Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumors

Abstract

PurposeInvestigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies.MethodsAZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80–400, 360–480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients.ResultsForty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years.ConclusionsIntermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.

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

“…Results were obtained from paired biopsies collected during two previous phase I studies (NCT01226316 and NCT01353781), albeit in metastatic solid malignancies (including those with PIK3CA mutation). These phase I studies also showed downregulation of PD biomarkers (e.g., pPRAS40 and pGSK3b) following capivasertib treatment, increased phosphorylation levels of AKT (consistent with ATP-competitive mechanism of action), and inhibition of FOXO nuclear translocation (13,17). Table 3.…”

AKT Inhibition in Solid Tumors With AKT1 Mutations

“…16 Testing these inhibitors in AKT1 -mutant patients using traditional clinical trial designs is challenging because, unlike many other oncogenes, AKT1 E17K is infrequent in all individual tumor lineages. To determine whether AKT1 -mutant cancers are sensitive to direct AKT inhibition and whether tumor lineage influences drug sensitivity, we performed a multicohort basket study of the orally administered pan-AKT inhibitor AZD5363 17 in patients with AKT1 -mutant solid tumors.…”

The PI3K Pathway in Human Disease

“…In early phase trials, the competitive AKT inhibitor AZD5363 showed promising activity in patients with tumors carrying the E17K mutation, as determined by tumor tissue and ctDNA analysis (Hyman et al, 2015; Tamura et al, 2016). In a trial of the AKT inhibitor ipatasertib (GDC-0068; Table S1) with abiraterone in metastatic castration-resistant prostate cancer (CRPC), an improved PFS response to ipatasertib in patients with PTEN loss (determined by FISH and NGS) but not in patients with intact PTEN (Hyman et al, 2015).…”