Comparison of Two Formulations of AZD5363 and the Effect of Food on Pharmacokinetic Exposure, Safety and Tolerability

The actual sampling times were used in the parameter calculations and PK parameters were derived using standard non-compartmental methods. Following the twice daily dosing in Cycle 1 at Day 4 and 11 for both the formulation switch and food effect investigations, the following PK parameters have been determined: Css max, tss max, Css min, area under the plasma concentration-time curve from zero to the end of the dosing interval (AUCss) and CLss/F. Css max, tss max were determined by inspection of the concentration-time profiles. AUCss was calculated using the linear up / log down trapezoidal rule. CLss/F was determined from the ratio of dose/AUCss. Ratio of AUCss for Day 4 to Day 11 have been derived.

Time frame: Day 4 and Day 11

Population: All patients who provided concentration-time data for AZD5363 for both capsule and tablet administration (Part A) or for both fed and fasted treatments and who were compliant with the standard dietary and evaluability requirements (Part B) were included in PK analysis set.

The actual sampling times were used in the pharmacokinetics (PK) parameter calculations and PK parameters were derived using standard non-compartmental methods. Following the twice daily dosing in Cycle 1 at Day 4 and 11 for both the formulation switch and food effect investigations, the following PK parameters have been determined: Maximum plasma concentration at steady state (Css max), time to Css,max (tss max), minimum plasma concentration at steady state (Css min), area under the plasma concentration-time curve from zero to the end of the dosing interval (AUCss) and apparent clearance (CLss/F). Css max, tss max were determined by inspection of the concentration-time profiles. AUCss was calculated using the linear up / log down trapezoidal rule. CLss/F was determined from the ratio of dose/AUCss. Ratio of Css,max for Day 4 to Day 11 have been derived.

Time frame: Day 4 and Day 11

Population: All patients who provided concentration-time data for AZD5363 for both capsule and tablet administration (Part A) or for both fed and fasted treatments and who were compliant with the standard dietary and evaluability requirements (Part B) were included in PK analysis set.

Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 guidelines for measurable, non-measurable, target lesions (TLs) and non-target lesions (NTLs) and the objective tumour response criteria was used. Categorisation of objective tumour response assessment was based on the RECIST 1.1 guidelines for response: CR (complete response, efined as disappearance of all target lesions), PR (partial response, defined as \>=30% decrease in the sum of the longest diameter of target lesions), SD (stable disease, defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression) and PD (progression of disease, defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion). BOR was the best overall response observed across the study and up to 36 weeks. Number of subjects with response (CR or PR) is described.

Time frame: Assessed every 6 weeks, up to 36 weeks

Population: Modified intent-to-treat analysis set: all patients who received at least one dose of study treatment with a baseline tumour assessment.

Disease control = confirmed complete response + confirmed partial response + stable disease at 12 weeks

Time frame: Week 12

Population: Modified intent-to-treat analysis set: all patients who received at least one dose of study treatment with a baseline tumour assessment.

PFS is defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from randomised therapy or receives another anti-cancer therapy prior to progression. Subjects who have not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions.

Time frame: Assessed every 6 weeks up to 36 weeks

Population: Modified intent-to-treat analysis set: all patients who received at least one dose of study treatment with a baseline tumour assessment.

Tumour size is the sum of the longest diameters of the target lesions. Target lesions are measurable tumour lesions. best percentage change in tumour size from baseline is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction from baseline based on all post baseline assessments.

Time frame: Assessed every 6 weeks up to 36 weeks

Population: Modified intent-to-treat analysis set: all patients who received at least one dose of study treatment with a baseline tumour assessment.

Tumour size is the sum of the longest diameters of the target lesions. Target lesions are measurable tumour lesions. The percentage change in target lesion tumour size at each week 12 for which data are available was obtained for each subject taking the difference between the sum of the target lesion at each week 12 and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline multiplied by 100 (i.e. (week 12) - baseline)/baseline \* 100).

Time frame: Week 12

Population: Modified intent-to-treat analysis set: all patients who received at least one dose of study treatment with a baseline tumour assessment.