1977 - Randomized phase II study of FOLFIRI plus ramucirumab (Rmab) versus FOLFOXIRI plus Rmab as first-line treatment for patients with metastatic colorectal cancer (mCRC): WJOG9216G

Background

Rmab, an anti-VEGFR-2 antibody, inhibits VEGF-A, -C, -D binding and endothelial cell proliferation, while bevacizumab (Bmab) binds to and blocks circulating VEGF-A. The RAISE trial showed the survival benefit of FOLFIRI plus Rmab compared with FOLFIRI plus placebo as second-line treatment for patients with mCRC. The TRIBE trial demonstrated that FOLFOXIRI plus Bmab improved overall response rate (ORR), progression-free survival and overall survival compared with FOLFIRI plus Bmab as induction therapy followed by maintenance therapy with fluorouracil (5-FU), l-leucovorin (l-LV) and Bmab. However, little is known about the role of Rmab in first-line setting and the comparison of induction followed by maintenance therapy with continuous therapy continued until progressive disease (PD) or unacceptable toxicity.

Trial design

WJOG9216G is an open-label, randomized phase II study evaluating FOLFIRI plus Rmab until PD (arm A) versus FOLFOXIRI plus Rmab for 8 to 12 cycles followed by maintenance therapy with 5-FU, l-LV and Rmab (arm B) for patients with mCRC. Eligibility criteria include histologically confirmed unresectable colorectal adenocarcinoma, age of 20-75 years, ECOG PS of 0 or 1, without UGT1A1 *6/ *6, *28/ *28 or *6/ *28, no history of prior chemotherapy for mCRC, and adequate organ function. Stratification criteria are institution, RAS status, history of adjuvant chemotherapy, and primary tumor location. Arm A comprises Rmab 8 mg/kg, irinotecan (IRI) 180 mg/m², l-LV 200 mg/m², and bolus 5-FU 400 mg/m² followed by a 46-hour continuous infusion (ci) of 5-FU 2400 mg/m² every 2 weeks until PD. Arm B consists of 8 to 12 cycles of FOLFOXIRI plus Rmab (Rmab 8 mg/kg, IRI 165 mg/m², oxaliplatin 85 mg/m², l-LV 200 mg/m², and 5-FU ci 3200 mg/m²) as induction therapy followed by 5-FU/l-LV plus Rmab until PD. Primary endpoint is ORR, and main secondary endpoints are PFS, PFS2, OS and safety. Sample size was calculated to be 120 (60 patients per arm), with a one-sided alpha of 10% and a power of 80%, assuming ORR of 50% in arm A and of 70% in arm B. This study has enrolled 23 patients as of April 28^th, 2018.

Clinical trial identification

UMIN000026527 (Release date: March 13^th, 2017).

Legal entity responsible for the study

West Japan Oncology Group.

Funding

Eli Lilly Japan K.K.

Editorial Acknowledgement

Disclosure

H. Yasui: Honoraria: Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Bristol-Myeres Squibb Japan, Takeda, Kyowa Hakko Kirin, Medicon, Ono Pharmaceutical, Daiichi Sankyo, Lilly Japan, Merk Serono, Terumo, Becton Dickinson, Nihonkayaku. H. Hara: Consulting or advisory role: Ono Pharmaceutical, Chugai Pharma, Merck Serono, and MSD; Honoraria from Chugai Pharma, Taiho Pharmaceutical, Merck Serono, Yakult Honsha, Lilly, Ono Pharmaceutical, Takeda; Author's institution has received research funding: AstraZeneca, Chugai Pharma, Merck Serono, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Daiichi Sankyo, Lilly, Pfizer, LSK BioPharma, Eisai, Incyte. E. Baba: Honoraria: Chugai Pharma, Lilly Pharma; Author's institution has received research funding: Chugai Pharma, Lilly Pharma, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Merck Serono Ltd. K. Yoshimura: Honoraria: Chugai Pharma, Lilly, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Takeda, Eisai. S. Hironaka: Consulting or advisory role: Astra Zeneca; Honoraria: Lilly, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Taiho Pharmaceutical, Yakult Honsha, Daiichi Sankyo. K. Muro: Honoraria: Takeda, Chugai Pharma, Yakult Honsha, Merck Serono, Taiho Pharmaceutical, Lilly, Ono Pharmacutical; Research funding: Ono Pharmaceutical, MSD, Daiichi Sankyo, Shionogi Pharma, Kyowa Hakko Kirin, Gilead Sciences. K. Yamazaki: Honoraria: Chugai Pharma, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Bristol-Myers Squibb Japan, Taiho Pharmaceutical, and Lilly; Author's institution has received research funding: Taiho Pharmaceutical. All other authors have declared no conflicts of interest.