Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Clinical cancer research, 2018-05, Vol.24 (9), p.2050-2059

Ort / Verlag

United States: American Association for Cancer Research Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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 -mutant breast and gynecologic cancers. MTDs were 320, 480, and 640 mg for continuous ( = 47), 4/7 ( = 21), and 2/7 ( = 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 -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 -mutant cohort were met. 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 -mutant cancers treated with AZD5363. .