459P - A Phase I Study to Assess the Safety and Tolerability of the Selective Akt Inhibitor Azd5363 in Japanese Patients with Advanced Solid Tumours

Abstract

ABSTRACT Aim: The PI3K/AKT/PTEN pathway is the most frequently deregulated signalling network in human cancer. AZD5363 is a potent and selective inhibitor of AKT1, 2 and 3. Methods: This was a Phase I, open-label, multicentre, dose-escalation study in Japanese patients (pts) with advanced solid tumours (NCT01353781). The primary objective was to assess the safety and tolerability of AZD5363. Secondary objectives included defining the maximum tolerated dose (MTD) and preliminary antitumour activity. Three dosing regimens were assessed: continuous, intermittent-1 (4-days-on/3-days-off; 4/3) and intermittent-2 (2-days-on/5-days-off; 2/5). At each dose level of the three regimens, 3–6 pts received a single oral dose of AZD5363, followed by 3–7 days washout and then bid dosing in 21-day cycles. The starting doses were 80 mg (continuous), 480 mg (intermittent-1) and 640 mg (intermittent-2). Results: 41 pts received bid treatment (continuous: 80 mg n = 3, 240 mg n = 7, 320 mg n = 6, 400 mg n = 5; intermittent-1 (4/3): 360 mg n = 8, 480 mg, n = 6; intermittent-2 (2/5): 640 mg n = 6); 2 pts continue treatment (480 mg [4/3] and 640 mg [2/5]). DLTs were only experienced with continuous dosing (all CTC grade 3): hypoxia (240 mg, 1 pt); diarrhoea (320 mg [2 pts]; 400 mg [1 pt]); rash and mucositis (400 mg, 1 pt). The MTD was determined as 320 mg in the continuous dosing regimen; MTDs have not been reached in either intermittent dosing regimen. Overall, the most common grade ≥3 AEs were hyperglycaemia, diarrhoea, neutropenia, lymphopenia and rash. Two partial responses (PR) were experienced by pts receiving intermittent AZD5363 dosing (480 mg [4/3] and 640 mg [2/5]). The AKT1 (E17K) mutation was identified in tumour tissue from both responders. One of these patients (ovarian cancer; endometrioid histology) maintained the PR for 2 years. Conclusions: The intermittent (4-days-on/3-days-off) AZD5363 dosing regimen has emerged as offering greater tolerability than continuous dosing, and has demonstrated tumour size reduction in some patients whose tumours harbour an AKT1 mutation. The intermittent regimens are being explored further in clinical studies. Disclosure: T. Esaki, T. Seto, F. Hirai, S. Arita, G. Toyokawa, J. Hashimoto, Y. Tanabe, M. Kodaira, K. Yonemori and K. Tamura: Corporate sponsored research – AstraZeneca; Y. Hoshino, H. Yamamoto, T. Kawata and J. Lindemann: AZ employee - stock ownership.