TAS-102 is an oral nucleoside antitumor agent, which demonstrated significant improvement in overall survival over placebo in patients (pts) with metastatic colorectal cancer (mCRC). Nintedanib is a triple angiokinase inhibitor of VEGFR (1, 2, 3), PDGFR (a, ß), and FGFR (1, 2, 3). A global phase III study is ongoing to compare nintedanib with placebo in pts with mCRC resistant to standard therapies. In preclinical models, the combination of TAS-102 plus nintedanib demonstrated enhanced activity against CRC compared with either drug alone (Suzuki N, et al. AACR 2016). This study investigates efficacy and safety of TAS-102 with nintedanib, and herein we present the results of the phase I part.
The key eligibility criteria were pts with mCRC refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-angiogenesis inhibitor and anti-EGFR antibody (if wild-type RAS) and without prior regorafenib. Phase I part was designed to determine the recommended phase II dose (RP2D) in a “3 + 3” cohort-based dose escalation design of nintedanib (150mg BID every day on level 1 and 200mg BID every day on level 2) adding to standard-dose of TAS-102.
Three patients were treated in level 1, and 6 pts in level 2. No dose-limiting toxicities were observed at either level. The most common grade 3 or worse treatment-associated adverse events were neutropenia (67%), anaemia (33%), and increased liver enzymes (22%; asymptomatic reversible grade 3 AST/ALT elevation without any bilirubin elevation). The disease control rate was 100%, and 8 pts (89%) showed any tumor shrinkage including one partial response. With a median follow-up of 113 days (ranging from 85 to 180 days), six patients still continued the study treatment. The relative dose intensity was 86.4% for TAS-102 and 89.8% for nintedanib. Drug–drug interaction was not indicated by pharmacokinetic analysis.
Standard-dose of TAS-102 with nintedanib 200 mg BID was tolerable and determined as RP2D. This combination regimen had a promising antitumor activity, which will be confirmed by ongoing phase II part.
Clinical trial identification
Clinical trial information: UMIN000017114. Release date: 13/April/2015
Legal entity responsible for the study
Declaration of Helsinki, Ministerial Ordinance on Good Clinical Practice
T. Nishina, E. Shinozaki, K. Yamaguchi: Other Substantive Relationships: (Honoraria (lecture fee) from: Taiho Pharmaceutical). Y. Komatsu: Corporate-sponsored Research: Boehringer Ingelheim GmbH Other Substantive Relationships: (Honoraria (lecture fee) from: Taiho Pharmaceutical). S. Yuki: Other Substantive Relationships:(Honoraria (lecture fee) from: Taiho Pharmaceutical, Merck Serono, Bristol-Myers Squibb, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Yakuhin, Eli Lilly Japan). K. Yamazaki: Other Substantive Relationships: (Honoraria (lecture fee) from: Taiho Pharmaceutical). H. Hara: Other Substantive Relationships: (Honoraria (lecture fee) from: Taiho Pharmaceutical, Merck Serono, Chugai Pharmaceutical, Eli Lilly Japan, Yakult Honsha). S. Nomura: Personal fees from Japan Breast Cancer Research Group: (JBCRG), and grants from Japan Agency for Medical Research and Development: (AMED), outside the submitted work. T. Yoshino: Corporate-sponsored Research: GlaxoSmithKline K.K. and Boehringer Ingelheim GmbH All other authors have declared no conflicts of interest.