Study of Capmatinib and Spartalizumab/Placebo in Advanced NSCLC Patients With MET Exon 14 Skipping Mutations
- Conditions
- Carcinoma, Non-Small-Cell Lung
- Interventions
- Registration Number
- NCT04323436
- Lead Sponsor
- Novartis Pharmaceuticals
- 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
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 31
- 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
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Run-in part Capmatinib capmatinib in combination with spartalizumab Randomized part - Arm 2 placebo Capmatinib capmatinib in combination with placebo Randomized part - Arm 2 placebo spartalizumab placebo capmatinib in combination with placebo Randomized part - Arm 1 spartalizumab Capmatinib capmatinib in combination with spartalizumab Randomized part - Arm 1 spartalizumab Spartalizumab capmatinib in combination with spartalizumab Run-in part Spartalizumab capmatinib in combination with spartalizumab
- Primary Outcome Measures
Name Time Method Randomized Part: Progression-Free Survival (PFS) by BIRC as Per RECIST 1.1 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 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 Outcome Measures
Name Time Method Run-in Part: Dose Intensity of Capmatinib From first dose of capmatinib to last dose, up to 2.4 years Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Run-in Part: Disease Control Rate (DCR) by Investigator Assessment as Per RECIST 1.1 Up to approximately 2 years and 4 months DCR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). Tumor response was based on local investigator assessment per RECIST v1.1.
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; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression).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 Number of participants with at least one dose reduction of capmatinib and number of participants with at least one dose interruption of capmatinib.
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. Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
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. PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.
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. PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUCtau calculation. A dosing interval (tau) is defined as 12 hours. The portion of area under the curve between 8 hours and 12 hours post-dose was calculated by extrapolation based on terminal elimination slop.
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. PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUCtau calculation. A dosing interval (tau) is defined as 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. PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Randomized Part: Dose Intensity of Capmatinib and Spartalizumab Up to 6 years Dose intensity is defined as the ratio of actual cumulative dose and duration of exposure.
Randomized Part: Duration of Response (DOR) by BIRC and Investigator Assessment as Per RECIST 1.1 Up to 6 years DOR is defined as the time from the date of first documented response (CR or PR) to the first documented progression per RECIST 1.1 or death due to any cause.
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 Number of participants with at least one dose reduction of spartalizumab and number of participants with at least one dose interruption of spartalizumab. Dose reductions were not allowed for spartalizumab.
Run-in Part: Dose Intensity of Spartalizumab From first dose of spartalizumab to last dose, up to 0.9 years Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in days and then multiplied by the duration of one cycle (28 days).
Run-in Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1 Up to approximately 2 years and 5 months 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. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on investigator assessment per RECIST v1.1. Progression is defined using RECIST v1.1 as at least 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm.
PFS was analyzed using Kaplan-Meier estimates.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. PK parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
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. Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
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. PK parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Randomized Part: Overall Survival (OS) Up to 12 years OS is defined as the time from date of start of treatment to date of death due to any cause.
Randomized Part: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab Up to 6 years Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab.
Randomized Part: Disease Control Rate (DCR) by BIRC and Investigator Assessment as Per RECIST 1.1 Up to 6 years DCR is defined as the percentage of participants with a best overall response of Complete Response (CR), Partial Response (PR), Stable Disease (SD), and non-CR/non-progressive disease (for subjects without target lesions). Tumor response based on BIRC and local investigator assessment per RECIST v1.1.
Randomized Part: Overall Response Rate (ORR) by BIRC and Investigator Assessment as Per RECIST 1.1 Up to 6 years ORR is defined as the percentage of participants with a best overall response of Complete Response (CR) and Partial Response (PR). Tumor response based on BIRC and local investigator assessment per RECIST v1.1.
Randomized Part: Time to Response (TTR) by BIRC and Investigator Assessment as Per RECIST 1.1 Up to 6 years TTR is defined as the time from the date of start of treatment to the first documented response of either CR or PR, which must be subsequently confirmed, according to RECIST 1.1.
Randomized Part: Change From Baseline in EORTC QLQ-LC13 Up to 6 years EORTC QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 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 score is based on its presence, hence yes or no. Scores are averaged and transformed to 0 to 100. A higher score indicates a higher presence of symptoms.
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 EORTC QLQ-LC13 is used in conjunction with the EORTC QLQ-C30 and provides information on an additional 13 items specifically related to lung cancer. The five domains of the LC13 include pain in chest, 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 score is based on its presence, hence yes or no. Scores are averaged and transformed to 0 to 100. A higher score indicates a higher presence of symptoms.
The time to definitive 10 points deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the corresponding scale score or death due to any cause.Randomized Part: Progression-Free Survival (PFS) by Investigator Assessment as Per RECIST 1.1 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 investigator assessment per RECIST v1.1.
Randomized Part: Change From Baseline in EORTC QLQ-C30 Up to 6 years The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items and is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact) and a global health status/QoL scale. All scales and single-item measures range in score from 0 to 100. For the functional and the global QoL scales, a higher score indicates better health. For the symptom scales, a higher score indicates more symptom burden. The QLQ-C30 summary score (0-100) is calculated as the mean of 13 of the 15 QLQ-C30 scale and item scores (excluding global QoL and financial impact), with a higher score indicating a better health-related QoL.
Randomized Part: Time to Definitive Deterioration in Global Health Status/QoL, Shortness of Breath and Pain Per EORTC QLQ-C30 Up to 6 years The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact) and a global health status/QoL scale. All scales and single-item measures range in score from 0 to 100. For the functional and the global QoL scales, a higher score indicates better health. For the symptom scales, a higher score indicates more symptom burden.
The time to definitive 10 points deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10 points relative to baseline worsening of the corresponding scale score or death due to any cause.Randomized Part: Change From Baseline in EQ-5D-5L Up to 6 years The EQ-5D-5L is a standardized measure of health utility that provides a single index value for one's health status. The EQ-5D-5L contains one item for each of five dimensions of health-related quality of life (HRQOL) (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Response options for each item vary from having no problems to extreme problems. Subject responses to the five dimensions of HRQOL reflect a specific health state that corresponds to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). A visual analog scale (ranging from 0 to 100) is also included to capture subject's rating of their overall health status. Higher scores of the EQ-5D-5L represent better health states.
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 Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods.
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 Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods.
Randomized Part: Maximum Observed Concentration (Cmax) of Capmatinib and Spartalizumab Up to 6 years Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
Randomized Part: Time to Reach Maximum Concentration (Tmax) of Capmatinib and Spartalizumab Up to 6 years Pharmacokinetic (PK) parameters calculated based on capmatinib and spartalizumab concentrations in plasma and serum, respectively, by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose.
Randomized Part: Number of Participants With Anti-spartalizumab Antibodies Baseline (pre-dose), up to 6 years Immunogenicity (IG) evaluated in serum samples. The assay to quantify and assess the IG was a validated homogeneous enzyme-linked immunosorbent assay (ELISA).
Trial Locations
- Locations (2)
Novartis Investigative Site
🇪🇸Valencia, Comunidad Valenciana, Spain
Massachusetts General Hospital Liver and Kidney TX
🇺🇸Boston, Massachusetts, United States