Phase Ib study of FOLFOXIRI plus ramucirumab as first-line treatment for patients with metastatic colorectal cancer

Purpose Ramucirumab, an anti-vascular endothelial growth factor (VEGF) receptor2 monoclonal antibody, inhibits VEGF-A, VEGF-C, and VEGF-D binding and endothelial cell proliferation. We conducted a phase Ib study to determine the recommended phase II dose (RP2D) of fluorouracil, l -leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus ramucirumab. Methods This phase Ib study investigated three dose levels of FOLFOXIRI plus ramucirumab (three dose levels of irinotecan and fluorouracil with fixed dose of oxaliplatin 85 mg/m 2 and ramucirumab 8 mg/kg on day 1, repeated every 2 weeks) in chemotherapy-naïve patients with metastatic colorectal cancer (mCRC). Dose-limiting toxicity (DLT) was assessed during the first cycle. Results A total of ten patients were enrolled. The first four patients received the treatment at dose level 0 (irinotecan 150 mg/m 2 and fluorouracil 2400 mg/m 2 ), and subsequent six patients were treated at dose level 1 (irinotecan 165 mg/m 2 and fluorouracil 3200 mg/m 2 ). No DLT was observed in the nine DLT-evaluable patients, which indicated that the RP2D was dose level 1. Grade 3 or worse adverse events included neutropenia (70%), hypertension (20%), and febrile neutropenia (10%). No treatment-related death was observed in any cycle. The overall response rate was 70%. Conclusion The RP2D of FOLFOXIRI plus ramucirumab was determined to be 8 mg/kg of ramucirumab, 165 mg/m 2 of irinotecan, 85 mg/m 2 of oxaliplatin, 200 mg/m 2 of l -leucovorin, and 3200 mg/m 2 of fluorouracil. Trial registration number UMIN000023277.