A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer.

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Date
2021-07-19ICR Author
Author
Sarker, D
Dawson, NA
Aparicio, AM
Dorff, TB
Pantuck, AJ
Vaishampayan, UN
Henson, L
Vasist, L
Roy-Ghanta, S
Gorczyca, M
York, W
Ganji, G
Tolson, J
de Bono, JS
Type
Journal Article
Metadata
Show full item recordAbstract
Purpose In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR) targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory phosphatase and tensin homolog (PTEN) activates phosphoinositide 3-kinase (PI3K)/AKT signaling and contributes to resistance to androgen-deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance. Patients and methods In this Phase I study (NCT02215096), patients with PTEN-deficient mCRPC, who progressed on prior enzalutamide, received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100 mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended Phase II dose (RP2D), and assess the 12-week non-progressive disease (PD) rate. Results Overall, 37 patients were enrolled; 36 received {greater than or equal to}1 dose of GSK2636771 (200 mg: n=22, 300 mg: n=12; 400 mg: n=2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n=1; 300 mg: n=2, 400 mg: n=2). No new or unexpected adverse events nor evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% CI: 28.2-71.8%, n=22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. 4/34 (12%) patients had prostate-specific antigen reduction of {greater than or equal to}50%. Conclusions Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.
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Research team
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2021-07-14
License start date
2022-07-19
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021