An Open Label, Phase 1, Randomized, Seven-treatment, Seven-period, Crossover Study to Assess the Relative Bioavailability, pH Effect, Food Effect, and Dose Proportionality of CC-292, a Potent and Orally Available Bruton's Tyrosine Kinase Inhibitor

Background and Objective CC-292 is a potent, selective, orally administered small molecule inhibitor of Bruton's tyrosine kinase (BTK). To support the clinical investigation of CC-292, a randomized, seven-treatment, seven-period, crossover study was conducted to assess the relative bioavailability, pH effect, food effect, and dose-proportionality of two formulated tablets of CC-292. Methods Healthy subjects (n = 24) were enrolled in the study and randomly assigned into different treatment sequences. Blood samples were collected at pre-specified time points to measure the drug concentrations in plasma. Statistical analyses were performed to compare the pharmacokinetics of CC-292 under different conditions. Results The relative bioavailability of the newly developed formulation [spray-dried dispersion (SDD)] to the reference formulation (P22) was 1.24. When a single dose of CC-292 SDD tablet was administered under fed conditions, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) increased by 10.9% and the maximum plasma drug concentration C-max) decreased by 19.4% compared to when CC-292 was administered under fasted conditions. When a single dose of CC-292 SDD tablet was administered after multiple doses of omeprazole, the area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)) decreased by 36.8% and the maximum plasma drug concentration C-max) decreased by 48.1% compared to when CC-292 was administered alone. Over a dose range of 100-300 mg (SDD formulation), CC-292 exhibited more than dose-proportional increases of drug exposures. Conclusions CC-292 was well tolerated when administered to healthy subjects as single oral doses under all conditions. Food intake had no clinically relevant impact on CC-292 pharmacokinetics compared to fasted conditions. Therefore, CC-292 can be administered with or without food. Co-administration of CC-292 with multiple doses of omeprazole (40 mg) decreased the pharmacokinetic exposure of CC-292. However, the effect was not clinically relevant.