Phase I results from a two-part Phase I/II study of cediranib in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer

Background Colorectal cancer (CRC) is the second most common malignancy in Japan. Inhibition of vascular endothelial growth factor (VEGF) signaling is a clinically validated therapeutic strategy in patients with metastatic CRC. Cediranib is an oral, highly potent VEGF signaling inhibitor of all three VEGF receptors. Methods This Phase I study investigated the safety, tolerability and pharmacokinetics of cediranib (20 or 30 mg) in combination with mFOLFOX6 in Japanese patients with previously untreated metastatic CRC. If the safety of the 20 mg dose was confirmed, a second cohort of patients was to be recruited to receive cediranib 30 mg + mFOLFOX6. Results Six patients received cediranib 20 mg + mFOLFOX6 and seven received cediranib 30 mg + mFOLFOX6. One patient in the initial cediranib 20 mg cohort experienced a dose-limiting toxicity (DLT; grade 3 bilirubin increase); no DLTs were observed in the 30 mg cohort. The most commonly reported adverse events were diarrhea, decreased appetite, peripheral neuropathy, hypertension and fatigue. Two patients in the 20 mg cohort and three in the 30 mg cohort experienced serious adverse events during all treatment courses. Cediranib was generally well tolerated in this patient population with no evidence to suggest any significant pharmacokinetic interactions between cediranib and fluorouracil or oxaliplatin. A preliminary evaluation showed that five of nine evaluable patients achieved a best response of partial response. Conclusion Cediranib (20 or 30 mg) in combination with mFOLFOX6 was considered tolerable according to the protocol-defined criteria, providing justification for the Phase II part of this study.