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

Abstract

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 100 mg once daily [q.d.] to 600 mg twice daily [b.i.d.]) and 15 received tablets (200 mg b.i.d. and 400 mg b.i.d.). DLT occurred in two patients: grade 2 suicidal ideation (600 mg b.i.d. capsule) and grade 3 depression (400 mg b.i.d. tablet). MTD was not reached. The highest studied dose determined to be safe as tablet was 400 mg 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 (Tmax ) was 1.0-4.0 hours; absorption was more rapid after dosing using tablets, with median Tmax of 1.0 hour on both days 1 and 15. Eight patients had a best overall response of stable disease. These data support further clinical development of capmatinib.

• Authors: Taito Esaki, Fumihiko Hirai, Akitaka Makiyama, Takashi Seto, Hideaki Bando, Yoichi Naito, Kiyotaka Yoh, Kae Ishihara, Tomoyuki Kakizume, Kazuto Natsume, Andrea Myers, Toshihiko Doi
• Journal: Cancer science (Cancer Sci) Vol. 110 Issue 4 Pg. 1340-1351 (Apr 2019) ISSN: 1349-7006 [Electronic] England
• PMID: 30724423 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• Benzamides
• Biomarkers
• Imidazoles
• Protein Kinase Inhibitors
• Triazines
• capmatinib

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Benzamides
• Biomarkers
• Female
• Humans
• Imidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms (drug therapy, metabolism, mortality, pathology)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Survival Analysis
• Treatment Outcome
• Triazines (administration & dosage, adverse effects, pharmacokinetics)