Non-Small Cell Lung Cancer
Conditions
Keywords
Mirati, MGCD265, MET, NSCLC
Brief summary
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
If testing has not already been performed, the study will provide for the testing.
Interventions
DRUGMGCD265
MGCD265 is a small molecule multi-targeted receptor tyrosine kinase inhibitor
Sponsors
Mirati Therapeutics Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Up to 3 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 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. | 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. |
| 1-Year Survival Rate | From date of first study treatment to death due to any cause, assessed up to 12 months | 1-Year Survival will be defined as the probability of survival at 1 year after the first dose. |
| Overall Survival | From date of first study treatment to death due to any cause, assessed up to 24 months. | Overall Survival will be defined as the time from date of first study treatment to death due to any cause |
| 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. | Number of patients experiencing treatment-emergent adverse events. |
| Blood Plasma Concentration of MGCD265 - AUC0-6 | 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 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. |
| Blood Plasma Concentration of MGCD265 - Cmax | 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 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. |
| Blood Plasma Concentration of MGCD265 - 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. Cycle 2, Day 1 and Day 15 at pre-dose and at 6 hours post-dose (4-8 hours). | 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. |
| Duration of Response | 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. | 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. |
| Blood Plasma Concentration of MGCD265 - Accumulation Ratio Cmax | 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 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. |
| Blood Plasma Concentration of MGCD265 - Peak to Trough Ratio | 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 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. |
| Blood Plasma Concentration of MGCD265 - Tmax | 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 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. |
| Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Activating Mutations | At baseline | 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. |
| Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Gene Amplifications | At baseline | 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. |
| 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 | Cycle 1 and Cycle 2 | MET Activating Mutations in ctDNA. Change from Baseline - Cycle 2 Day 15 - Pre-Dose Standard Deviation not evaluable |
| Blood Plasma Concentration of MGCD265 - Accumulation Ratio AUC0-6 | 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 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. |
Countries
Australia, Canada, Hungary, Italy, Poland, South Korea, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Sponsor approval of each potential patient's genetic testing following prescreening, whether performed by the study central lab or a Sponsor-approved local lab, was filed prior to proceeding to full clinical screening. All patients considered eligible for the study following clinical screening were submitted to Sponsor for registration approval.
Participants by arm
| Arm | Count |
|---|---|
| MET Activating Mutations in Tumor Tissue MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with MET activating mutations in tumor tissue. | 28 |
| MET Gene Amplifications in Tumor Tissue MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with MET gene amplifications in tumor tissue. | 20 |
| MET Activating Mutations in ctDNA MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with MET activating mutations in the blood (circulating tumor DNA). | 8 |
| MET Gene Amplifications in ctDNA MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with MET gene amplifications in the blood (circulating tumor DNA). | 12 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Survival Follow-up Period | Death | 12 | 14 | 3 | 9 |
| Survival Follow-up Period | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Survival Follow-up Period | Study Terminated by Sponsor | 12 | 4 | 2 | 3 |
| Survival Follow-up Period | Withdrawal by Subject | 4 | 0 | 1 | 0 |
| Treatment Period | Adverse Event | 7 | 4 | 0 | 5 |
| Treatment Period | Clinical Disease Progression | 0 | 0 | 0 | 1 |
| Treatment Period | Death | 0 | 0 | 1 | 0 |
| Treatment Period | Global Deterioration of Health | 3 | 3 | 0 | 1 |
| Treatment Period | Lack of Efficacy | 17 | 11 | 5 | 5 |
| Treatment Period | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Treatment Period | Non-compliance | 0 | 0 | 1 | 0 |
| Treatment Period | Patient Still on Treatment/Study | 0 | 1 | 1 | 0 |
