1. 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
- Author
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Banerji, Udai, Dean, Emma J, Pérez-Fidalgo, J Alejandro, Batist, Gerald, Bedard, Philippe L, You, Benoit, Westin, Shannon N, Kabos, Peter, Garrett, Michelle D, Tall, Mathew, Ambrose, Helen, Barrett, J Carl, Carr, T Hedley, Cheung, S Y Amy, Corcoran, Claire, Cullberg, Marie, Davies, Barry R, de Bruin, Elza C, Elvin, Paul, Foxley, Andrew, Lawrence, Peter, Lindemann, Justin P O, Maudsley, Rhiannon, Pass, Martin, Rowlands, Vicky, Rugman, Paul, Schiavon, Gaia, Yates, James, Schellens, Jan H M, Banerji, Udai, Dean, Emma J, Pérez-Fidalgo, J Alejandro, Batist, Gerald, Bedard, Philippe L, You, Benoit, Westin, Shannon N, Kabos, Peter, Garrett, Michelle D, Tall, Mathew, Ambrose, Helen, Barrett, J Carl, Carr, T Hedley, Cheung, S Y Amy, Corcoran, Claire, Cullberg, Marie, Davies, Barry R, de Bruin, Elza C, Elvin, Paul, Foxley, Andrew, Lawrence, Peter, Lindemann, Justin P O, Maudsley, Rhiannon, Pass, Martin, Rowlands, Vicky, Rugman, Paul, Schiavon, Gaia, Yates, James, and Schellens, Jan H M
- 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 rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: 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 PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050-9. ©2017 AACRSee related commentary by Costa and Bosch, p. 2029.
- Published
- 2018