definition as evidenced by sequencing from tumor block Gastrointestinal Stromal Tumor Gastrointestinal Stromal Tumors null --- D842V ---

9 A Phase 1, Open-label, Dose-escalation and Expansion Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CDX-0158 in Adult Patients With KIT Positive Advanced Solid Tumors.

This is a dose-escalation Phase 1 study designed to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose, and the safety profile of CDX-0158 in patients with KIT-positive advanced solid malignancies refractory to standard therapy or for which no standard therapy exists.

NCT02642016 Advanced Cancer Biological: CDX-0158 (formerly known as KTN-0158)

If documented to have SDH deficient or PDGFRA-D842V GIST, no prior therapy is required for study entry. --- D842V ---

10 A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Crenolanib in Subjects With Advanced or Metastatic Gastrointestinal Stromal Tumors With a D842V Mutation in the PDGFRA Gene

This is a multicenter, randomized, double-blinded, placebo-controlled, trial of oral crenolanib versus oral placebo in combination with best supportive care in subjects with advanced or metastatic GIST with a D842V mutation in the PDGFRA gene. Approximately 120 subjects will be randomized in a 2:1 ratio to receive either crenolanib 100 mg or matching placebo orally (PO) 3 times daily (TID) in combination with best supportive care.

NCT02847429 GIST With D842V Mutated PDGFRA Gene Drug: Crenolanib Drug: Placebo

A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial of Crenolanib in Subjects With Advanced or Metastatic Gastrointestinal Stromal Tumors With a D842V Mutation in the PDGFRA Gene. --- D842V ---

Randomized Trial of Crenolanib in Subjects With D842V Mutated GIST This is a multicenter, randomized, double-blinded, placebo-controlled, trial of oral crenolanib versus oral placebo in combination with best supportive care in subjects with advanced or metastatic GIST with a D842V mutation in the PDGFRA gene. --- D842V ---

Randomized Trial of Crenolanib in Subjects With D842V Mutated GIST This is a multicenter, randomized, double-blinded, placebo-controlled, trial of oral crenolanib versus oral placebo in combination with best supportive care in subjects with advanced or metastatic GIST with a D842V mutation in the PDGFRA gene. --- D842V --- --- D842V ---

Inclusion Criteria: 1. Histologically or cytologically-confirmed advanced or metastatic GIST with a D842V mutation in the PDGFRA gene as determined by central laboratory testing 2. Measurable disease as per modified RECIST 1.1 • A lesion in an area that was previously treated with local therapy (e.g. --- D842V ---

chemotherapy, tyrosine kinase inhibitors, immunotherapy, or investigational agents) or investigational device within 3 weeks or 5 half-lives (if the drug's half-life in subject is known) prior to randomization, whichever is shorter Inclusion Criteria: 1. Histologically or cytologically-confirmed advanced or metastatic GIST with a D842V mutation in the PDGFRA gene as determined by central laboratory testing 2. Measurable disease as per modified RECIST 1.1 • A lesion in an area that was previously treated with local therapy (e.g. --- D842V ---

chemotherapy, tyrosine kinase inhibitors, immunotherapy, or investigational agents) or investigational device within 3 weeks or 5 half-lives (if the drug's half-life in subject is known) prior to randomization, whichever is shorter GIST With D842V Mutated PDGFRA Gene null --- D842V ---

11 A Phase I Study to Assess the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Properties of Oral HQP1351 in Patients With GIST or Other Solid Tumors.

This study is a Multi-center, Open-label Phase 1 Study to Determine the Recommend Phase 2 Dose (RP2D) and Evaluate PK/PD and preliminary Efficacy of HQP1351 in Patients With GIST or Other Solid Tumors.