| Treatment Period | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | MET Gene Amplifications in ctDNA | MET Activating Mutations in Tumor Tissue | MET Gene Amplifications in Tumor Tissue | MET Activating Mutations in ctDNA | Total |
|---|---|---|---|---|---|
| Age, Customized Mean (STD) | 64.8 years STANDARD_DEVIATION 11.09 | 70.7 years STANDARD_DEVIATION 6.02 | 61.8 years STANDARD_DEVIATION 13.17 | 59.1 years STANDARD_DEVIATION 7.7 | 65.7 years STANDARD_DEVIATION 10.51 |
| Body Mass Index | 21.80 kg/m^2 STANDARD_DEVIATION 4.18 | 25.16 kg/m^2 STANDARD_DEVIATION 4.58 | 24.92 kg/m^2 STANDARD_DEVIATION 4.46 | 22.24 kg/m^2 STANDARD_DEVIATION 2.34 | 24.24 kg/m^2 STANDARD_DEVIATION 4.49 |
| Current Stage Locally Advanced | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Current Stage Metastatic | 11 Participants | 27 Participants | 19 Participants | 8 Participants | 65 Participants |
| ECOG Performance Status 0 | 2 Participants | 10 Participants | 6 Participants | 2 Participants | 20 Participants |
| ECOG Performance Status 1 | 6 Participants | 16 Participants | 12 Participants | 6 Participants | 40 Participants |
| ECOG Performance Status 2 | 4 Participants | 2 Participants | 2 Participants | 0 Participants | 8 Participants |
| ECOG Performance Status 3 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| ECOG Performance Status 4 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 28 Participants | 20 Participants | 7 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 167.70 cm STANDARD_DEVIATION 8.98 | 168.63 cm STANDARD_DEVIATION 9.74 | 173.18 cm STANDARD_DEVIATION 8.77 | 161.11 cm STANDARD_DEVIATION 8.1 | 169.43 cm STANDARD_DEVIATION 9.52 |
| Primary Disease Histology Adenocarcinoma | 6 Participants | 22 Participants | 18 Participants | 7 Participants | 53 Participants |
| Primary Disease Histology Large Cell Carcinoma | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Primary Disease Histology Other | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 5 Participants |
| Primary Disease Histology Squamous Cell Carcinoma | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 8 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 4 Participants | 6 Participants | 2 Participants | 14 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 21 Participants | 13 Participants | 6 Participants | 50 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 6 Participants | 2 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 21 Participants | 13 Participants | 6 Participants | 50 Participants |
| Region of Enrollment Australia | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Region of Enrollment Hungary | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Italy | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Poland | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Region of Enrollment South Korea | 2 Participants | 2 Participants | 6 Participants | 0 Participants | 10 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 7 Participants | 23 Participants | 10 Participants | 5 Participants | 45 Participants |
| Sex: Female, Male Female | 6 Participants | 16 Participants | 4 Participants | 6 Participants | 32 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 16 Participants | 2 Participants | 36 Participants |
| Smoking History Current Smoker | 3 Participants | 0 Participants | 4 Participants | 1 Participants | 8 Participants |
| Smoking History Lifetime Non-Smoker | 2 Participants | 10 Participants | 2 Participants | 3 Participants | 17 Participants |
| Smoking History Past Smoker | 7 Participants | 18 Participants | 14 Participants | 4 Participants | 43 Participants |
| Weight | 61.58 kg STANDARD_DEVIATION 13.56 | 70.85 kg STANDARD_DEVIATION 17.64 | 75.33 kg STANDARD_DEVIATION 17.77 | 60.97 kg STANDARD_DEVIATION 8.68 | 69.37 kg STANDARD_DEVIATION 16.85 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 28 | 14 / 20 | 3 / 8 | 9 / 12 | 38 / 68 |
| other Total, other adverse events | 28 / 28 | 20 / 20 | 7 / 8 | 12 / 12 | 67 / 68 |
| serious Total, serious adverse events | 12 / 28 | 10 / 20 | 4 / 8 | 7 / 12 | 33 / 68 |
Outcome results
Primary
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.
Time frame: Up to 3 months
Population: Modified Intent-to-Treat (mITT) Population defined as all patients who received at least one dose of MGCD265
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MET Activating Mutations in Tumor Tissue | Objective Response Rate | 10.7 percentage of participants |
| MET Gene Amplifications in Tumor Tissue | Objective Response Rate | 15.0 percentage of participants |
| MET Activating Mutations in ctDNA | Objective Response Rate | 25.0 percentage of participants |
| MET Gene Amplifications in ctDNA | Objective Response Rate | 0.0 percentage of participants |
p-value: 0.9495% CI: [2.27, 28.23]exact test
p-value: 0.7995% CI: [3.21, 37.89]exact test
p-value: 0.4795% CI: [3.19, 65.09]Exact Test
p-value: >0.99995% CI: [0, 26.46]Exact test
Secondary
1-Year Survival Rate
1-Year Survival will be defined as the probability of survival at 1 year after the first dose.
