Study of Capmatinib and Spartalizumab/Placebo in Advanced NSCLC Patients With MET Exon 14 Skipping Mutations

Study Overview
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Brief Summary
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A double-blind, placebo controlled, randomized, phase II study evaluating the efficacy and safety of capmatinib (INC280) and spartalizumab (PDR001) combination therapy versus capmatinib and placebo as first line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping (METΔex14) mutations

Detailed Description
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The purpose of this study was to evaluate the efficacy and safety of capmatinib in combination with spartalizumab in treatment naive patients with EGFR wild-type, ALK rearrangement negative advanced NSCLC, harboring METΔex14 mutations. A run-in part (Part 1) was conducted to determine the anti-tumor activity and safety of capmatinib in combination with spartalizumab. Upon review of safety data and confirmation of anti-tumor activity in Part 1, the randomized part (Part 2) was planned to be initiated to compare the efficacy and safety of capmatinib plus spartalizumab to capmatinib plus placebo. Combined treatment of METΔex14 mutated NSCLC with capmatinib and spartalizumab is expected to result in improved efficacy compared to each single agent due to direct targeting of an oncogenic driver (MET) as well as more efficient stimulation of an anti-tumor immune response than with PD-1 blockade alone. The study enrollment was halted on 28-Jul-2021 per sponsor's decision. The enrollment halt decision was based on lack of tolerability observed in capmatinib and spartalizumab combination treatment in the run-in part (Part 1) of the trial. Following the study enrollment halt during Part 1 (Run in Part), Part 2 was not initiated. Immediately following the enrollment halt: All ongoing subjects were discontinued from spartalizumab treatment and continue to receive single agent capmatinib, given the proven tolerability and efficacy of capmatinib monotherapy in this study indication. Enrolled subjects who had not started study treatment were to receive capmatinib single agent treatment from the start

Official Title
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A Double-blind, Placebo Controlled, Randomized, Phase II Study Evaluating the Efficacy and Safety of Capmatinib and Spartalizumab vs Capmatinib and Placebo as 1st Line Treatment for Advanced NSCLC Patients With MET exon14 Skipping Mutations

