Phase I, open-label, dose-finding study of GSK2636771, a phosphoinositide 3-kinase (PI3K)β inhibitor, in combination with enzalutamide in male subjects with metastatic castration-resistant prostate cancer (mCRPC)

Abstract

Background: GSK2636771 is a potent, adenosine triphosphate (ATP) competitive, selective, oral inhibitor of the PI3Kβ isoform that inhibits the growth of phosphatase and tensin homolog (PTEN) deficient tumor cells in preclinical models. Resistance to the androgen receptor (AR) inhibitor enzalutamide (Xtandi®) may be mediated through upregulation of the PI3K pathway. Thus, GSK2636771 may enhance PTEN deleted prostate cancer cell kill. Methods: Within 30-days of documented progression on enzalutamide, subjects with PTEN deficient mCRPC are enrolled and treated with enzalutamide plus GSK2636771 in either dose escalation (DE) or dose expansion (DX) phases. Treatment continues until progressive disease (PD), unacceptable toxicities, consent withdrawal, or death. The primary objective is to assess safety, tolerability and determine the recommended phase 2 dose of this treatment combination. Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics, biomarkers, and clinical activity per PCWG2/ RECIST 1.1. All subjects receive 160 mg enzalutamide once daily (QD) + GSK2636771 starting at 300mg QDusing a standard 3+3 DE design with planned 100 mg incremental escalations or de-escalation. Results: In this ongoing study, 23 subjects received this treatment combination; 7 at 300 mg, 16 at 200 mg.Most AEs were Grade 1 or 2, with diarrhea themost common treatment-related AE (9/23; [39%]). Dose-limiting toxicities (DLTs) included Grade 3 hypocalcemia and reversible Grade 3 acute renal failure at 300mg and Grade 3 rash at 200mg. PK parameters suggested no drug-drug interaction between enzalutamide and GSK2636771. Among 13 evaluable patients at 200mg, 1 had a radiological partial response, and 2 had maximum PSA reductions of >50%. Five subjects have been treated for ≥6months. DE of 300 mg and DX of 200mg cohorts are ongoing. Conclusions: Our preliminary data indicate that GSK2636771 in combination with enzalutamide is largely well tolerated and confirm the clinical relevance of PI3Kβ inhibition in PTEN-deficient mCRPC. GSK funds this study.