Abstract 30: The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors.

Background: Dovitinib (TKI258) is an oral receptor tyrosine kinase inhibitor with demonstrated antitumor activity in patients with advanced cancer including metastatic renal cell carcinoma (mRCC). This phase 1 study was designed to determine the relative bioavailability of 2 capsule formulations of dovitinib (Arm 1), the anhydrate clinical service form (CSF) and the monohydrate final market image (FMI), and to assess the effect of food on dovitinib exposure in the preferred formulation (Arm 2) in patients with advanced solid tumors. Both arms employed crossover designs. Materials and methods: In Arm 1, patients received a single 500-mg dose of either the CSF or FMI formulation, followed by 7 days of rest and then a single 500-mg dose of the other formulation. Blood samples were collected to determine plasma pharmacokinetic (PK) profiles. The relative bioavailability of FMI vs CSF was determined using a linear mixed effects model fitted to log-transformed PK parameters Cmax and AUC0-tlast. In Arm 2, patients received 300 mg of the FMI capsule once daily for 22 days and were randomized to 1 of 6 sequences each with crossover between 3 fed states (no meal [NM], low-fat [LF] meal, or high-fat [HF] meal) during 3 periods (days 1-8, days 9-14, and days 16-22). The relative bioavailability of dovitinib under LF and HF vs the NM state was determined using the same model as described in Arm 1 for the PK parameters Cmax and AUC0-tlast. Results: Based on the interim analysis, PK was assessed in 16 evaluable patients in Arm 1. The geometric mean ratios (GMR; 90% CI) for Cmax and AUC0-tlast comparing FMI vs CSF were 0.94 (0.85-1.04) and 0.88 (0.80-0.95), respectively. Based on comparable bioavailability, Arm 2 employed the FMI formulation. PK was assessed in 19 patients. Cmax GMR (90% CI) was 0.94 (0.83-1.06) and 1.07 (0.94-1.21) for HF/NM and LF/NM, respectively. AUC0-tlast GMR (90% CI) was 1.00 (0.91-1.11) and 1.09 (0.99-1.20) for HF/NM and LF/NM, respectively. Conclusions: The oral bioavailability of the FMI and CSF formulations were comparable, and there was no clinically relevant effect of HF or LF food on the bioavailability of dovitinib. Based on these results, dovitinib can be taken with or without food, and the FMI capsule formulation was selected for the ongoing pivotal phase 3 study of dovitinib compared with sorafenib in patients with mRCC. Citation Format: Sunil Sharma, Carolyn D. Britten, Joanne Mortimer, Swarupa Kulkarni, Michelle Quinlan, Alaeddin Homsi, Eugene Tan, Suraj Anand, Angela Liu, Jeffrey Scott, Daniel George. The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 30. doi:10.1158/1538-7445.AM2013-30