Study of Capmatinib and Spartalizumab Combination Therapy vs Docetaxel in Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this trial was to evaluate the safety and efficacy of capmatinib in combination with spartalizumab in adult participants with epidermal growth factor receptor (EGFR) wild type (for exon 19 deletions and exon 21 L858R substitution mutations), anaplastic lymphoma kinase (ALK) rearrangement negative in locally advanced (stage IIIB, not eligible for definitive chemo-radiation) or metastatic (stage IV) Non-small cell lung cancer (NSCLC) after failure of platinum doublet and checkpoint inhibitor treatment.

Detailed Description
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This was a two-part prospectively designed, multicenter, open-label, randomized phase II study. Part 1: Run-in. Prior to the randomized part of the study, a run-in to assess the safety and tolerability as well as preliminary efficacy of the capmatinib and spartalizumab combination was conducted. Participants were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days. A review was planned to take place after all participants had at least 24 weeks of follow-up. The decision to expand the study to the randomized part was to be based on the safety, tolerability, and preliminary efficacy of the capmatinib and spartalizumab combination. Part 2: Randomized. Subjects were planned to be randomized to one of the following arms in a 2:1 ratio: 1) combination of capmatinib 400 mg BID and spartalizumab 400 mg i.v. once every 28 days; 2) docetaxel 75 mg/m2 i.v. following local guidelines as per standard of care and product labels. Based on the results obtained in the run-in part of the study, the randomized part was not opened. For the run-in part of the study, the treatment period began on Cycle 1 Day 1 and continued in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of informed consent, pregnancy, lost to follow-up, or death irrespective of start of new anti-neoplastic therapy. After treatment discontinuation, all subjects were followed for safety evaluations during the safety follow-up period, and the subject's status was collected every 8 weeks as part of the survival follow-up

Official Title
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Phase II Multicenter Randomized Two-arm Study of Capmatinib and Spartalizumab Combination Therapy vs Docetaxel in Pretreated Adult Patients With EGFR Wild-type ALK Rearrangement Negative Advanced/Metastatic Non-small Cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Capmatinib
* Drug: Spartalizumab
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed locally advanced/metastatic (stage IIIB/IV), EGFR wild-type, ALK rearrangement negative, non-small cell lung cancer Subject had demonstrated progression following one prior platinum doublet and one prior PD-(L)1 checkpoint inhibitor (either alone or in combination, the most recent treatment regimen must have contained a PD-(L)1 checkpoint inhibitor) Subjects must be candidates for single agent docetaxel Subjects must have at least one lesion evaluable by RECIST 1.1 Exclusion Criteria: Prior treatment with a MET inhibitor or HGF (Hepatocyte growth factor) targeting therapy Any untreated central nervous system (CNS) lesion Use of any live vaccines against infectious diseases within 12 weeks of initiation of study treatment. Other protocol-defined inclusion/exclusion criteria might 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
Intervention Model: Single Group Assignment
Interventional Model Description: Run-in part was single group. Randomized part (parallel design) was not opened.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Run-in part: capmatinib + spartalizumab<br>Participants (enrolled in the run-in part) were treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days | Drug: Capmatinib<br>* Capmatinib 400 mg (tablets) orally taken twice daily<br>* Other names: INC280;Drug: Spartalizumab<br>* Spartalizumab 400 mg via intravenous infusion once every 28 days<br>* Other names: PDR001;|
| Experimental: Randomized part: capmatinib+spartalizumab<br>Participants (enrolled in the randomized part) treated with capmatinib 400 mg twice daily (BID) and spartalizumab 400 mg intravenously (i.v.) once every 28 days | Drug: Capmatinib<br>* Capmatinib 400 mg (tablets) orally taken twice daily<br>* Other names: INC280;Drug: Spartalizumab<br>* Spartalizumab 400 mg via intravenous infusion once every 28 days<br>* Other names: PDR001;|
| Active Comparator: Randomized part: docetaxel<br>Participants (enrolled in the randomized part) treated with docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days | Drug: Docetaxel<br>* Docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Run-in Part: Percentage of Participants With Dose Limiting Toxicities (DLTs) | A DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol. | From the day of the first dose of study medication up to 56 days | 
| Run-in Part: Percentage of Participants With Adverse Events (AEs) | Percentage of participants with AEs, including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0: Grade 1: mild; Grade 2: moderate; Grade 3: severe or medically significant; Grade 4: life-threatening consequences; Grade 5: Death | From the day of the first dose of study medication to 150 days after the last dose of spartalizumab, or 30 days after the last dose of capmatinib (whichever is later) up to maximum duration of approximately 1.7 years | 
| Run-in Part: Percentage of Participants With at Least One Dose Reduction. | Percentage of participants with at least one dose reduction. Dose reductions were only allowed for capmatinib | From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks | 
| Run-in Part: Percentage of Participants With at Least One Dose Interruption | Percentage of participants with at least one dose interruption. Dose interruptions were allowed for capmatinib and spartalizumab. | From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks | 
| Run-in Part: Relative Dose Intensity Received by Participants | The relative dose intensity of capmatinib and spartalizumab is computed as the ratio of dose intensity and planned dose intensity, multiplied by 100. | From the day of the first dose of study medication to end of treatment, assessed up to maximum duration of 68 weeks | 
