A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA -Mutated Breast and Gynecologic Cancers

作者：Udai Banerji, Emma Dean, José Alejandro Pérez Fidalgo, Gerald Batist, Philippe L. Bédard, Benoît You, Shannon N. Westin, Peter Kabos, Michelle D. Garrett, Mathew Tall, Helen Ambrose, J. Carl Barrett, T. Hedley Carr, S.Y. Amy Cheung, Claire Corcoran, Marie Cullberg, Barry R. Davies, Elza C. de Bruin, Paul Elvin, Andrew Foxley, Peter Lawrence, Justin P.O. Lindemann, Rhiannon Maudsley, Martin Pass, Vicky Rowlands, Paul Rugman, Gaia Schiavon, James Yates, Jan H.M. Schellens · 发表于：Clinical Cancer Research · 年份：2017 · DOI：10.1158/1078-0432.ccr-17-2260 · 被引用次数：147 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Advanced Breast Cancer Therapies、Chronic Lymphocytic Leukemia Research

Abstract Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity. Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers. Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response ...