Time frame: From date of first study treatment to death due to any cause, assessed up to 12 months
Population: Modified Intent-to-Treat (mITT) Population defined as all patients who received at least one dose of MGCD265
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MET Activating Mutations in Tumor Tissue | 1-Year Survival Rate | 50.47 percentage |
| MET Gene Amplifications in Tumor Tissue | 1-Year Survival Rate | 34.92 percentage |
| MET Activating Mutations in ctDNA | 1-Year Survival Rate | 54.69 percentage |
| MET Gene Amplifications in ctDNA | 1-Year Survival Rate | 13.89 percentage |
Secondary
Assess Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time in the Selected Population
Time frame: At baseline and at time of confirmation of response to treatment
Population: The study was closed early due to sponsor portfolio prioritization and not due to any patient safety issues. Based on limited individual patient data for whom baseline and post-treatment values were available, the statistical analyses as planned could not be performed. Screening and end of treatment detection results provided.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MET Activating Mutations in Tumor Tissue | Assess Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time in the Selected Population | Detected at Screening | 2 participants |
| MET Activating Mutations in Tumor Tissue | Assess Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time in the Selected Population | Detected at End of Treatment | 2 participants |
| MET Gene Amplifications in Tumor Tissue | Assess Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time in the Selected Population | Detected at Screening | 2 participants |
| MET Gene Amplifications in Tumor Tissue | Assess Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time in the Selected Population | Detected at End of Treatment | 1 participants |
Secondary
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.
Time frame: At baseline
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Activating Mutations | Positive by both PCR and NGS | 9 Participants |
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Activating Mutations | Positive by PCR and Negative by NGS | 1 Participants |
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Activating Mutations | Negative by PCR and Positive by NGS | 1 Participants |
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Activating Mutations | Negative by both PCR and NGS | 0 Participants |
Secondary
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.
Time frame: At baseline
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Gene Amplifications | Positive by both FISH and NGS | 8 Participants |
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Gene Amplifications | Positive by FISH and Negative by NGS | 6 Participants |
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Gene Amplifications | Negative by FISH and Positive by NGS | 7 Participants |
| MET Activating Mutations in Tumor Tissue | Assess Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA) - MET Gene Amplifications | Negative by both FISH and NGS | 0 Participants |
Secondary
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.
Time frame: 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.
Population: PK Analysis Set consisted of all patients who received at least one dose of active study drug and had sufficient data to assess any of the PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Accumulation Ratio AUC0-6 | 6.42 ratio | Geometric Coefficient of Variation 87.2 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of MGCD265 - Accumulation Ratio AUC0-6 | 9.88 ratio | Geometric Coefficient of Variation 96.4 |
Secondary
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.
Time frame: 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.
Population: PK Analysis Set consisted of all patients who received at least one dose of active study drug and had sufficient data to assess any of the PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Accumulation Ratio Cmax | 4.07 ratio | Geometric Coefficient of Variation 79.7 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of MGCD265 - Accumulation Ratio Cmax | 5.35 ratio | Geometric Coefficient of Variation 100.9 |
Secondary
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.
Time frame: 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.
Population: PK Analysis Set consisted of all patients who received at least one dose of active study drug and had sufficient data to assess any of the PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of MGCD265 - AUC0-6 | 250.8 h*ng/mL | Geometric Coefficient of Variation 98 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of MGCD265 - AUC0-6 | 1565 h*ng/mL | Geometric Coefficient of Variation 54 |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of MGCD265 - AUC0-6 | 185.5 h*ng/mL | Geometric Coefficient of Variation 98.8 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of MGCD265 - AUC0-6 | 1837 h*ng/mL | Geometric Coefficient of Variation 51.3 |
Secondary
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.
Time frame: 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).
