Yosuke Kito1,2, Hironaga Satake3,4, Hiroya Taniguchi5,6, Takeshi Yamada7, Yoshiki Horie8, Taito Esaki9, Tadamichi Denda10, Hisateru Yasui4, Naoki Izawa8, Toshiki Masuishi6, Toshikazu Moriwaki7, Keita Mori11, Kentaro Yamazaki12. 1. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan. kitoyo9100@gmail.com. 2. Department of Medical Oncology, Ishikawa Prefectural Central Hospital, 2-1, Kuratsuki-higashi, Kanazawa, Ishikawa, 920-8530, Japan. kitoyo9100@gmail.com. 3. Cancer Treatment Center, Kansai Medical University Hospital, Osaka, Japan. 4. Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan. 5. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. 6. Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 7. Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 8. Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan. 9. Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan. 10. Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan. 11. Clinical Research Center, Shizuoka Cancer Center, Shizuoka, Japan. 12. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
Abstract
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.
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.