Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer |
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| Institution: | 1. Horizon Oncology Center, Lafayette, IA;2. Mercy Health St. Mary''s, Grand Rapids, MI;3. ProNAi Therapeutics, Inc., Vancouver, BC, Canada;4. Sierra Oncology, Inc. (formerly ProNAi Therapeutics, Inc.), Vancouver, BC, Canada;5. Wayne State University, Detroit, MI;1. Moores Cancer Center, University of California San Diego, La Jolla, USA;;2. Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan;;3. Department of Medical Oncology, University of Milan, Milan, Italy;;4. Department of Medical Oncology, Yale University School of Medicine, New Haven, USA;;5. Department of Medicine, Léon Bérard Center, Lyon;;6. Department of Medicine, Hospices Civils de Lyon, University of Lyon, Lyon, France;;7. Department of Medicine, West German Cancer Center, University Hospital Essen of the University Duisburg-Essen, Essen, Germany;;8. Department of Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium;;9. Department of Medical Oncology, Hospital Clínic de Barcelona, University of Barcelona, Barcelona;;10. Medical Oncology Department, Vall d''Hebron University Hospital, Barcelona, Spain;;11. Oncology Department Mastology, Centre Oscar Lambret, Lille, France;;12. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston;;13. Department of Medicine, Brigham and Women’s Hospital, Boston, USA;;14. Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium;;15. Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan;;16. Department of Medical Oncology, Centre Antoine Lacassagne, FHU OncoAge, Nice;;17. Department of Medical Oncology, Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy, France;;18. Department of Medical Oncology, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy;;19. Biodesix Inc., Boulder, USA;;20. Staburo GmbH, Munich, Germany on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany;;21. Biometrics and Data Management, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA;;22. Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany;;23. Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria;;24. TA Oncology, Boehringer Ingelheim, Danmark A/S, Denmark;;25. Institut Roi Albert II, Service d’Oncologie Médicale, Cliniques Universitaires Saint-Luc, Brussels;;26. Institut de Recherche Clinique et Expérimentale (Pole MIRO), Université Catholique de Louvain, Brussels, Belgium |
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| Abstract: | BackgroundThe phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC.Materials and methodsPatients with CRPC who had progressed on AA therapy received escalating doses of either buparlisib or dactolisib, along with fixed doses of AA (1000 mg once daily (qd)) and prednisone (5 mg twice daily (bid)). The primary objective was to define the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) of either buparlisib or dactolisib in combination with AA. Secondary objectives included safety, antitumour activity (Prostate Cancer Working Group 2 (PCWG2) criteria; 30% of prostate-specific antigen (PSA) decline at ≥week 12) and pharmacokinetic (PK) profile.ResultsIn buparlisib + AA arm, 25 patients received buparlisib + AA (median age, 67 years; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1/2 for 7/17/1 patients, respectively). At 100 mg qd; two patients experienced dose-limiting toxicities (DLTs) (grade 3 hyperglycaemia; grade 2 asthenia), and this was the maximum buparlisib dose explored. Buparlisib + AA showed a 26% lower median area under the curve from time zero to 24°h (AUC0–24) and 48% lower median maximum serum concentration (Cmax) versus the single-agent buparlisib assessed in first-in-human study. No objective response and few PSA decreases were reported.In dactolisib + AA arm, 18 patients (median age, 71 years; ECOG PS of 0/1 for 6/12 patients, respectively) received dactolisib + AA at the first dose level (200 mg bid). Five patients had 9 DLTs (grades 2&3 stomatitis; grade 3 hyperglycaemia; grades 2& 3 diarrhoea; grades 1& 2 pyrexia, grade 2 vomiting, and grade 2 chills).ConclusionsBased on the assessment of available pharmacokinetics, safety, and efficacy data, no further study is planned for either buparlisib or dactolisib in combination with AA in CRPC. |
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| Keywords: | Abiraterone acetate (AA) Buparlisib (BKM120) Castration-resistant prostate cancer (CRPC) Dactolisib (BEZ235) |
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