Population: PK Analysis Set consisted of all patients who received at least one dose of active study drug and had sufficient data to assess any of the PK parameters. No results are reported for C2D15 because the number of observations were less than 3 for the 1050 mg BID (Soft Gel Capsule).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Cmax | 69.77 ng/mL | Geometric Coefficient of Variation 87.1 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Cmax | 279.2 ng/mL | Geometric Coefficient of Variation 54.6 |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of MGCD265 - Cmax | 60.49 ng/mL | Geometric Coefficient of Variation 103.9 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of MGCD265 - Cmax | 328.1 ng/mL | Geometric Coefficient of Variation 49.8 |
| Tablet 750 mg BID C2D1 | Blood Plasma Concentration of MGCD265 - Cmax | 214 ng/mL | Geometric Coefficient of Variation 69.4 |
| Tablet 750 mg BID C2D15 | Blood Plasma Concentration of MGCD265 - Cmax | 138 ng/mL | Geometric Coefficient of Variation 100 |
| Soft Gel 1050 mg BID C2D1 | Blood Plasma Concentration of MGCD265 - Cmax | 386 ng/mL | Geometric Coefficient of Variation 13.9 |
Secondary
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.
Time frame: 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).
Population: PK Analysis Set consisted of all patients who received at least one dose of active study drug and had sufficient data to assess any of the PK parameters. No results are reported for C2D15 because the number of observations were less than 3 for the 1050 mg BID (Soft Gel Capsule).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Ctrough | 264 ng/mL | Geometric Coefficient of Variation 52.5 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of MGCD265 - Ctrough | 337 ng/mL | Geometric Coefficient of Variation 59.2 |
| Tablet 750 mg BID C2D1 | Blood Plasma Concentration of MGCD265 - Ctrough | 203 ng/mL | Geometric Coefficient of Variation 80.9 |
| Tablet 750 mg BID C2D15 | Blood Plasma Concentration of MGCD265 - Ctrough | 255 ng/mL | Geometric Coefficient of Variation 37.5 |
| Soft Gel 1050 mg BID C2D1 | Blood Plasma Concentration of MGCD265 - Ctrough | 345 ng/mL | Geometric Coefficient of Variation 48.5 |
Secondary
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.
Time frame: 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.
Population: PK Analysis Set consisted of all patients who received at least one dose of active study drug and had sufficient data to assess any of the PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Peak to Trough Ratio | 1.09 ratio | Geometric Coefficient of Variation 13.4 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of MGCD265 - Peak to Trough Ratio | 1.08 ratio | Geometric Coefficient of Variation 10.4 |
Secondary
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.
Time frame: 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.
Population: PK Analysis Set consisted of all patients who received at least one dose of active study drug and had sufficient data to assess any of the PK parameters.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Tmax | 6.00 hours |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of MGCD265 - Tmax | 2.00 hours |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of MGCD265 - Tmax | 6.00 hours |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of MGCD265 - Tmax | 6.00 hours |
Secondary
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
Time frame: Cycle 1 and Cycle 2
Population: The Pharmacodynamics Evaluable Population Population defined as all patients in the mITT population for whom PD analytical results were available. Overall number of participants analyzed at baseline and post-baseline are different due to samples not being collected post-baseline for some patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 15 - Pre-Dose | 96641.3 pg/mL | Standard Deviation 144021.14 |
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Baseline | 443494.7 pg/mL | Standard Deviation 228345.48 |
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 1 Day 15 - Pre-Dose | 577631.4 pg/mL | Standard Deviation 221350.47 |
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 1 Day 15 - Pre-Dose | 122074.7 pg/mL | Standard Deviation 166978.07 |
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 1 - Pre-Dose | 560790.3 pg/mL | Standard Deviation 216802.34 |
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 1 - Pre-Dose | 144802.6 pg/mL | Standard Deviation 158943.04 |
| MET Activating Mutations in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 15 - Pre-Dose | 551625.9 pg/mL | Standard Deviation 234249.28 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 1 Day 15 - Pre-Dose | 568938.8 pg/mL | Standard Deviation 129859.54 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 1 Day 15 - Pre-Dose | 94110.4 pg/mL | Standard Deviation 87158.09 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 1 - Pre-Dose | 582800.9 pg/mL | Standard Deviation 140742.66 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 1 - Pre-Dose | 120815.6 pg/mL | Standard Deviation 133979.33 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 15 - Pre-Dose | 169374.6 pg/mL | Standard Deviation 70996.25 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Baseline | 461985.2 pg/mL | Standard Deviation 122069.25 |
