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

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03647488
• Other study ID #: CINC280D2201
• Secondary ID: 2018-001420-19
• Status: Completed
• Phase: Phase 2
• Start date: December 26, 2018
• Est. completion date: September 7, 2020

Study information

• Verified date: January 2022
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: September 7, 2020
• Est. primary completion date: September 7, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms

Intervention

Drug:
• Capmatinib
Capmatinib 400 mg (tablets) orally taken twice daily
• Spartalizumab
Spartalizumab 400 mg via intravenous infusion once every 28 days
• Docetaxel
Docetaxel 75mg/m2 i.v. following local guidelines as per standard of care and product labels once every 21 days

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Leuven
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	LILLE Cédex
Germany	Novartis Investigative Site	Koeln
Israel	Novartis Investigative Site	Tel Aviv
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
United States	Highlands Oncology Group	Fayetteville	Arkansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Israel,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Plain language trial summaries are available on this link