NCT03594422 Gastrointestinal Stromal Tumor (GIST) Solid Tumor, Adult Drug: HQP1351

MeSH:Gastrointestinal Stromal Tumors Neoplasms

HPO:Gastrointestinal stroma tumor Neoplasm

Among them, GIST patients are required primary imatinib resistance (PDGFRA D842V mutation or NF1 mutation) or failed to previous treatment with imatinib or imatinib and at least one other TKI. 3. ECOG≤ 2. 4. Estimated survival at least 3 months. --- D842V ---

12 Compassionate Use of Crenolanib for Cancers With Platelet Derived Growth Factor Receptor Alpha (PDGFRa) Mutations, PDGFRa Amplifications or Fms-like Tyrosine Kinase 3 (FLT3) Mutations

Compassionate use of crenolanib for patients with serious life-threatening illness that have exhausted all available therapies used to treat the disease, with no other viable therapy options, who is not eligible for clinical trials. This program is designed to evaluate the requests on a patient by patient basis. Patients must have documented evidence of a point mutation in position 842 in platelet derived growth factor receptor alpha (PDGFRA-D842V) or amplification of PDGFRA or internal tandem duplication within the FMS-like tyrosine kinase 3 (FLT3-ITD) or point mutations within the tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD)

NCT03620318 FLT3-ITD Mutation FLT3/TKD Mutation PDGFR-Alpha D842V PDGFRA Gene Amplification Drug: Crenolanib besylate

Patients must have documented evidence of a point mutation in position 842 in platelet derived growth factor receptor alpha (PDGFRA-D842V) or amplification of PDGFRA or internal tandem duplication within the FMS-like tyrosine kinase 3 (FLT3-ITD) or point mutations within the tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) Inclusion Criteria: - Subject must have a serious life threatening cancer with FLT3/PDGFRa mutation or PDGFRa amplification who has exhausted all other treatment options - Subject and their partner (if adults) must use 2 forms of contraception during study and for 3 months following last dose of study drug Exclusion Criteria: - Subject is eligible for enrollment in an ongoing clinical trial - Subject has any condition which, in the investigator's opinion makes the subject unsuitable for participation Inclusion Criteria: - Subject must have a serious life threatening cancer with FLT3/PDGFRa mutation or PDGFRa amplification who has exhausted all other treatment options - Subject and their partner (if adults) must use 2 forms of contraception during study and for 3 months following last dose of study drug Exclusion Criteria: - Subject is eligible for enrollment in an ongoing clinical trial - Subject has any condition which, in the investigator's opinion makes the subject unsuitable for participation FLT3-ITD Mutation FLT3/TKD Mutation PDGFR-Alpha D842V PDGFRA Gene Amplification This program is being offered on a patient by patient basis while phase 3 studies with crenolanib are ongoing. --- D842V ---

Patients must have documented evidence of a point mutation in position 842 in platelet derived growth factor receptor alpha (PDGFRA-D842V) or amplification of PDGFRA or internal tandem duplication within the FMS-like tyrosine kinase 3 (FLT3-ITD) or point mutations within the tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) Inclusion Criteria: - Subject must have a serious life threatening cancer with FLT3/PDGFRa mutation or PDGFRa amplification who has exhausted all other treatment options - Subject and their partner (if adults) must use 2 forms of contraception during study and for 3 months following last dose of study drug Exclusion Criteria: - Subject is eligible for enrollment in an ongoing clinical trial - Subject has any condition which, in the investigator's opinion makes the subject unsuitable for participation Inclusion Criteria: - Subject must have a serious life threatening cancer with FLT3/PDGFRa mutation or PDGFRa amplification who has exhausted all other treatment options - Subject and their partner (if adults) must use 2 forms of contraception during study and for 3 months following last dose of study drug Exclusion Criteria: - Subject is eligible for enrollment in an ongoing clinical trial - Subject has any condition which, in the investigator's opinion makes the subject unsuitable for participation FLT3-ITD Mutation FLT3/TKD Mutation PDGFR-Alpha D842V PDGFRA Gene Amplification This program is being offered on a patient by patient basis while phase 3 studies with crenolanib are ongoing. --- D842V --- --- D842V ---

13 Early Access Program (EAP) for Avapritinib in Patients With Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST)

This is a US, multicenter, open-label expanded access program to provide access to avapritinib until such time that avapritinib becomes available through other mechanisms or the Sponsor chooses to discontinue the program.

