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A Phase 1 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

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, and others. (2018) A Phase 1 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. Clinical Cancer Research, 24 (9). ISSN 1078-0432. E-ISSN 1557-3265. (doi:10.1158/1078-0432.CCR-17-2260) (KAR id:63859)

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Abstract

Purpose: This Phase 1, 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 WHO performance status 0–1. 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: Maximum tolerated doses were 320 mg, 480 mg 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 CTCAE grade ?3 events, hyperglycemia (20%). The recommended Phase 2 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 pre-specified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA cohort were met.

Conclusions: At the recommended Phase 2 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.

Item Type: Article
DOI/Identification number: 10.1158/1078-0432.CCR-17-2260
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Michelle Garrett
Date Deposited: 06 Oct 2017 08:19 UTC
Last Modified: 13 Mar 2020 04:09 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/63859 (The current URI for this page, for reference purposes)
Garrett, Michelle D.: https://orcid.org/0000-0002-3939-1673
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