Clinical Study of Oral cMET Inhibitor INC280 in Adult Patients With EGFR Wild-type Advanced Non-small Cell Lung Cancer (Geometry Mono-1)

Study Overview
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Brief Summary
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A phase II study to evaluate antitumor activity of oral cMET inhibitor INC280 in adult patients with EGFR wild-type, advanced non-small cell lung cancer (NSCLC) as measured by overall response rate (ORR). The study will also evaluate safety and pharmacokinetics of INC280.

Official Title
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A Phase II, Multicenter Study of Oral cMET Inhibitor INC280 in Adult Patients With EGFR Wild-type (wt), Advanced Non-small Cell Lung Cancer (NSCLC)(Geometry Mono-1)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: INC280 (capmatinib)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage IIIB or IV NSCLC (any histology) at the time of study entry Histologically or cytologically confirmed diagnosis of NSCLC that is: EGFR wt as per patient standard of care by a validated test AND ALK-negative rearrangement as part of the patient standard of care by a validated test AND (by central assessment) either: Cohort 1: Pre-treated patients with cMET GCN ≥ 6 or Cohort 2: Pre-treated patients with cMET GCN ≥4 and < 6, or Cohort 3: Pre-treated patients with cMET GCN < 4, or Cohort 4: Pre-treated patients with cMET mutations regardless of cMET GCN, or Cohort 5: Treatment-naïve patients with cMET dysregulation, or Cohort 6: Pre-treated patients with either cMET GCN ≥ 10 without cMET mutations or cMET mutations regardless of cMET GCN, or Cohort 7: Treatment-naïve patients with cMET mutations regardless of cMET GCN To be eligible for Cohorts 1-4, patients must have failed one or two prior lines of systemic therapy for advanced/metastatic disease To be eligible for Cohort 6, patients must have failed one prior line of systemic therapy for advanced/metastatic disease To be eligible for Cohort 5 and Cohort 7, patients must not have received any systemic therapy for advanced/metastatic disease At least one measurable lesion as defined by RECIST 1.1 Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03). Patients with any grade of alopecia are allowed to enter the study. Patients must have adequate organ function ECOG performance status (PS) of 0 or 1 Details and other protocol-defined inclusion criteria may apply Exclusion Criteria: Prior treatment with crizotinib, or any other cMET or HGF inhibitor Patients with characterized EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 mutations Patients with characterized ALK-positive rearrangement Clinically significant, uncontrolled heart diseases. Patients receiving treatment with medications that cannot be discontinued at least 1 week prior to first INC280 treatment and for the duration of the study: Strong inducers of CYP3A4 Impairment of GI function or GI disease that may significantly alter the absorption of INC280 Patients receiving treatment with any enzyme-inducing anticonvulsant Applicable to Cohorts 1-4 and Cohort 6 only: Previous anti-cancer and investigational agents within 4 weeks or ≤ 5 x half-life of the agent (whichever is longer) before first dose Pregnant or nursing women Women of child-bearing potential, unless they are using highly effective methods of contraception Sexually active males unless they use a condom during intercourse Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis Other protocol-defined exclusion criteria may apply

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: cMET GCN ≥ 6<br>Pre-treated patients with cMET GCN ≥ 6 treated with INC280 at 400mg BID as second or third line | Drug: INC280 (capmatinib)<br> <br> |
| Experimental: cMET GCN ≥ 4 and < 6<br>Pre-treated patients with cMET GCN ≥ 4 and < 6 treated with INC280 at 400 mg BID as second or third line | Drug: INC280 (capmatinib)<br> <br> |
| Experimental: cMET GCN < 4<br>Pre-treated patients with cMET GCN < 4 treated with INC280 at 400mg BID as second or third line | Drug: INC280 (capmatinib)<br> <br> |
| Experimental: cMET mutations<br>Pre-treated patients with cMET mutations regardless of cMET GCN treated with INC280 at 400mg BID as second or third line | Drug: INC280 (capmatinib)<br> <br> |
| Experimental: cMET dysregulation - treatment-naïve<br>Treatment-naïve patients with cMET dysregulation treated with INC280 at 400mg BID | Drug: INC280 (capmatinib)<br> <br> |
| Experimental: cMET dysregulation - second line<br>Pre-treated patients with cMET deregulation treated with INC280 at 400 mg BID as second line | Drug: INC280 (capmatinib)<br> <br> |
| Experimental: cMET mutations treatment-naïve<br>Treatment-naïve patients with cMET mutations regardless of cMET GCN treated with INC280 at 400mg BID | Drug: INC280 (capmatinib)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Proportion of patients with a best overall response defined as complete response (CR) or partial response (PR) by Blinded Independent Review Committee (BIRC) assessment per RECIST 1.1 | at least 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) - Key Secondary | Calculated as the time from the date of the first documented CR or PR by Blinded Independent Review Committee (BIRC) per RECIST 1.1 to the first documented progression or death due to any cause for patients with PR or CR. | at least 18 weeks | 
| Overall Response Rate (ORR) | ORR (complete response (CR)+ partial response (PR)) per RECIST 1.1 by investigator assessment | at least 18 weeks | 
| Duration of Response (DOR) | DOR per RECIST 1.1 by investigator assessment | at least 18 weeks | 
| Time to Response (TTR) | TTR per RECIST 1.1 both by BIRC and investigator assessment | at least 18 weeks | 
| Disease Control Rate (DCR) | DCR per RECIST 1.1 both by BIRC and investigator assessment | at least 18 weeks | 
| Progression-free Survival (PFS) | PFS per RECIST 1.1 both by BIRC and investigator assessment | at least 18 weeks | 
| Overall Survival (OS) | OS, defined as time from first dose of INC280 to death due to any cause | at least 18 weeks | 
| Number of patients with incidence of adverse events and serious adverse events, change in vital signs, laboratory results (hematology, blood chemistry, and urinalysis) and ECG. | Safety of INC280 | at least 18 weeks | 
| Cmax, Cmin and plasma concentration-time profiles of INC280 | Pharmacokinetics of INC280 and metabolite CMN288 | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MET inhibitor, Non Small Cell Lung, Non Small Cell Lung Cancer, Non-small cell lung cancer, NSCLC, INC280, EGFR wild-type (wt), advanced non-small cell lung cancer, advanced/metastatic disease, Non-small cell lung carcinoma (NSCLC), treatment of lung cancer after first metastasis, lung cancer, lung adenocarcinoma, Non small cell lung carcinoma, MET exon 14 deletion, METex14del, MET exon 14 skipping, MET exon 14 mutation, MET mutation, MET amplification, MET dysregulation, MET activation, MET signaling, MET pathway, met, cMET, Geometry mono-1, Geometry