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

Abstract

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 28th, 2018.