A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK

Abstract

PurposeAZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet.MethodsAdults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a ‘4-days-on/3-days-off’ schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and Cmax ratios of 0.75–1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2).ResultsIn evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and Cmax were 0.90 (0.77–1.06) and 1.02 (0.86–1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later tmax and lower Cmax after food versus overnight fast. Fed and fasted AUCτ and Cmax ratios were 0.89 (0.76–1.05) and 0.67 (0.55–0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states.ConclusionsPK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

Proliferation and AKT Activity Biomarker Analyses after Capivasertib (AZD5363) Treatment of Patients with ER+ Invasive Breast Cancer (STAKT)

“…3). The PK data reported here are consistent with the emerging PK profile for capivasertib that indicates a median time to C max of 2 hours (range, 0.5-6 hours), with a terminal half-life of approximately 10 hours (range, 7-15 hours) after the first dose (11,13,17). Weak dose-response relationships (percentage change from baseline) were identified for the two primary biomarkers (pGSK3b and pPRAS40) and Ki67.…”

“…The safety profile of capivasertib was previously reported, and the most frequently reported side effects are gastrointestinal events (diarrhea, vomiting, and nausea), fatigue, hyperglycemia, and maculopapular rash (7,11,13). The safety assessment of capivasertib in the STAKT study reported was, by nature of a window-of-opportunity study, short in comparison with prior and ongoing studies of the compound.…”

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients withAKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer

“…In this multicohort Phase I study, we sequentially explored the safety and efficacy of the pan-AKT inhibitor capivasertib, initially alone and later in combination with fulvestrant, in ER+ AKT1 E17K -mutant MBC patients. The safety profile was similar to that in prior reports (29,34,45), although combination therapy appeared better tolerated, likely because of the lower dose of capivasertib (400 mg bid 4 days on, 3 days off) administered with fulvestrant compared with the monotherapy dose of capivasertib (480 mg bid 4 days on, 3 days off), as suggested by the dose-response relationship observed for key capivasertib-related toxicities such as hyperglycemia (46).…”

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

“…These promising results suggest that inhibiting both Akt and β-catenin pathways may represent a new therapeutic way of treating HCC that would, however, require further preclinical and clinical investigations [ 75 ]. AZD5363 was tested in a phase-I trial in multiple advanced solid tumors including HCC, and it showed acceptable safety and tolerability profiles [ 68 ]. Moreover, it is still under investigation in a large phase-I study, the MATCH screening trial, that includes multiple solid tumors harboring druggable mutations including Akt mutations (NCT02465060).…”