Results of OAK: A phase 1, open-label, multicentre study to compare two dosage forms of AZD5363 and to explore the effect of food on the pharmacokinetic (PK) exposure, safety, and tolerability of AZD5363 in patients with advanced solid malignancies.

Background: AZD5363 is a potent pan-Akt inhibitor and acts on cancers by blocking a cell survival pathway. AZD5363, administered to patients in the fasted state, was originally formulated as a capsule (C). For patient convenience and ease of manufacture a tablet (T) formulation has been developed. In vitro work has indicated that T and C perform similarly; PK comparability needed to be verified to introduce T to the clinical programme. The effect of food on PK, safety and tolerability was unknown. Methods: Part A assessed whether PK of T was comparable to C when both were given as a 480 mg bd dose in a 4 days on / 3 days off schedule; patients received T (Week 1) followed by C (Week 2). Part B examined the effect of a standardised meal on PK of T; patients received T in the fasted state (Week 1) and 30 minutes after a meal (Week 2). PK was assessed on the last day of weekly dosing in each of the cross-overs. Results: Part A data are available in 13 evaluable patients. AUCss and Css,max observations for T and C were comparable with GLS mean ratios (90% CIs) of 0.9 (0.79 to 1.03) and 1.01 (0.88 to 1.16) respectively. CIs of the ratios lay within the 0.75 to 1.33 pre-specified limits. Median tss,max was shorter for T than C (1.03 vs 2.03 h respectively), consistent with the in vitro dissolution data. T and C safety data were comparable and consistent with the known safety profile for AZD5363. Part B data are available from 10 patients. PK profiles for T(fasted) versus T(fed) indicated a later tmax and lower exposurein the fed state. GLS mean ratios of Css,max and AUCsswere 0.86 (0.74 to 1.01) and 0.68 (0.57 to 0.81) respectively. No significant differences in safety profiles were noted between the fasted and fed states. Conclusions: PK, safety and tolerability of the tablet and capsule formulations of AZD5363 are comparable. Tablets are being introduced across the ongoing clinical trials. Food has been shown to reduce the rate and extent of absorption of AZD5363 without a discernible effect on safety and tolerability; the existing food restrictions in ongoing clinical trials will be maintained. Clinical trial information: NCT01895946