Phase I dose-escalation study of capmatinib (INC280) in Japanese patients with advanced solid tumors

Capmatinib is a highly specific, potent and selective MET inhibitor. This was an open-label, multicenter, dose-escalation, phase I study conducted in Japanese patients with advanced solid tumors (not selected based on their MET status). The primary objective was to determine the maximum tolerated dose (MTD) and/or highest studied dose being safe. Secondary objectives included safety, pharmacokinetics and preliminary antitumor activity. Dose escalation was guided by a Bayesian Logistic Regression Model dependent on dose-limiting toxicities (DLT) in cycle 1. Of 44 adult Japanese patients with confirmed advanced solid tumors enrolled, 29 received capmatinib capsules (doses ranging from 100mg once daily [q.d.] to 600mg twice daily [b.i.d.]) and 15 received tablets (200mg b.i.d. and 400mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600mg b.i.d. capsule) and grade 3 depression (400mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400mg b.i.d., whereas it is not yet determined for capsules. Most common adverse events suspected to be drug-related were increased blood creatinine, nausea, decreased appetite, vomiting and diarrhea. Following repeated daily dosing up to day 15 by q.d. or b.i.d. regimen using capsules, median time to reach maximum plasma drug concentration (T-max) was 1.0-4.0hours; absorption was more rapid after dosing using tablets, with median T-max of 1.0hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.