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

被引：16

作者：

Sarker, Debashis ^{[1
,2
]}

Dawson, Nancy A. ^{[3
]}

Aparicio, Ana M. ^{[4
]}

Dorff, Tanya B. ^{[5
]}

Pantuck, Allan J. ^{[6
]}

Vaishampayan, Ulka N. ^{[7
]}

Henson, Lynn ^{[8
]}

Vasist, Lakshmi ^{[8
]}

Roy-Ghanta, Sumita ^{[8
]}

Gorczyca, Michele ^{[8
]}

York, Whitney ^{[8
]}

Ganji, Gopinath ^{[8
]}

Tolson, Jerry ^{[9
]}

de Bono, Johann S. ^{[10
,11
]}

机构：

[1] Kings Coll London, London, England

[2] Guys Hosp, London, England

[3] Georgetown Lombardi Comprehens Canc Ctr, Washington, DC USA

[4] MD Anderson Canc Ctr, Houston, TX USA

[5] City Hope Canc Ctr, Duarte, CA USA

[6] Univ Calif Los Angeles, Los Angeles, CA 90024 USA

[7] Univ Michigan, Ann Arbor, MI 48109 USA

[8] GSK, Collegeville, PA USA

[9] Biogen, Durham, NC USA

[10] Inst Canc Res, London, England

[11] Royal Marsden Hosp, London, England

来源：

CLINICAL CANCER RESEARCH | 2021年 / 27卷 / 19期

关键词：

PTEN; DESIGN; TUMORS; PI3K;

D O I：

10.1158/1078-0432.CCR-21-1115

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 PTEN activates 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 PI3K beta 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, and assess the 12-week non-progressive disease (PD) rate. Results: Overall, 37 patients were enrolled; 36 received >= 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 or 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% confidence interval: 28.2-71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of >= 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.

引用

页码：5248 / 5257

页数：10