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.
Date
2017-10-24ICR Author
Author
Banerji, U
Dean, EJ
Pérez-Fidalgo, JA
Batist, G
Bedard, PL
You, B
Westin, SN
Kabos, P
Garrett, MD
Tall, M
Ambrose, H
Barrett, JC
Carr, TH
Cheung, SYA
Corcoran, C
Cullberg, M
Davies, BR
de Bruin, EC
Elvin, P
Foxley, A
Lawrence, P
Lindemann, JPO
Maudsley, R
Pass, M
Rowlands, V
Rugman, P
Schiavon, G
Yates, J
Schellens, JHM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Breast Neoplasms
Genital Neoplasms, Female
Neoplasm Metastasis
Pyrimidines
Pyrroles
Protein Kinase Inhibitors
Neoplasm Staging
Treatment Outcome
Area Under Curve
Mutation
Adult
Aged
Middle Aged
Female
Male
Proto-Oncogene Proteins c-akt
Class I Phosphatidylinositol 3-Kinases
Molecular Targeted Therapy
Biomarkers, Tumor
Research team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Language
eng
Date accepted
2017-10-19
License start date
2018-05
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (9), pp. 2050 - 2059
Publisher
AMER ASSOC CANCER RESEARCH