| MET Gene Amplifications in Tumor Tissue | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 15 - Pre-Dose | 630505.5 pg/mL | Standard Deviation 133180.58 |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 15 - Pre-Dose | 44093.0 pg/mL | — |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 1 Day 15 - Pre-Dose | 594277.3 pg/mL | Standard Deviation 49746.18 |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 1 - Pre-Dose | 662385.3 pg/mL | Standard Deviation 41039.78 |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 15 - Pre-Dose | 482109.0 pg/mL | — |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Baseline | 450112.5 pg/mL | Standard Deviation 80809.29 |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 1 Day 15 - Pre-Dose | 144164.8 pg/mL | Standard Deviation 51740.94 |
| MET Activating Mutations in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 1 - Pre-Dose | 212272.8 pg/mL | Standard Deviation 86344.15 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 1 Day 15 - Pre-Dose | -257537.5 pg/mL | Standard Deviation 1102955.1 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 15 - Pre-Dose | 184161.0 pg/mL | Standard Deviation 161224.04 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 1 - Pre-Dose | 742344.9 pg/mL | Standard Deviation 620417.99 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Baseline | 961383.1 pg/mL | Standard Deviation 1665608.92 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Change from Baseline - Cycle 2 Day 1 - Pre-Dose | -219038.2 pg/mL | Standard Deviation 1085522.39 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 1 Day 15 - Pre-Dose | 775242.8 pg/mL | Standard Deviation 679349.02 |
| MET Gene Amplifications in ctDNA | Blood Plasma Concentration of Soluble MET (sMET) Biomarker | Actual - Cycle 2 Day 15 - Pre-Dose | 628011.8 pg/mL | Standard Deviation 291532.85 |
Secondary
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.
Time frame: 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.
Population: Modified Intent-to-Treat (mITT) Population defined as all patients who received at least one dose of MGCD265
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MET Activating Mutations in Tumor Tissue | Duration of Response | 85 days |
| MET Gene Amplifications in Tumor Tissue | Duration of Response | 170 days |
| MET Activating Mutations in ctDNA | Duration of Response | NA days |
Secondary
Number of Patients Experiencing Treatment-emergent Adverse Events
Number of patients experiencing treatment-emergent adverse events.
Time frame: Date of first dose to 28 days after the last dose, up to an average of 5.1 months on treatment.
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MET Activating Mutations in Tumor Tissue | Number of Patients Experiencing Treatment-emergent Adverse Events | 28 Participants |
| MET Gene Amplifications in Tumor Tissue | Number of Patients Experiencing Treatment-emergent Adverse Events | 20 Participants |
| MET Activating Mutations in ctDNA | Number of Patients Experiencing Treatment-emergent Adverse Events | 8 Participants |
| MET Gene Amplifications in ctDNA | Number of Patients Experiencing Treatment-emergent Adverse Events | 12 Participants |
Secondary
Overall Survival
Overall Survival will be defined as the time from date of first study treatment to death due to any cause
Time frame: From date of first study treatment to death due to any cause, assessed up to 24 months.
Population: Modified Intent-to-Treat (mITT) Population defined as all patients who received at least one dose of MGCD265
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MET Activating Mutations in Tumor Tissue | Overall Survival | 16.32 months |
| MET Gene Amplifications in Tumor Tissue | Overall Survival | 7.04 months |
| MET Activating Mutations in ctDNA | Overall Survival | NA months |
| MET Gene Amplifications in ctDNA | Overall Survival | 4.08 months |
Secondary
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.
Time frame: 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.
Population: Modified Intent-to-Treat (mITT) Population defined as all patients who received at least one dose of MGCD265
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MET Activating Mutations in Tumor Tissue | Progression Free Survival | 3.95 months |
| MET Gene Amplifications in Tumor Tissue | Progression Free Survival | 4.84 months |
| MET Activating Mutations in ctDNA | Progression Free Survival | 3.39 months |
| MET Gene Amplifications in ctDNA | Progression Free Survival | 2.76 months |