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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

Clinical cancer research, 2018-05, Vol.24 (9), p.2050-2059 [Peer Reviewed Journal]

2017 American Association for Cancer Research. ;Copyright American Association for Cancer Research Inc May 1, 2018 ;ISSN: 1078-0432 ;EISSN: 1557-3265 ;DOI: 10.1158/1078-0432.ccr-17-2260 ;PMID: 29066505

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Title:
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: 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
Subjects: Adult ; Aged ; AKT protein ; Area Under Curve ; Biomarkers, Tumor ; Breast ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; Class I Phosphatidylinositol 3-Kinases - genetics ; Diarrhea ; Dosage ; Evaluation ; Experimental design ; Female ; Genital Neoplasms, Female - drug therapy ; Genital Neoplasms, Female - genetics ; Genital Neoplasms, Female - metabolism ; Genital Neoplasms, Female - pathology ; Humans ; Hyperglycemia ; Inhibitors ; Male ; Middle Aged ; Molecular Targeted Therapy ; Mutation ; Nausea ; Neoplasm Metastasis ; Neoplasm Staging ; Patients ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Plasma levels ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - adverse effects ; Protein Kinase Inhibitors - pharmacokinetics ; Protein Kinase Inhibitors - therapeutic use ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Pyrimidines - administration & dosage ; Pyrimidines - adverse effects ; Pyrimidines - pharmacokinetics ; Pyrimidines - therapeutic use ; Pyrroles - administration & dosage ; Pyrroles - adverse effects ; Pyrroles - pharmacokinetics ; Pyrroles - therapeutic use ; Safety ; Schedules ; Solid tumors ; Toxicity ; Treatment Outcome ; Tumors
Is Part Of: Clinical cancer research, 2018-05, Vol.24 (9), p.2050-2059
Description: 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. .
Publisher: United States: American Association for Cancer Research Inc
Language: English
Identifier: ISSN: 1078-0432
EISSN: 1557-3265
DOI: 10.1158/1078-0432.ccr-17-2260
PMID: 29066505
Source: Geneva Foundation Free Medical Journals at publisher websites
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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

2017 American Association for Cancer Research. ;Copyright American Association for Cancer Research Inc May 1, 2018 ;ISSN: 1078-0432 ;EISSN: 1557-3265 ;DOI: 10.1158/1078-0432.ccr-17-2260 ;PMID: 29066505

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