ESMO 2017: Phase I, Open-label, Dose-Finding Study of GSK2636771, a phosphoinositide 3-kinase β inhibitor, in Combination with Enzalutamide in Male Subjects with Metastatic Castration-Resistant Prostate Cancer
For this study, 23 patients with PTEN deficient mCPRC with documented progression on enzalutamide (within 30-days) were enrolled and treated with enzalutamide plus GSK2636771 in either dose escalation or dose expansion phases. Treatment continues until progressive disease, unacceptable toxicities, consent withdrawal, or death. The primary objective was to assess safety, tolerability and determine the recommended phase II dose of this treatment combination. Secondary objectives included: (i) evaluation of pharmacokinetics, (ii) pharmacodynamics, (iii) biomarkers, and (iv) clinical activity per PCWG2/RECIST 1.1. All subjects received 160 mg enzalutamide once daily (QD) + GSK2636771 starting at 300mg QD using a standard 3 + 3 dose escalation design with planned 100 mg incremental escalations or de-escalation. In this ongoing study, the 23 subjects received the following treatment combination: 300 mg GSK2636771 (n=7), or 200 mg GSK2636771 (n=16). Most adverse events were Grade 1 or 2, with diarrhea the most common treatment-related adverse event (39%). Dose-limiting toxicities included Grade 3 hypocalcemia and reversible Grade 3 acute renal failure at 300 mg GSK2636771 and Grade 3 rash at 200 mg GSK2636771. Pharmacokinetic parameters suggested no drug-drug interaction between enzalutamide and GSK2636771. Among 13 evaluable patients at 200 mg GSK2636771, one had a radiological partial response, and two had maximum PSA reductions of > 50%. Five subjects have been treated for ≥6 months. Dose escalation of 300 mg and dose expansion of 200 mg cohorts are ongoing.
The authors concluded that based on preliminary data, GSK2636771 in combination with enzalutamide is largely well tolerated and confirm the clinical relevance of PI3Kβ inhibition in PTEN-deficient mCRPC.
Reference:
1. Mateo J, Ganji G, Lemech C, et al. A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2017 Jun 23 [Epub ahead of print].
Speaker: Pasquale Rescigno, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
Co-Authors: J. De Bono (Sutton, United Kingdom) A. Aparicio (Houston, United States of America) S. Chowdhury (London, United Kingdom) P. Twardowski (Duarte, United States of America) N. Dawson (Washington D.C., United States of America) U. Vaishampayan (Detroit, United States of America) A. J. Pantuck (Los Angeles, United States of America) Y. Zhou (Collegeville, United States of America) D. Fecteau (Collegeville, United States of America)
G. Ganji (King of Prussia, United States of America) J. Tolson (RTP, United States of America)
D. A. Smith (Durham, United States of America) J. Medina (Collegeville, United States of America) L. Yan (Collegeville, United States of America)
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain