Phase I Study of Cediranib in Combination with Oxaliplatin and Infusional 5-Fluorouracil in Patients with Advanced Colorectal Cancer

Abstract

Purpose: Cediranib is a potent oral inhibitor of the tyrosine kinase activity associated with all subtypes of vascular endothelial growth factor receptor. Purposes of this study were to determine the recommended phase II dose of cediranib in combination with standard doses of modified FOLFOX-6 (mFOLFOX-6), and the tolerability, safety, pharmacokinetics, and antitumor activity of this combination in patients with untreated metastatic colorectal cancer. Experimental Design: Cediranib was administered daily orally at a starting dose of 30 mg and escalated to 45 mg daily, and mFOLFOX-6 was repeated every 14 days. Pharmacokinetic studies were done for oxaliplatin, 5-fluorouracil, and cediranib. Response was assessed by Response Evaluation Criteria in Solid Tumors every four cycles. Results: Sixteen patients received 150 cycles of treatment (median, 6; range, 1-20 cycles). Of 9 patients enrolled at the 30-mg dose level, 1patient experienced grade 3 diarrhea during cycle 1. No dose-limiting toxicity was observed in 7 patients at the 45-mg dose level. Common grade 3 toxicities related to cediranib included hypertension, diarrhea, fatigue, and anorexia. Of 14 patients evaluable for response, there were 6 partial responses (42.9 %; 95 % confidence interval, 17.7-71.1%) and 6 stable disease. The median progression-free survival was 9.3 months. There were no pharmacokinetic interactions between cediranib and 5-fluorouracil or free plasma intact oxaliplatin. Conclusions: Toxicities of this combination were manageable and consistent with previous studies. The recommended phase II dose is cediranib at 30 mg daily continuously in combination with standard doses of mFOLFOX-6. Cediranib and mFOLFOX-6 has promising antitumor activity and this combination warrants further investigation.

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

“…Two doses of cediranib (20 mg and 30 mg) were investigated in this Phase I study. This decision was consistent with the previous selection of both doses for the HORIZON Phase II/III program of evaluation in Western patients with CRC [15,16], which was itself based in part on Phase I data showing cediranib 20 mg or 30 mg in combination with mFOLFOX6 to be tolerable, with preliminary evidence of antitumor activity [11,13]. Since the present study was the first to investigate the addition of cediranib to mFOLFOX6 in Japanese patients, determination of the tolerability of cediranib 20 mg or 30 mg in combination with mFOLFOX6 was required to provide justification for continuation to the Phase II part of the study.…”

“…In a Phase I study of Japanese patients with advanced solid tumors, cediranib was well tolerated as a monotherapy at doses of ≤30 mg/day [9]. Subsequent Phase I combination studies demonstrated that cediranib was generally well tolerated at doses up to 30 mg/day in combination with various anticancer agents [10][11][12][13][14].…”

Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial

“…Results with small-molecule multikinase inhibitors with a broader spectrum of inhibitory targets than mAbs (35) have also been mixed, although limited data are available in addition to the results reported here (36)(37)(38)(39)(40). In 2 phase III trials in mCRC, adding vatalanib (targets VEGFR1-3, PDGFRb, and KIT) to first-or second-line FOLFOX4 did not improve PFS or overall survival (36,37), and a phase III study of sunitinib (targets VEGFR1-3, PDGFRa/b, KIT, FLT3, CSF1R, RET) with FOLFIRI failed to show an improvement in the primary endpoint of PFS (41).…”

Phase II Study of Cediranib in Patients with Advanced Gastrointestinal Stromal Tumors or Soft-Tissue Sarcoma

“…In vitro, cediranib has been shown to inhibit two mutant forms of KIT (V654A, N822K) associated with secondary resistance to imatinib, but has not been shown to inhibit all mutants thought to be responsible for the development of resistance to imatinib and sunitinib (10). In phase I and II studies, cediranib has demonstrated evidence of antitumor activity in patients with advanced solid tumors, both as a single agent and in combination with other anticancer strategies (11)(12)(13)(14)(15)(16)(17).…”