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Spartalizumab
* Drug: Capmatinib
* Drug: spartalizumab placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed locally advanced or metastatic NSCLC which is EGFR wild-type, ALK rearrangement negative and METΔex14 mutated No prior systemic therapy for advanced/metastatic disease (neo-adjuvant/adjuvant treatment completed > 12 months before relapse are permitted) Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 Measurable disease as per RECIST 1.1 Known PD-L1 tumor expression status (applicable to Randomized part 2 only) Key Exclusion Criteria: Prior treatment with a PD-1/PD-L1 inhibitor, MET inhibitor or HGF inhibitor Presence of symptomatic CNS metastases or requiring local CNS-directed therapy (radiotherapy or surgery), or increasing doses of corticosteroids 2 weeks prior to study entry Impaired cardiac function or clinically significant cardiac disease Presence or history of interstitial lung disease, non-infectious pneumonitis or interstitial pneumonitis, including clinically significant radiation pneumonitis History of allogenic bone marrow or solid organ transplant Radiotherapy to lung fields ≤ 4 weeks or to any other anatomic site ≤ 2 weeks prior to start of study treatment (palliative radiotherapy for bone lesions is allowed) Other inclusion and exclusion criteras 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: Run-in part: single arm, open-label. Randomized part: two-arms parallel assignment, double-blinded, placebo control
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Run-in part<br>capmatinib in combination with spartalizumab | Drug: Spartalizumab<br>* Concentrate for solution for infusion<br>* Other names: PDR001;Drug: Capmatinib<br>* Film-coated tablet<br>* Other names: INC280;|
| Experimental: Randomized part - Arm 1 spartalizumab<br>capmatinib in combination with spartalizumab | Drug: Spartalizumab<br>* Concentrate for solution for infusion<br>* Other names: PDR001;Drug: Capmatinib<br>* Film-coated tablet<br>* Other names: INC280;|
| Experimental: Randomized part - Arm 2 placebo<br>capmatinib in combination with placebo | Drug: Capmatinib<br>* Film-coated tablet<br>* Other names: INC280;Drug: spartalizumab placebo<br>* dextrose 5% in water (D5W) for infusion<br>* Other names: PDR001 placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate by Investigator assessment as per RECIST 1.1 | Run-in part To evaluate the anti-tumor activity of capmatinib in combination with spartalizumab | 2.5 years | 
| Progression Free survival (PFS) by BIRC as per RECIST 1.1 | Randomized part To compare the efficacy of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (AE) and Serious Adverse events (SAE) incidence | Run-in part To assess safety of capmatinib in combination with spartalizumab | 2.5 years | 
| Number of patients with dose interruptions, reductions, and dose intensity | Run-in part To assess tolerability of capmatinib in combination with spartalizumab | 2.5 years | 
| Efficacy measurements per RECIST 1.1 : Disease Control Rate (DCR) by investigator asessment | Run-in part Disease Control Rate (DCR) to further evaluate the anti-tumor activity of capmatinib in combination with spartalizumab | 2.5 years | 
| Efficacy measurements per RECIST 1.1 : Progression Free Survival (PFS) by investigator assessment | Run in part Progression Free Survival (PFS) to further evaluate the anti-tumor activity of capmatinib in combination with spartalizumab | 2.5 years | 
| Pharmacokinetics (PK): Cmax | Run-in part To evaluate the PK of capmatinib and spartalizumab | 2.5 years | 
| Pharmacokinetics (PK): Tmax | Run-in part To evaluate the PK of capmatinib and spartalizumab | 2.5 years | 
| Pharmacokinetics (PK): AUClast | Run-in part To evaluate the PK of capmatinib and spartalizumab | 2.5 years | 
| Pharmacokinetics (PK): AUCtau | Run-in part To evaluate the PK of capmatinib and spartalizumab | 2.5 years | 
| Overall survival (OS) | Randomized part To compare overall survival of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 12 years | 
| Adverse events (AE) and Serious Adverse events (SAE) incidence | Randomized part To assess safety of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Number of patients with dose interruptions, reductions, and dose intensity | Randomized part To assess tolerability of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Efficacy measurements per RECIST 1.1: Progression Free Survival (PFS) by investigator assessment | Randomized part Progression Free Survival (PFS) to further evaluate the anti-tumor activity of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Efficacy measurements per RECIST 1.1: Disease Control Rate (DCR) by BIRC and investigator assessment | Randomized part Disease Control Rate (DCR) to further evaluate the anti-tumor activity of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Efficacy measurements per RECIST 1.1: Duration of Response (DOR) by BIRC and investigator assessment | Randomized part Duration of Response (DOR) to further evaluate the anti-tumor activity of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Efficacy measurements per RECIST 1.1: Overall Response Rate (ORR) by BIRC and investigator assessment | Randomized part Overall Response Rate (ORR) to further evaluate the anti-tumor activity of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Efficacy measurements per RECIST 1.1: Time to Response (TTR) by BIRC and investigator assessment | Randomized part Time to Response (TTR) To further evaluate the anti-tumor activity of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Change from baseline in EORTC QLQ-C30 questionnaires | Randomized part To evaluate patient reported outcomes of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Change from baseline in EQ-LC13 questionnaires | Randomized part To evaluate patient reported outcomes of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Change from baseline in EQ-5D-5L questionnaires | Randomized part To evaluate patient reported outcomes of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Time to definitive 10 points deterioration symptom scores for pain in chest, coughing and dyspnea per QLQ-LC13 questionnaire | Randomized part To evaluate patient reported outcomes of capmatinib in combination with spartalizumab versus capmatinib plus placebo | 6 years | 
| Pharmacokinetics (PK): Cmax | Randomized part To evaluate the PK of capmatinib and spartalizumab | 6 years | 
| Pharmacokinetics (PK): Tmax | Randomized part To evaluate the PK of capmatinib and spartalizumab | 6 years | 
| Pharmacokinetics (PK): AUCtau | Randomized part To evaluate the PK of capmatinib and spartalizumab | 6 years | 
| Pharmacokinetics (PK): AUClast. | Randomized part To evaluate the PK of capmatinib and spartalizumab | 6 years | 
| Antidrug antibodies (ADA) prevalence at baseline on treatment with spartalizumab | Randomized part To evaluate the prevalence of immunogenicity of spartalizumab in combination with capmatinib | 6 years | 
| Antidrug antibodies (ADA) incidence on treatment with spartalizumab | Randomized part To evaluate the incidence of immunogenicity of spartalizumab in combination with capmatinib | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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capmatinib, spartalizumab, MET mutation, EGFR wild-type, ALK negative mutation