Dose finding phase Ib study of FOLFOXIRI plus ramucirumab as first-line therapy for patients with metastatic colorectal cancer: The initial safety analysis

Abstract

Introduction: Ramucirumab (Rmab), an anti‐VEGFR‐2 monoclonal antibody, inhibits VEGF‐A, ‐C, ‐D binding and endothelial cell proliferation, although bevacizumab (Bmab) binds to and blocks circulating VEGF‐A. Recently, Rmab showed survival benefit in combination with FOLFIRI for metastatic colorectal cancer (mCRC) patients who were failed to Bmab plus oxaliplatin (OX)‐based chemotherapy. FOLFOXIRI plus Bmab is established as one of the first‐line treatments for mCRC patients based on the results of the TRIBE study. We conducted a phase Ib study to determine the recommended phase II dose (RP2D) of FOLFOXIRI plus Rmab. Methods: 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; OX 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), which was defined as grade (G) 4 neutropenia continuing for >7 days, febrile neutropenia, G 4 thrombocytopenia and G 3/4 non‐hematological toxicities during the first cycle, and delay in starting the second cycle for > 14 days. The RP2D was defined as the highest dose level where no more than 2 of 6 patients experience the DLT. Results: 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). Among them, the data during the first cycle were fixed in 9 patients at the cut‐off date of 14 March 2017. The patients' characteristics were as follows: median age (range), 64 (44‐68); male/female, 5/4; ECOG PS 0/1, 7/2; RAS wild/mutant, 1/8; UGT1A1∗1∗1/∗1∗6/∗1∗28, 4/0/5. One patient was excluded for the DLT evaluation due to lack of safety evaluation on day 8 of the first cycle. No DLT was observed in the 8 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=4), G 1/2 anorexia (n=3), G 2 allergic reaction (n=1), G 1 fatigue (n=3), G 1 peripheral neuropathy (n=3), G 1 nausea (n=2) and G 1 stomatitis (n=2). G‐CSF was administered in 2 patients during the first cycle. Conclusion: The RP2D for FOLFOXIRI plus Rmab was determined at the level 1 (5‐FU 3200 mg/m2, OX 85 mg/m2, IRI 165 mg/m2 and Rmab 8 mg/kg). A randomized phase II study of FOLFIRI plus Rmab versus FOLFOXIRI plus Rmab for chemotherapy‐naïve mCRC patients (WJOG9216G trial) is on‐going. The update results will be presented in the congress.