Ramucirumab (Rmab), an anti-VEGFR-2 antibody, inhibits VEGF-A, -C, -D binding and endothelial cell proliferation, although bevacizumab (Bmab) binds to and blocks circulating VEGF-A. We conducted a phase Ib study to determine the recommended phase II dose (RP2D) of FOLFOXIRI plus Rmab for metastatic colorectal cancer (mCRC) patients.
The eligibility criteria included patients with histologically confirmed unresectable colorectal adenocarcinoma, aged 20-75 years, ECOG PS 0-1 (patients > 70 years were eligible if their ECOG PS was 0), wild-type or heterozygous UGT1A1 *28 or *6, no history of prior chemotherapy, and adequate organ function. Three dose levels were planned as follows; oxaliplatin and Rmab dose was fixed at 85 mg/m2 and 8 mg/kg, respectively. Level 1: 5-fluorouracil (5-FU) 3200 mg/m2, irinotecan (IRI) 165 mg/m2, Level 0 as starting dose: 5-FU 2400 mg/m2, IRI 150 mg/m2, and Level -1: 5-FU 2400 mg/m2, IRI 120 mg/m2. Patients were enrolled with a 3 + 3 design manner to evaluate the dose-limiting toxicity (DLT) in the first cycle.
From September 2016 to February 2017, we enrolled a total of 10 patients (4 patients in the Level 0 and 6 patients in the Level 1). The patients’ characteristics were as follows: median age (range), 64 (44-68); male/female, 6/4; ECOG PS 0/1, 8/2; RAS wild/mutant, 1/9; UGT1A1 *1*1/*1*28, 4/6. One patient was excluded for the DLT evaluation due to lack of safety evaluation on cycle 1 day 8. No DLT was observed in the 9 DLT-evaluable patients. In the first cycle, major adverse events were G 4 neutropenia (n = 2), G 3 neutropenia (n = 1), G 3 hypertension (n = 1), G 1/2 diarrhea (n = 6), G 1/2 anorexia (n = 3), G 2 allergic reaction (n = 1), G 1 fatigue (n = 4), G 1 peripheral neuropathy (n = 4), G 1 nausea (n = 2) and G 1 stomatitis (n = 2). G-CSF was administered in 2 patients during the first cycle.
The RP2D for FOLFOXIRI plus Rmab was determined at the Level 1. A randomized phase II study of FOLFIRI plus Rmab versus FOLFOXIRI plus Rmab for chemotherapy-naïve mCRC patients (WJOG9216G trial; UMIN000026527) is on-going. The update results will be presented in the congress.
Clinical trial identification
Legal entity responsible for the study
Shizuoka Cancer Center
Shizuoka Cancer Center
All authors have declared no conflicts of interest.