NCT03862885 GIST Drug: Avapritinib

4. Patient has received 3 or more TKI therapies including imatinib, or the patient has GIST that carries a mutation in exon 18 of the PDGFRA gene (such as D842V). 5. --- D842V ---

14 Efficacy and Safety of Anlotinib in Patients With Advanced Gastrointestinal Stromal Tumor After Failure of Imatinib: a Prospective, Single Arm and Multicenter Trial

Gastrointestinal stromal tumors (GIST) compose approximately 20% of soft tissue sarcomas with an annual incidence of approximately 7 per million population. GISTs occur throughout the GI tract, most commonly in the stomach or small intestine. The main treatment for localised GIST is surgical resection. At least 40% of these patients will develop recurrence or metastasis following complete resection. Local recurrence, liver metastases and/or dissemination within the abdominal cavity are the most common clinical manifestations. Although imatinib and sunitinib has greatly improved the quality of life and survival of patients with advanced GIST. Analysis of clinical trials revealed that patients with tumours with KIT exon 17 or 18 mutations, with a second mutation in KIT exon 17 or 18, had worse responses to imatinib and sunitinib. Some patients with PDGFRA D842V mutation do not respond to the present standard therapies. Anlotinib (1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-Yl] oxy] methyl]cyclopropanamine dihydrochloride) , a multi-targeted tyrosine kinase inhibitor (TKI), characterized as a highly selective and potent c-KIT, VEGFR, PDGFR, FGFR inhibitor. In vitro and in vivo, Anlotinib has a broad spectrum of inhibitory action on tumor angiogenesis and growth, which showed broad activity against soft tissue sarcoma and GIST with D842V, D816H, V560G and V654A mutations. In 2015, the US FDA granted orphan drug treatment for ovarian cancer.

NCT04106024 Gastrointestinal Stromal Tumors Drug: Anlotinib

MeSH:Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

Some patients with PDGFRA D842V mutation do not respond to the present standard therapies. --- D842V ---

In vitro and in vivo, Anlotinib has a broad spectrum of inhibitory action on tumor angiogenesis and growth, which showed broad activity against soft tissue sarcoma and GIST with D842V, D816H, V560G and V654A mutations. --- D842V ---

15 A Multicentre, Comparative, Placebo-controlled, Double-blinded, Phase II Study of the Efficacy of Lenvatinib in Patients With Locally Advanced or Metastatic GIST After Failure of Imatinib and Sunitinib

The primary objective is to compare the efficacy of lenvatinib plus Best Supportive Care versus Placebo plus Best Supportive Care in the treatment of patients with advanced GIST, after failure of imatinib and sunitinib.

NCT04193553 Gastro Intestinal Stromal Tumour Drug: Lenvatinib Drug: Placebo Other: Best supportive care

MeSH:Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

Patient with a documented mutation in PDGFRA exon 18 (D842V substitution). --- D842V ---

16 A Phase I/II Clinical Study of Avapritinib in Chinese Subjects With Unresectable or Metastatic Gastrointestinal Stromal Tumor

This study is an open-label, multicenter, phase I/II study to evaluate the safety, PK and clinical efficacy of avapritinib in Chinese subjects with unresectable or metastatic GIST. The study consists of two parts: dose escalation (phase I) and dose expansion (phase II).

