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A multicentre phase I/II study of TAS-102 with nintedanib in patients with metastatic colorectal cancer refractory to standard therapies (N-TASK FORCE: EPOC1410); Phase I results

Date

08 Oct 2016

Session

Poster Display

Presenters

Tomohiro Nishina

Citation

Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370

Authors

T. Nishina1, Y. Kuboki2, E. Shinozaki3, S. Fukuoka2, T. Kajiwara1, K. Shitara2, K. Yamaguchi3, Y. Komatsu4, S. Yuki5, K. Yamazaki6, H. Hara7, N. Mochizuki8, M. Fukutani9, H. Hasegawa10, S. Matsuda9, M. Wakabayashi9, S. Nomura10, A. Sato10, A. Ohtsu2, T. Yoshino2

Author affiliations

  • 1 Department Of Gastrointestinal Medical Oncology, Shikoku Cancer Center, 791-0280 - Matsuyama/JP
  • 2 Department Of Gi Oncology, National Cancer Center Hospital East, Kashiwa/JP
  • 3 Department Of Gastroenterology, Cancer Institute Hospital of JFCR, 135-8550 - Tokyo/JP
  • 4 Department Of Cancer Chemotherapy, Hokkaido University Hospital, 060-8638 - Sapporo/JP
  • 5 Gastroenterology And Hepatology, Hokkaido University Hospital, 060-8638 - Sapporo/JP
  • 6 Division Of Gastrointestinal Oncology, Shizuoka Cancer Center, 411-8777 - Shizuoka/JP
  • 7 Department Of Gastroenterology, Saitama Cancer Center, Saitama/JP
  • 8 Department Of Pharmacy, National Cancer Center Hospital East, Kashiwa/JP
  • 9 Office Of Clinical Research Support, National Cancer Center Hospital East, Kashiwa/JP
  • 10 Office Of Clinical Research Support, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
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Resources

Background

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.

Methods

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.

Results

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.

Conclusions

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

Funding

Boehringer Ingelheim

Disclosure

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.

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