Abstract 4640: Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258)
Authors: Sarantopoulos John , Goel Sanjay , Chung Vincent , Munster Pamela , Pant Shubham , Patel Manish , Infante Jeffrey , Tawbi Hussein , Becerra Carlos , Bruce Justine , Kabbinavar Fairooz , Kaufman Howard , Lockhart A. Craig , Tan Eugene , Yang Shu , Diallo Mariama , Scott Jeffrey , Sharma Sunil 
Published: May 2015

Abstract
Background Dovitinib (TKI258) is an oral receptor tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. A phase 3 study in renal cell carcinoma used a capsule (cap) formulation of dovitinib. However, the planned commercial formulation is a tablet (tab). Therefore, this study evaluated the bioequivalence of the tab and cap formulations using a crossover design.
Methods Patients (pts) ≥ 18 years of age with advanced solid tumors (excluding breast cancer) were randomized to receive caps or tabs (500 mg po once daily, 5 days on/2 days off) for 3 weeks, followed by the same dose and schedule of the other formulation for 1 week. Following the bioequivalence phase, pts could continue to receive dovitinib caps (500 mg once a day, 5 days on/2 days off). Blood samples for dovitinib plasma concentrations were collected before and after the fifth dose in weeks 3 and 4. The pharmacokinetic (PK) analysis set (PAS) comprised pts with ≥ 2 evaluable PK profiles following cap and tab administration, who did not vomit ≤ 4 hours after dosing on blood collection days and received ≥ 7 of the first 10 doses and 4 consecutive days of dosing prior to blood collection. A linear mixed-effects model was fitted to log-transformed parameters (area under the curve [AUClast] and maximal concentration [Cmax]).
Results A total of 173 pts were randomized to receive the cap/tab sequence (n = 88) or the tab/cap sequence (n = 85). The median age was 60 years, and the most common primary sites of cancer were colon (n = 48), lung (n = 18), and rectum (n = 14). Sixty-nine pts were in the PAS (32 in the cap/tab sequence and 37 in the tab/cap sequence). The most common reason for PAS exclusion was dose interruption due to disease progression or adverse events (AEs). Geometric means of PK parameters were similar for the tab vs cap formulations: AUClast (5379 vs 5705 h·ng/mL), Cmax (247 vs 252 ng/mL), half-life (14.5 vs 15.3 h), oral clearance (89.5 vs 82.5 L/h), and apparent volume of distribution (1876 vs 1823 L). The geometric mean ratios (90% CI) for AUClast and Cmax comparing tab vs cap were 0.95 (0.88-1.01) and 0.98 (0.91-1.05), respectively. In pts who received at least 1 dose of dovitinib throughout the entire study (including the postbioequivalence phase; n = 168), the most common AEs suspected to be related to study drug (any grade) were diarrhea (58.9%), nausea (50.0%), fatigue (42.3%), vomiting (41.7%), and decreased appetite (20.8%). Grade 3/4 AEs were &lt; 5% except for fatigue (11.9%), diarrhea (5.4%), and hypertension (5.4%).
Conclusions The tab and cap formulations were bioequivalent. The safety profile was similar to that observed in other dovitinib studies in pts with advanced solid tumors. The tab formulation is used in selected current studies and will be used in future clinical dovitinib studies.
Citation Format: John Sarantopoulos, Sanjay Goel, Vincent Chung, Pamela Munster, Shubham Pant, Manish Patel, Jeffrey Infante, Hussein Tawbi, Carlos Becerra, Justine Bruce, Fairooz Kabbinavar, Howard Kaufman, A. Craig Lockhart, Eugene Tan, Shu Yang, Mariama Diallo, Jeffrey Scott, Sunil Sharma. Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4640. doi:10.1158/1538-7445.AM2014-4640