NCT04254939 Gastrointestinal Stromal Tumors Drug: CS3007 (BLU-285)

MeSH:Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

For phase I study, the subject must have histologically or cytologically confirmed unresectable or metastatic GIST that progressed after imatinib and at least one additional TKI treatment, or who cannot tolerate the standard treatment or have D842V mutation in the PDGFRα gene. --- D842V ---

2. For phase II study: i) Group 1: Chinese subjects with unresectable GIST harboring D842V mutation in PDGFRα gene. --- D842V ---

Patients must not have a known D842V mutation in PDGFRα gene. --- D842V ---

17 A Phase II, Single Arm Study of Avelumab In Combination With Axitinib in Patients With Unresectable/Metastatic Gastrointestinal Stromal Tumor After Failure of Standard Therapy - AXAGIST

To assess anti-tumor activity of avelumab in combination with axitinib in patients with unresectable/metastatic GIST after progression on second or third line treatment (after failure on at least of imatinib and sunitinib) in terms of progression-free survival (PFS)

NCT04258956 Gastrointestinal Stromal Tumors Drug: Axitinib

MeSH:Gastrointestin Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

- Patients with PDGFRA D842V mutations are not eligible for this study. --- D842V ---

18 Phase 1, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Subjects With Advanced Gastrointestinal Stromal Tumor

This study will assess the safety, efficacy, and pharmacokinetics of DS-6157a in participants with advanced gastrointestinal stromal tumors (GIST).

NCT04276415 Gastrointestinal Stromal Tumors Drug: DS-6157a

MeSH:Gastrointestinal Stromal Tumors

HPO:Gastrointestinal stroma tumor

Inclusion Criteria: - Written informed consent - At least 20 years old in Japan or 18 years old in other countries at the time of signature of the informed consent form (ICF), following local regulatory requirements - Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 - Has histopathologically documented unresectable and/or metastatic GIST meeting the criteria below: - Dose Escalation (Part 1): Participants should meet one of the following criteria: 1. (For US sites only) Participants with GIST who have progressed on or are intolerant to imatinib (IM) and at least one post-IM treatment or who are not candidates for post-IM standard of care treatment 2. (For Japan sites only) Participants with GIST who have received all the existing standard of care treatments or who are not candidates for one or more available post-IM standard of care treatments 3. Participants with GIST who are not candidates for IM or curative intent surgical treatment (i.e., participants without activating KIT or platelet-derived growth factor receptor alpha (PDGFRa) mutations, with PDGFRa D842V mutations, or are KIT negative by local results) - Dose Expansion (Part 2) Cohort 1: Participants with GIST who have progressed on or are intolerant to IM and at least one post-IM treatment - Dose Expansion (Part 2) Cohort 2: Participants with GIST who have progressed on IM and had not received a post-IM treatment (2nd line) - Consents to provide fresh tumor biopsy tissue samples both before and on DS-6157a treatment for the measurement of GPR20 levels by immunohistochemistry and other biomarkers - Has a left ventricular ejection fraction (LVEF) ≥50% by either echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within 28 days before study treatment - Has at least 1 measurable lesion based on RECIST Version 1.1 as assessed by the Investigator - Has adequate organ function within 7 days before the start of study treatment, defined as: 1. Platelet count ≥100,000/mm^3 2. Hemoglobin ≥8.5 g/dL 3. Absolute neutrophil count ≥1,500/mm^3 4. Creatinine clearance ≥50 mL/min 5. Aspartate aminotransferase ≤3 × upper limit of normal (ULN) (if liver metastases are present, ≤5 × ULN) 6. Alanine aminotransferase ≤3 × ULN (if liver metastases are present, ≤5 × ULN) 7. Total bilirubin ≤1.5 × ULN or ≤3.0 × ULN for participants with documented history of Gilbert's Syndrome - Has an adequate treatment washout period prior to start of study treatment, defined as: 1. Major surgery: ≥4 weeks (or 2 weeks for minor surgeries) 2. Radiation therapy: ≥3 weeks (or 2 weeks for palliative radiation excluding pelvic radiation) 3. Systemic anti-cancer therapy (except for anti-androgen for prostate cancer and bisphosphonate, denosumab, or medroxyprogesterone acetate for bone metastases): - Cytotoxic chemotherapy: ≥3 weeks or 5 times the terminal elimination half-life (t½) of the chemotherapeutic agent, whichever is shorter - Antibody and antibody-conjugates therapy: ≥3 weeks or 5 times the t½, whichever is longer - Prior tyrosine kinase inhibitors (TKIs): washout period from 2 to 21 days depending on the TKI - Immunotherapy: ≥4 weeks. --- D842V ---

