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/m2 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/m2 and fluorouracil 2400 mg/m2), and subsequent six patients were treated at dose level 1 (irinotecan 165 mg/m2 and fluorouracil 3200 mg/m2). 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/m2 of irinotecan, 85 mg/m2 of oxaliplatin, 200 mg/m2 of l-leucovorin, and 3200 mg/m2 of fluorouracil.
Trial registration number: UMIN000023277.
Keywords: Dose-limiting toxicity; FOLFOXIRI; Metastatic colorectal cancer; Ramucirumab; Recommended phase II dose.