This study assessed the safety and efficacy of escalating doses INC280 when added to gefitinib in patients with lung cancer that were known to have dysregulation of the c-MET pathway and who had failed after benefiting on a prior treatment with either gefitinib or erlotinib.
The Phase Ib dose escalation part was aimed at the determination of the MTD/RP2D of capmatinib in combination with 250 mg gefitinib in patients with NSCLC patients with epidermal growth factor receptor (EGFR) mutation and cMET dysregulation and showing disease progression following EGFR tyrosine-kinase inhibitor (EGFR TKI) therapy. Dose escalation started with a dose of 100 mg/day to a maximum of 1200 mg/day, as capsule or tablet formulation. Successive cohorts of patients were to receive increasing doses of capmatinib in combination with a 250 mg once daily (qd) dose of gefitinib until the MTD/RP2D of capmatinib had been determined. The Phase II dose expansion part consisted of 400 mg capmatinib twice daily (bid), as either capsules or tablets, in combination with 250 mg gefitinib.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
161
Phase Ib: Frequency of Dose Limiting Toxicities (DLTs)
A dose-limiting toxicity (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.
Time frame: Up to 215 weeks
Phase II : Overall Response Rate (ORR)
Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (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 Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
Time frame: Until disease progression, up to 60.8 weeks
Phase Ib and II: Number of Participants With Adverse Events (AEs)
Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time frame: Up to 421 weeks
Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs)
Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Time frame: Up to 421 weeks
Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level
Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.
Time frame: Up to 417 weeks
Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level
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Novartis Investigative Site
Woolloongabba, Queensland, Australia
Novartis Investigative Site
East Bentleigh, Victoria, Australia
Novartis Investigative Site
Auckland, Australia
Novartis Investigative Site
Leuven, Belgium
Novartis Investigative Site
Guangzhou, Guangdong, China
Novartis Investigative Site
Shanghai, Shanghai Municipality, China
Novartis Investigative Site
Beijing, China
Novartis Investigative Site
Guangzhou, China
Novartis Investigative Site
Strasbourg, France
Novartis Investigative Site
Toulouse, France
...and 21 more locations
Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability
Time frame: Up to 417 weeks
Phase II: Overall Survival (OS)
Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause
Time frame: From date of treatment until death due to any cause, up to 70.2 months
Phase II: Progression Free Survival (PFS)
Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.
Time frame: Up to 60.8 months
Phase II: Duration of Response (DoR)
Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer.
Time frame: Up to 23.2 months
Phase I: PK Parameters AUCtau of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Phase I: PK Parameters Cmax of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Phase I: PK Parameters Tmax of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)
Phase I: PK Parameters Half-life of INC280 and Gefitinib
PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda\_z) of a semi-logarithmic plasma concentration-time curve
Time frame: Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days)