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

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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 <i>PIK3CA</i>-mutant breast and gynecologic cancers.<b>Results:</b> MTDs were 320, 480, and 640 mg for continuous (<i>n</i> = 47), 4/7 (<i>n</i> = 21), and 2/7 (<i>n</i> = 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 <i>PIK3CA</i>-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 rate; therefore, the criteria to stop further recruitment to the <i>PIK3CA</i>-mutant cohort were met.<b>Conclusions:</b> At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with <i>PIK3CA</i>-mutant cancers treated with AZD5363. <i>Clin Cancer Res; 24(9); 2050-9. ©2017 AACR</i><i>See related commentary by Costa and Bosch, p. 2029</i>.