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
Overview
- Phase
- Phase 2
- Intervention
- Spartalizumab
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 31
- Locations
- 2
- Primary Endpoint
- Randomized Part: Progression-Free Survival (PFS) by BIRC as Per RECIST 1.1
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
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
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 was 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 * Enrolled subjects who had not started study treatment were to receive capmatinib single agent treatment from the start
Investigators
Eligibility Criteria
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)
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)
Arms & Interventions
Run-in part
capmatinib in combination with spartalizumab
Intervention: Spartalizumab
Run-in part
capmatinib in combination with spartalizumab
Intervention: Capmatinib
Randomized part - Arm 1 spartalizumab
capmatinib in combination with spartalizumab
Intervention: Spartalizumab
Randomized part - Arm 1 spartalizumab
capmatinib in combination with spartalizumab
Intervention: Capmatinib
Randomized part - Arm 2 placebo
capmatinib in combination with placebo
Intervention: Capmatinib
Randomized part - Arm 2 placebo
capmatinib in combination with placebo
Intervention: spartalizumab placebo
Outcomes
Primary Outcomes
Randomized Part: Progression-Free Survival (PFS) by BIRC as Per RECIST 1.1
Time Frame: Up to 6 years
PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause. Tumor response based on blinded independent review committee (BIRC) assessment per RECIST v1.1.
Run-in Part: Overall Response Rate (ORR) by Investigator Assessment as Per RECIST 1.1
Time Frame: Up to approximately 2 years and 4 months
Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response of Complete Response (CR) or Partial Response (PR). For RECIST v1.1, 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; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Secondary Outcomes
- Run-in Part: Dose Intensity of Capmatinib(From first dose of capmatinib to last dose, up to 2.4 years)
- Run-in Part: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1(Up to approximately 2 years and 4 months)
- Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib(From first dose of capmatinib to last dose, up to 2.4 years)
- Run-in Part: Maximum Observed Plasma Concentration (Cmax) of Capmatinib(pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.)
- Run-in Part: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib(pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.)
- Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib(pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.)
- Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Spartalizumab(pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.)
- Run-in Part: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab(pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.)
- Randomized Part: Dose Intensity of Capmatinib and Spartalizumab(Up to 6 years)
- Randomized Part: Duration of Response (DOR) by BIRC and Investigator Assessment as Per RECIST 1.1(Up to 6 years)
- Run-in Part: Number of Participants With Dose Reductions and Dose Interruptions of Spartalizumab(From first dose of spartalizumab to last dose, up to 0.9 years)
- Run-in Part: Dose Intensity of Spartalizumab(From first dose of spartalizumab to last dose, up to 0.9 years)
- Run-in Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1(Up to approximately 2 years and 5 months)
- Run-in Part: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib(pre-dose and 1, 2, 4 and 8 hours after morning dose on Cycle 3 Day 1. The duration of one cycle was 28 days.)
- Run-in Part: Maximum Observed Serum Concentration (Cmax) of Spartalizumab(pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.)
- Run-in Part: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab(pre-infusion and 1, 72, 168, 336 and 672 hours after completion of the spartalizumab infusion on Cycle 3 Day 1. The duration of the infusion was approximately 30 minutes. The duration of one cycle was 28 days.)
- Randomized Part: Overall Survival (OS)(Up to 12 years)
- Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab(Up to 6 years)
- Randomized Part: Disease Control Rate (DCR) by BIRC and Investigator Assessment as Per RECIST 1.1(Up to 6 years)
- Randomized Part: Overall Response Rate (ORR) by BIRC and Investigator Assessment as Per RECIST 1.1(Up to 6 years)
- Randomized Part: Time to Response (TTR) by BIRC and Investigator Assessment as Per RECIST 1.1(Up to 6 years)
- Randomized Part: Change From Baseline in EORTC QLQ-LC13(Up to 6 years)
- Randomized Part: Time to Definitive 10 Points Deterioration Symptom Scores for Pain in Chest, Coughing and Dyspnea Per QLQ-LC13 Questionnaire(Up to 6 years)
- Randomized Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1(Up to 6 years)
- Randomized Part: Change From Baseline in EORTC QLQ-C30(Up to 6 years)
- Randomized Part: Time to Definitive Deterioration in Global Health Status/QoL, Shortness of Breath and Pain Per EORTC QLQ-C30(Up to 6 years)
- Randomized Part: Change From Baseline in EQ-5D-5L(Up to 6 years)
- Randomized Part: Area Under the Concentration-time Curve From Time Zero to the End of a Dosing Interval (AUCtau) of Capmatinib and Spartalizumab(Up to 6 years)
- Randomized Part: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib and Spartalizumab(Up to 6 years)
- Randomized Part: Maximum Observed Concentration (Cmax) of Capmatinib and Spartalizumab(Up to 6 years)
- Randomized Part: Time to Reach Maximum Concentration (Tmax) of Capmatinib and Spartalizumab(Up to 6 years)
- Randomized Part: Number of Participants With Anti-spartalizumab Antibodies(Baseline (pre-dose), up to 6 years)