A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment

Study Overview
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Brief Summary
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This study assessed the safety and efficacy of escalating doses INC280 when added to gefitinib in patients with lung cancer that were known to have dysregulation of the c-MET pathway and who had failed after benefiting on a prior treatment with either gefitinib or erlotinib.

Detailed Description
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The Phase Ib dose escalation part was aimed at the determination of the MTD/RP2D of capmatinib in combination with 250 mg gefitinib in patients with NSCLC patients with epidermal growth factor receptor (EGFR) mutation and cMET dysregulation and showing disease progression following EGFR tyrosine-kinase inhibitor (EGFR TKI) therapy. Dose escalation started with a dose of 100 mg/day to a maximum of 1200 mg/day, as capsule or tablet formulation. Successive cohorts of patients were to receive increasing doses of capmatinib in combination with a 250 mg once daily (qd) dose of gefitinib until the MTD/RP2D of capmatinib had been determined. The Phase II dose expansion part consisted of 400 mg capmatinib twice daily (bid), as either capsules or tablets, in combination with 250 mg gefitinib.

Official Title
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A Phase IB/II, Open Label, Multicenter Study of INC280 Administered Orally in Combination With Gefitinib in Adult Patients With EGFR Mutated, c-MET-amplified Non-small Cell Lung Cancer Who Have Progressed After EGFR Inhibitor Treatment

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: INC280
* Drug: Gefitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented EGFR mutation Documented c-MET dysregulation Prior clinical benefit on EGFR inhibitors and then subsequent progression -≥ 18 year old Life expectancy of ≥ 3 months ECOG performance status ≤ 2 Exclusion Criteria: Unable to swallow tables once or twice daily Previous treatment with c-MET inhibitor Any unresolved toxicity from previous anticancer therapy greater than grade 1 History of cystic fibrosis History of acute or chronic pancreatitis Unable to undergo MRI or CT scans Known history of HIV Undergone a bone marrow or solid organ transplant Clinically significant wound or lung tumor lesions with increased likelihood of bleeding Pregnant or nursing

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INC280 100 mg Cap QD Phase Ib<br>cap=capsule; QD=once daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 200 mg Cap QD Phase Ib<br>cap=capsule; QD=once daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 400 mg Cap QD Phase Ib<br>cap=capsule; QD=once daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 800 mg Cap QD Phase Ib<br>cap=capsule; QD=once daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 200 mg Cap BID Phase Ib<br>cap=capsule; BID=twice daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 400 mg Cap BID Phase Ib<br>cap=capsule; BID=twice daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 600 mg Cap BID Phase Ib<br>cap=capsule; BID=twice daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 200 mg Tab BID Phase Ib<br>tab=tablet; BID=twice daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 400 mg Tab BID Phase Ib<br>tab=tablet; BID=twice daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 400 mg Cap BID Phase II<br>cap=capsule; BID=twice daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|
| Experimental: INC280 400 mg Tab BID Phase II<br>tab=tablet; BID=twice daily | Drug: INC280<br>* During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.<br>* Other names: Capmatinib;Drug: Gefitinib<br>* Gefitinib 250 mg taken once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) | A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol. | Up to 215 weeks | 
| Phase II : Overall Response Rate (ORR) | Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | Until disease progression, up to 60.8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib and II: Number of Participants With Adverse Events (AEs) | Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | Up to 421 weeks | 
| Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) | Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 | Up to 421 weeks | 
| Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level | Number of patients with dose reductions of INC280 by dose level as a measure of tolerability. | Up to 417 weeks | 
| Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level | Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability | Up to 417 weeks | 
| Phase II: Overall Survival (OS) | Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause | From date of treatment until death due to any cause, up to 70.2 months | 
| Phase II: Progression Free Survival (PFS) | Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. | Up to 60.8 months | 
| Phase II: Duration of Response (DoR) | Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer. | Up to 23.2 months | 
| Phase I: PK Parameters AUCtau of INC280 and Gefitinib | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | 
| Phase I: PK Parameters Cmax of INC280 and Gefitinib | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | 
| Phase I: PK Parameters Tmax of INC280 and Gefitinib | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | 
| Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days) | 
| Phase I: PK Parameters Half-life of INC280 and Gefitinib | PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda_z) of a semi-logarithmic plasma concentration-time curve | Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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EGFR, c-MET, Lung cancer, Gefitinib, Erlotinib, Non-small cell lung cancer (NSCLC), lung adenocarcinoma, large-cell lung carcinoma