Study of Capmatinib Efficacy in Comparison With Docetaxel in Previously Treated Participants With Non-small Cell Lung Cancer Harboring MET Exon 14 Skipping Mutation

Study Overview
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Brief Summary
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The purpose of the study is to learn whether the study drug (capmatinib) helps to control lung cancer better compared to a single agent chemotherapy (docetaxel) and whether it is safe when given to patients suffering from a particular type of lung cancer. This type of cancer is called non-small cell lung cancer (NSCLC) with certain specific genetic alterations (called mutations) of a gene called MET, within a specific part of the gene called exon 14.

Detailed Description
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Approximately 90 patients with advanced or metastatic lung cancer, with these specific mutations in the MET gene but without changes in their epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genes, will be enrolled in this study. Participants will be randomly assigned to get either capmatinib or docetaxel in a 2 to 1 ratio. The randomization will be stratified by prior lines of systemic therapy received for advanced/metastatic disease (one line vs. two lines). During treatment, visits will be scheduled every 21 days. For all participants, the respective treatment (either with capmatinib or docetaxel) may be continued beyond initial disease progression as per RECIST 1.1 (as assessed by the investigator and confirmed by BIRC) if, in the judgment of the investigator, there is evidence of clinical benefit, and the participant wishes to continue on the study treatment. After treatment discontinuation, all participants will be followed for safety evaluations during the safety follow-up period, and the participant's status will be collected every 12 weeks as part of the survival follow-up. Participants randomized to docetaxel treatment will be eligible to crossover to receive capmatinib treatment after BIRC-confirmed, RECIST 1.1-defined progressive disease and after meeting the eligibility criteria prior to crossover.

Official Title
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A Phase III, Randomized, Controlled, Open-label, Multicenter, Global Study of Capmatinib Versus SoC Docetaxel Chemotherapy in Previously Treated Patients With EGFR wt, ALK Negative, Locally Advanced or Metastatic (Stage IIIB/IIIC or IV) NSCLC Harboring MET Exon 14 Skipping Mutation (METΔex14).

