Injectable azacitidine (AZA) has been evaluated in a variety of malignancies, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and solid tumors. CC-486, the oral formulation of AZA, allows extended dosing schedules (>7 days per 28-day treatment cycle) to increase AZA exposure to malignant cells over the course of the cycle. CC-486 is under investigation in phase 3 clinical trials as maintenance therapy for patients with AML in first complete remission after induction chemotherapy (NCT01757535) and in lower-risk MDS with concurrent thrombocytopenia and RBC transfusion dependence (NCT01566695). In these studies, patients receive CC-486 300 mg QD administered in two 150 mg tablets. A single 300 mg CC-486 tablet is in development for market approval.
Evaluate the bioequivalence (BE) of a single 300 mg CC-486 tablet relative to two 150 mg CC-486 tablets, and the food effect (FE) on the bioavailability of the CC-486 300 mg tablet.
This was a phase 1, randomized, crossover study (NCT01519011). Adult patients had hematologic malignancies or solid tumors relapsed/refractory to prior therapy for which no standard treatments were available, and ECOG PS scores 0-2. The BE phase assessed pharmacokinetic (PK) parameters of CC-486 administered as two 150 mg tablets (formulation A) and as one 300 mg tablet (formulation B). Patients were randomized 1:1 to receive each formulation at least 48 hours apart. In the FE phase, patients were randomized to receive formulation B on each of 2 PK study days under fed (high fat, ∼800-1000 calories) and fasted conditions. PK parameters, including area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal half-life (t1/2), apparent total clearance (CL/F) and volume of distribution (Vz/F) were analyzed. BE of formulations A and B, and absence of FE on formulation B, were indicated when the 90% CI of the ratios of geometric means (RGM) based on log-transformed data for AUC∞ and Cmax between formulations A and B, and between fed and fasted conditions, were within 80%>125%.
30 patients were enrolled in the BE phase (median age 68.5 yrs, range 46-86); 3 patients (10%) had hematologic malignancies and 27 (90%) had solid tumors. Formulations A and B were bioequivalent: the Cmax RGM was 101.5% (90% CI 89.9, 114.7) and AUC∞ RGM was 105.7% (95.0, 117.6). Median Tmax was 1.0 hour for both formulations.
57 patients enrolled in the FE phase (median age 62 yrs, 31-88); all had solid tumors. Despite a lower Cmax under fed condition (RGM 78.9% [90%CI 68.6, 90.7]), overall drug exposure was similar (AUC∞ RGM 108.9% [90%CI 98.5, 120.5]) (Figure A). Consistent with an effect of gastric emptying, median Tmax was reached at 2 hrs and 1 hr post-dose in fed and fasted states, respectively (Figure B) and mean t1/2 was 0.78 and 0.58 hr postdose. CL/F and Vz/F were comparable in fed and fasted states. Moderate to high intersubject variability was observed for all CC-486 PK parameters (Figure A).
A single oral CC-486 300 mg tablet is bioequivalent to two 150 mg tablets. The PK profile for the CC-486 300 mg tablet under fed and fasted conditions was comparable although Cmax occurred later and was decreased in fed vs. fasted condition. Systemic drug exposure (AUC∞) in fed and fasted states was similar and within the bioequivalence limits. Limited differences in other CC-486 PK parameters between fed and fasted states are not expected to have a clinical impact.