Phase 2 Study of MGCD265 in Patients With Non-Small Cell Lung Cancer With Activating Genetic Alterations in MET

Study Overview
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Brief Summary
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MGCD265 is an orally administered receptor tyrosine kinase inhibitor that targets MET and other receptors. This study is a Phase 2 trial of MGCD265 in patients with locally advanced, unresectable or metastatic non-small cell lung cancer (NSCLC) that has activating genetic changes of the MET gene (mutation or amplification [increase number of gene copies]). Testing for tumor gene changes can be performed in tumor tissue or blood samples. Patients must have previously received treatment with chemotherapy. The number of patients to be enrolled will depend on how many enrolled patients experience tumor size reduction. MGCD265 will be administered orally, twice daily. The study is designed to evaluate whether the number of patients experiencing tumor size reduction is substantially higher than would be expected with other available treatments.

Detailed Description
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If testing has not already been performed, the study will provide for the testing.

Official Title
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Phase 2, Parallel-Arm Study of MGCD265 in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer With Activating Genetic Alterations in Mesenchymal-Epithelial Transition Factor

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: MGCD265


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of non-small cell lung cancer Metastatic or locally advanced disease Prior platinum chemotherapy or immunotherapy Test result showing genetic change in MET tumor gene At least one tumor that can be measured on a radiographic scan Exclusion Criteria: Prior treatment with inhibitor of MET or HGF Prior positive test for EGFR mutation or ALK gene rearrangement Uncontrolled tumor in the brain

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>MGCD265 in patients with MET activating mutations in tumor tissue | Drug: MGCD265<br>* MGCD265 is a small molecule multi-targeted receptor tyrosine kinase inhibitor<br>|
| Experimental: Arm 2<br>MGCD265 in patients with MET gene amplifications in tumor tissue | Drug: MGCD265<br>* MGCD265 is a small molecule multi-targeted receptor tyrosine kinase inhibitor<br>|
| Experimental: Arm 3<br>MGCD265 in patients with MET activating mutations in blood (circulating tumor DNA) | Drug: MGCD265<br>* MGCD265 is a small molecule multi-targeted receptor tyrosine kinase inhibitor<br>|
| Experimental: Arm 4<br>MGCD265 in patients with MET gene amplifications in blood (circulating tumor DNA) | Drug: MGCD265<br>* MGCD265 is a small molecule multi-targeted receptor tyrosine kinase inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Objective disease response is defined as the percent of patients documented by investigator assessment to have a confirmed Complete Response (CR) or Partial Response (PR) in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for target and non-target lesions as assessed by CT or MRI. CR is defined as complete disappearance of all target lesions with the exception of nodal disease; PR is defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions; Stable Disease (SD) is concluded when the response does not qualify for CR, PR or Progression; Progressive Disease (PD) is defined as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed with a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing non-target lesions. | Up to 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of Response (DR) will be defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of Objective Progression of Disease (PD) or to death due to any cause in the absence of documented PD. | From date of the first documentation of objective tumor response (CR or PR) to the first documentation of Objective Progression of Disease (PD) or to death due to any cause in the absence of documented PD, assessed up to 24 months. | 
| Progression Free Survival | Progression-free survival (PFS) will be defined as the time from date of first study treatment to first PD or death due to any cause in the absence of documented PD. Per RECIST 1.1, Progressive Disease (PD) is defined as a 20% increase in the 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, or unequivocal progression of pre-existing non-target lesions. | The time from date of first study treatment to first PD or death due to any cause in the absence of documented PD, up to 24 months. | 
| 1-Year Survival Rate | 1-Year Survival will be defined as the probability of survival at 1 year after the first dose. | From date of first study treatment to death due to any cause, assessed up to 12 months | 
| Overall Survival | Overall Survival will be defined as the time from date of first study treatment to death due to any cause | From date of first study treatment to death due to any cause, assessed up to 24 months. | 
| Number of Patients Experiencing Treatment-emergent Adverse Events | Number of patients experiencing treatment-emergent adverse events. | Date of first dose to 28 days after the last dose, up to an average of 5.1 months on treatment. | 
| Blood Plasma Concentration of MGCD265 - AUC0-6 | Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose. | Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. | 
| Blood Plasma Concentration of MGCD265 - Cmax | Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. On Cycle 2, samples were collected on Day 1 and Day 15 at pre-dose and at 6 hours post-dose (4-8 hours). Note: Assessment of Cmax and Tmax are limited by the sparse blood sampling schedule post dose (i.e., only 2 blood draws post-dose in Cycle 1 and only 1 sample collected post-dose in Cycle 2). The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose. | Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. Cycle 2, Day 1 and Day 15 at pre-dose and at 6 hours post-dose (4-8 hours). | 
| Blood Plasma Concentration of MGCD265 - Ctrough | Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. On Cycle 2, samples were collected on Day 1 and Day 15 at pre-dose and at 6 hours post-dose (4-8 hours). The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose. | Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. Cycle 2, Day 1 and Day 15 at pre-dose and at 6 hours post-dose (4-8 hours). | 
| Blood Plasma Concentration of MGCD265 - Accumulation Ratio AUC0-6 | Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose. Accumulation Ratio AUC0-6 = AUC0-6 C1D15/ AUC0-6 C1D1. | Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. | 
| Blood Plasma Concentration of MGCD265 - Accumulation Ratio Cmax | Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose. Accumulation Ration Cmax = Cmax C1D15/ Cmax C1D1. | Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. | 
| Blood Plasma Concentration of MGCD265 - Peak to Trough Ratio | Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose. Peak to trough ratio calculated as C1D15 Cmax/Ctrough. | Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. | 
| Blood Plasma Concentration of MGCD265 - Tmax | Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. Note: Assessment of Cmax and Tmax are limited by the sparse blood sampling schedule post dose (i.e., only 2 blood draws post-dose in Cycle 1 and only 1 sample collected post-dose in Cycle 2). The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose. | Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. | 
| Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Activating Mutations | Only a sub-set of patients had different molecular techniques completed, therefore a correlation analysis was not performed. Patients with positive identification by two different analytical techniques are tabulated for MET Activating Mutations. | At baseline | 
| Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Gene Amplifications | Only a sub-set of patients had different molecular techniques completed, therefore a correlation analysis was not performed. Patients with positive identification by two different analytical techniques are tabulated for MET Gene Amplifications. | At baseline | 
| Assess Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time in the Selected Population |  | At baseline and at time of confirmation of response to treatment | 
| Blood Plasma Concentration of Soluble MET (sMET) Biomarker | MET Activating Mutations in ctDNA. Change from Baseline - Cycle 2 Day 15 - Pre-Dose Standard Deviation not evaluable | Cycle 1 and Cycle 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mirati, MGCD265, NSCLC, MET