| Randomized Part: Overall Survival (OS) | OS is defined as the time from date of start of treatment to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last known date patient alive. Results are not available because randomized part never started. | From start of treatment to death due to any cause, assessed until the end of the study (up to a planned duration of 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) Based on RECIST 1.1 and as Per Investigator Assessment | ORR is defined as the percentage of subjects with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and as per investigator assessment. 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. ORR results for randomized part are not available because randomized part never started. | From start of treatment until end of treatment, assessed up to 68 weeks (run-in part) | 
| Disease Control Rate (DCR) Based on RECIST 1.1 and as Per Investigator Assessment | DCR is defined as the percentage of subjects with best overall response of CR or PR or stable disease based on RECIST 1.1 and as per investigator assessment. 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. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression. DCR results for randomized part are not available because randomized part never started. | From start of treatment until end of treatment, assessed up to 68 weeks (run-in part) | 
| Progression Free Survival (PFS) | PFS is defined as the time from the date of start of treatment to the date of the first documented radiological progression or death due to any cause. For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. Progression is defined using RECIST 1.1 and as per investigator assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. PFS results for randomized part are not available because randomized part never started. | From start of treatment until the first documented radiological progression or death, whichever comes first, assessed up to 68 weeks (run-in part) | 
| Time to Response (TTR) Based on RECIST 1.1 and as Per Investigator Assessment | 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. TTR was evaluated according to RECIST 1.1 and as per investigator assessment. 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. For run-in part, TTR results are not available because there were no participants achieving response (CR or PR) For randomized part , TTR results are not available because randomized part never started. | From start of treatment to the first documented response of either complete response or partial response, assessed up to 68 weeks (run-in part) | 
| Duration of Response (DOR) Based on RECIST 1.1 and as Per Investigator Assessment | DOR is the time between the date of first documented response(CR or PR) and the date of first documented progression or death due to underlying cancer based on RECIST1.1 and as per investigator assessment. If progression or death has not occurred, the subject is censored at the date of last adequate tumor assessment. CR: Disappearance of all non-nodal target lesions and 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. Progression: at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. The sum must also demonstrate an absolute increase of at least 5 mm. Results are not available because there were no participants achieving response in the run-in part and randomized part never started | From first documented response (CR or PR) to first documented progression or death, whichever came first, assessed up to 68 weeks (run-in part) | 
| AUClast of Capmatinib | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods. | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | 
| AUCtau of Capmatinib | AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods. | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | 
| Maximum Plasma Concentration (Cmax) of Capmatinib | The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods. | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | 
| Time to Reach Maximum (Tmax) Plasma Concentration of Capmatinib | Tmax is the time to reach maximum (peak) plasma concentration of capmatinib after single dose administration (time). Tmax was calculated using non-compartmental methods. | Cycle 3 day 1 at predose, 0.5 hours (h), 1h, 2h, 4h and 8h postdose. Each Cycle is 28 days | 
| AUClast of Spartlizumab | AUClast is the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration. AUClast was calculated using non-compartmental methods. | CCycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | 
| AUCtau of Spartlizumab | AUCtau is the area under the plasma concentration-time curve from time zero to the end of the dosing interval Tau. AUCtau was calculated using non-compartmental methods. | Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | 
| Maximum Plasma Concentration (Cmax) of Spartlizumab | The maximum (peak) observed plasma concentration after single dose administration. Cmax was calculated using non-compartmental methods. | Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | 
| Time to Reach Maximum (Tmax) Plasma Concentration of Spartlizumab | Tmax is the time to reach maximum (peak) plasma concentration of spartlizumab after single dose administration (time). Tmax was calculated using non-compartmental methods. | Cycle 3 day 1 at predose and 1 hour postdose (up to 1.53 hours postdose), cycle 3 day 4 (=72 hours postdose), cycle 3 day 8 (=168 hours postdose) and cycle 3 day 15 (=336 hours postdose). Each Cycle is 28 days | 
| Spartalizumab Antidrug Antibodies (ADA) Prevalence at Baseline | ADA prevalence at baseline was calculated as the proportion of participants who had an ADA positive result at baseline | Cycle 1 Day 1 at predose. Each Cycle is 28 days | 
| Spartalizumab ADA Incidence On-treatment | ADA incidence on treatment was calculated as the proportion of participants who were treatment-induced ADA positive (post-baseline ADA positive with ADA-negative sample at baseline) and treatment-boosted ADA positive (post-baseline ADA positive with titer that is at least the fold titer change greater than the ADA-positive baseline titer) | Predose at Cycle (C)1 Day (D)1, C2D1, C3D1, C4D1, C6D1, C8D1, C10D1, C12D1, thereafter every 6 cycles until discontinuation, and end of treatment (EOT), 30-day and 150-day after EOT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-small-cell lung carcinoma, Non-small-cell lung cancer, NSCLC, epidermal growth factor receptor wild type, EGFRwt, Anaplastic lymphoma kinase negative, ALK-, INC280, capmatinib and spartalizumab, combination therapy, docetaxel