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Capmatinib
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Stage IIIB/IIIC (not amenable to surgery, radiation or multi modality therapy) or IV NSCLC (according to Version 8 of the American Joint Committee on Cancer (AJCC) Staging Manual) at the time of study entry. Histologically or cytologically confirmed diagnosis of NSCLC that is: EGFR wt. Assessed as part of participant's standard of care by a validated test for EGFR mutations as per local guidelines. The EGFR wt status (for EGFR mutations that predict sensitivity to EGFR therapy, including, but not limited to exon 19 deletions and exon 21 L858R substitution mutations. AND ALK rearrangement negative. Assessed as part of participant's standard of care by a validated test. AND has METΔex14 mutation as determined by Novartis-designated central laboratory or by locally performed, tissue-based test, validated according to local regulation, from a Clinical Laboratory Improvement Amendments (CLIA)-certified US laboratory or an accredited local laboratory outside of the US. The positive METΔex14 mutation result as determined per local test must be documented in the participant's source documents and in the CRF prior to entering main screening. Mandatory provision of a formalin-fixed, paraffin embedded tumor tissue sample (archival tumor block or slides, or a newly obtained tumor sample) with quality and quantity sufficient to allow assessment of METΔex14 mutation status (as defined in the study [laboratory manual]). This pertains to all participants, including those who have a METΔex14 mutation result from a local test. Tumor samples must contain at least 10% tumor content. 6. Participants must have progressed on one or two prior lines of Progressed on one or two prior lines of systemic therapy for advanced/metastatic disease (stage IIIB/IIIC [not candidates for surgery, radiation or multi modality therapy] or IV NSCLC) and must be docetaxel naïve and candidates for single agent chemotherapy (docetaxel). Treatment failure is defined as documented disease progression or intolerance to treatment., however participants must have progressed on or after the last therapy before study entry. At least one measurable lesion as defined by RECIST 1.1 Adequate organ function Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Participants must have a life expectancy of at least 3 months. Key Exclusion Criteria: Prior treatment with any MET inhibitor or HGF-targeting therapy. Participants with symptomatic central nervous system (CNS) metastases who are neurologically unstable or have required increasing doses of steroids within the 2 weeks prior to study entry to manage CNS symptoms. Participants with known druggable molecular alterations (such as ROS1and RET rearrangement, BRAF mutation, KRAS mutation, NTRK fusion, etc.) which might be a candidate for alternative targeted therapies. Presence or history of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention). Substance abuse, active infection or other severe, acute, or chronic medical or psychotic conditions or laboratory abnormalities that in the opinion of the investigator may increase the risk associated with study participation Other protocol-defined inclusion/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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants randomized to docetaxel treatment will be eligible to crossover to receive capmatinib treatment after blinded independent review committee (BIRC)-confirmed, RECIST 1.1- defined disease progression.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capmatinib<br>400mg of capmatinib tablets, administered orally twice daily | Drug: Capmatinib<br>* 400mg of capmatinib tablets administered orally twice daily<br>* Other names: INC280;|
| Active Comparator: Docetaxel<br>Docetaxel 75 mg/m2 solution administered by intravenous infusion on Day 1 of every 21-day cycle | Drug: Docetaxel<br>* Docetaxel 75 mg/m2 by intravenous infusion every 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) per blinded independent review committee (BIRC) using RECIST v1.1 | Progression free survival is defined as the time from the date of randomization to the date of the first documented progression assessed by BIRC according to RECIST 1.1, or death due to any cause | From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response (ORR) per RECIST 1.1 by BIRC | Percentage of participants with confirmed best overall response (BOR) of complete response (CR) or partial response (PR), assessed by BIRC according to RECIST 1.1. | Up to approximately 21 months | 
| Overall response (ORR) per RECIST 1.1 by investigator | Percentage of participants with confirmed BOR of CR or PR, assessed by local review according to RECIST 1.1. | Up to approximately 21 months | 
| Time to response (TTR) per RECIST 1.1 by BIRC | Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by BIRC according to RECIST 1.1. | From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months | 
| Time to response (TTR) per RECIST 1.1 by investigator | Time from date of randomization to first documented response of either CR or PR, which must be subsequently confirmed, assessed by local review according to RECIST 1.1. | From date of randomization to first documented response of either CR or PR, assessed up to approximately 21 months | 
| Duration of response (DOR) per RECIST 1.1 by BIRC | Time from the date of first documented response (CR or PR) to the first documented progression by BIRC per RECIST 1.1 or death due to any cause. | From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months | 
| Duration of response (DOR) per RECIST 1.1 by investigator | Time from the date of first documented response (CR or PR) to the first documented progression by local review per RECIST 1.1 or death due to any cause. | From first documented response to first documented progression or death due to any cause, whichever comes first, assessed up to approximately 21 months | 
| Disease Control Rate (DCR) per RECIST 1.1 by BIRC | Percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) assessed by BIRC according to RECIST 1.1 | Up to approximately 21 months | 
| Disease Control Rate (DCR) per RECIST 1.1 by investigator | Percentage of participants with a BOR of confirmed CR, PR and SD assessed by local review according to RECIST 1.1 | Up to approximately 21 months | 
| Progression free survival (PFS) per investigator using RECIST v1.1 | Time from the date of randomization to the date of the first documented progression assessed by local review according to RECIST 1.1, or death due to any cause | From randomization to the date of first documented progression or death from any cause, whichever comes first, assessed up to approximately 21 months | 
| Overall survival (OS) | OS is defined as the time from the date of randomization to the date of death due to any cause. | From randomization to death due to any cause, assessed up to approximately 42 months | 
| Overall intracranial response rate (OIRR) | Percentage of participants with confirmed best overall intracranial response (BOIR) of CR or partial response (PR), as assessed by BIRC review per RANO-BM criteria. | Up to approximately 21 months | 
| Duration of intracranial response (DOIR) | Time from date of first documented intracranial response (CR or PR) to first documented intracranial progression per RANO-BM assessed by BIRC or date of death due to underlying cause of cancer. | From date of first documented intracranial response (CR or PR) to first documented intracranial progression, assessed up to approximately 21 months | 
| Time to intracranial response (TTIR) | Time from date of randomization to first documented intracranial response of either CR or PR, per RANO-BM criteria and assessed by BIRC, which must be subsequently confirmed. | From date of randomization to first documented intracranial response of either CR or PR, assessed up to approximately 21 months | 
| Intracranial disease control rate (IDCR) | Percentage of participants with a BOR of confirmed CR, PR and stable disease (SD) (or non-CR/non-PD) per RANO-BM, assessed by BIRC. | Up to approximately 21 months | 
| Plasma capmatinib concentration | Plasma concentrations of capmatinib. Blood samples will be collected at indicated time points for pharmacokinetic analysis. | Cycle (C) 1 Day (D) 15 pre-dose, 1 and 4 hours post-dose, C3 D1 pre-dose. Each cycle duration is 21 days. | 
| Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. The questionnaire is composed of both multi-item scales and single-item measures based on the participants experience over the past week. These include five domains (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/HRQoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Change from baseline in EORTC QLQ-C30 scores will be assessed | Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days. | 
| Change from baseline in score as per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13) | EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire. The five domains of the questionnaire include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from not at all to very much. Pain is score based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms. Change from baseline in EORTC QLQ-LC13 scores will be assessed | Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days. | 
| Change from baseline in score as per European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) questionnaire | EQ-5D-5L is a standardized measure to assess the overall health-related quality of life in patients. The EQ-5D-5L consists of 2 parts- the descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each with 5 levels: from 1 (no problems) to 5 (extreme problems). The EQ VAS is a self-perceived health score assessed using a visual analogue scale that ranges from 0 (the worst imaginable health) to 100 (the best imaginable health), with higher scores indicating higher health utility. Change from baseline in EQ-5D-5L scores will be assessed | Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment . Each cycle duration is 21 days. | 
| Time to symptom deterioration for chest pain, cough and dyspnea assessed using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Lung Cancer Module (QLQ-LC13) | EORTC QLQ-LC13 is a 13-item lung cancer specific questionnaire. The five domains of the questionnaire include pain, dyspnea, coughing and hemoptysis, and are based on their presence over the past week. All but the pain domain are scored on a 4 point Likert scale ranging from not at all to very much. Pain is score based on its presence, hence yes or no. A higher score indicates a higher presence of symptoms. Time to symptom deterioration for chest pain, cough and dyspnea will be assessed | Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment. Each cycle duration is 21 days. | 
| Time to deterioration for global health status /QoL assessed using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 | EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. The questionnaire is composed of both multi-item scales and single-item measures based on the participants experience over the past week. These include five domains (physical, role, emotional, cognitive and social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/HRQoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Time to deterioration in QoL from EORTC-QLQ-C30 will be assessed. | Cycle (C) 1 Day (D) 1, C3 D1 and then every 6 weeks up to approximately 21 months, end of treatment and 6, 12 , 18 weeks post treatment. Each cycle duration is 21 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MET∆ex14, Non small cell lung cancer, Non small cell lung carcinoma, NSCLC, INC280, capmatinib, MET mutation, MET exon14, MET exon14 skipping, MET exon14 deletion, METex14, METex14del, EGFRwt, Epidermal growth factor receptor wild type, ALK negative, docetaxel