- Has evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, as manifest by the detectable viral load (HBV-DNA or HCV-RNA, respectively) - Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will also be excluded), or pregnant as confirmed by pregnancy tests performed within 7 days before study treatment - Women who plan to become pregnant while in the study and for at least 7 months after the last administration of study treatment - Men who plan to father a child while in the study and for at least 4 months after the last administration of study treatment - Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, substance abuse, or other medical condition that would increase the risk of toxicity or interfere with participation of the participant or evaluation of the clinical study Inclusion Criteria: - Written informed consent - At least 20 years old in Japan or 18 years old in other countries at the time of signature of the informed consent form (ICF), following local regulatory requirements - Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 - Has histopathologically documented unresectable and/or metastatic GIST meeting the criteria below: - Dose Escalation (Part 1): Participants should meet one of the following criteria: 1. (For US sites only) Participants with GIST who have progressed on or are intolerant to imatinib (IM) and at least one post-IM treatment or who are not candidates for post-IM standard of care treatment 2. (For Japan sites only) Participants with GIST who have received all the existing standard of care treatments or who are not candidates for one or more available post-IM standard of care treatments 3. Participants with GIST who are not candidates for IM or curative intent surgical treatment (i.e., participants without activating KIT or platelet-derived growth factor receptor alpha (PDGFRa) mutations, with PDGFRa D842V mutations, or are KIT negative by local results) - Dose Expansion (Part 2) Cohort 1: Participants with GIST who have progressed on or are intolerant to IM and at least one post-IM treatment - Dose Expansion (Part 2) Cohort 2: Participants with GIST who have progressed on IM and had not received a post-IM treatment (2nd line) - Consents to provide fresh tumor biopsy tissue samples both before and on DS-6157a treatment for the measurement of GPR20 levels by immunohistochemistry and other biomarkers - Has a left ventricular ejection fraction (LVEF) ≥50% by either echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within 28 days before study treatment - Has at least 1 measurable lesion based on RECIST Version 1.1 as assessed by the Investigator - Has adequate organ function within 7 days before the start of study treatment, defined as: 1. Platelet count ≥100,000/mm^3 2. Hemoglobin ≥8.5 g/dL 3. Absolute neutrophil count ≥1,500/mm^3 4. Creatinine clearance ≥50 mL/min 5. Aspartate aminotransferase ≤3 × upper limit of normal (ULN) (if liver metastases are present, ≤5 × ULN) 6. Alanine aminotransferase ≤3 × ULN (if liver metastases are present, ≤5 × ULN) 7. Total bilirubin ≤1.5 × ULN or ≤3.0 × ULN for participants with documented history of Gilbert's Syndrome - Has an adequate treatment washout period prior to start of study treatment, defined as: 1. Major surgery: ≥4 weeks (or 2 weeks for minor surgeries) 2. Radiation therapy: ≥3 weeks (or 2 weeks for palliative radiation excluding pelvic radiation) 3. Systemic anti-cancer therapy (except for anti-androgen for prostate cancer and bisphosphonate, denosumab, or medroxyprogesterone acetate for bone metastases): - Cytotoxic chemotherapy: ≥3 weeks or 5 times the terminal elimination half-life (t½) of the chemotherapeutic agent, whichever is shorter - Antibody and antibody-conjugates therapy: ≥3 weeks or 5 times the t½, whichever is longer - Prior tyrosine kinase inhibitors (TKIs): washout period from 2 to 21 days depending on the TKI - Immunotherapy: ≥4 weeks. --- D842V ---

HPO Nodes