PMID- 28282611 OWN - NLM STAT- MEDLINE DCOM- 20170807 LR - 20211122 IS - 1879-0852 (Electronic) IS - 0959-8049 (Linking) VI - 76 DP - 2017 May TI - Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer. PG - 36-44 LID - S0959-8049(17)30085-0 [pii] LID - 10.1016/j.ejca.2017.01.024 [doi] AB - BACKGROUND: The 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 METHODS: Patients 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. RESULTS: In 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 degrees h (AUC(0-24)) 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). CONCLUSIONS: Based 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. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Massard, Christophe AU - Massard C AD - Drug Development Department, Gustave Roussy, University of Paris Sud, Villejuif, France; Department of Cancer Medicine, Gustave Roussy, University of Paris Sud, Villejuif, France. Electronic address: christophe.massard@gustaveroussy.fr. FAU - Chi, Kim Nguyen AU - Chi KN AD - BC Cancer Agency, Vancouver, Canada. FAU - Castellano, Daniel AU - Castellano D AD - University Hospital 12 de Octubre, CIBER-ONC, Madrid, Spain. FAU - de Bono, Johann AU - de Bono J AD - Institute of Cancer Research, London, UK. FAU - Gravis, Gwenaelle AU - Gravis G AD - Institut Paoli-Calmettes, Marseille, France. FAU - Dirix, Luc AU - Dirix L AD - St. Augustinus Hospital, Antwerp, Belgium. FAU - Machiels, Jean-Pascal AU - Machiels JP AD - Institut Roi Albert II, Service d'Oncologie Medicale, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Experimentale, Universite catholique de Louvain, Brussels, Belgium. FAU - Mita, Alain AU - Mita A AD - Cedars-Sinai Medical Center, Los Angeles, CA, USA. FAU - Mellado, Begona AU - Mellado B AD - Medical Oncology Department, Hospital Clinic, IDIBAPS, Barcelona, Spain. FAU - Turri, Sabine AU - Turri S AD - Novartis Pharma S.A.S, Rueil-Malmaison, France. FAU - Maier, Joan AU - Maier J AD - Novartis Pharma AG, Basel, Switzerland. FAU - Csonka, Denes AU - Csonka D AD - Novartis Pharma AG, Basel, Switzerland. FAU - Chakravartty, Arunava AU - Chakravartty A AD - Novartis Healthcare Pvt. Ltd., Hyderabad, India. FAU - Fizazi, Karim AU - Fizazi K AD - Department of Cancer Medicine, Gustave Roussy, University of Paris Sud, France. LA - eng PT - Clinical Trial, Phase I PT - Journal Article DEP - 20170320 PL - England TA - Eur J Cancer JT - European journal of cancer (Oxford, England : 1990) JID - 9005373 RN - 0 (Aminopyridines) RN - 0 (Imidazoles) RN - 0 (Morpholines) RN - 0 (NVP-BKM120) RN - 0 (Quinolines) RN - EC 3.4.21.- (KLK3 protein, human) RN - EC 3.4.21.- (Kallikreins) RN - EC 3.4.21.77 (Prostate-Specific Antigen) RN - EM5OCB9YJ6 (Abiraterone Acetate) RN - RUJ6Z9Y0DT (dactolisib) SB - IM EIN - Eur J Cancer. 2017 Aug;81:242. PMID: 28606464 CIN - Eur J Cancer. 2017 Aug;81:226-227. PMID: 28629596 MH - Abiraterone Acetate/administration & dosage/pharmacokinetics MH - Aged MH - Aged, 80 and over MH - Aminopyridines/administration & dosage/pharmacokinetics MH - Antineoplastic Combined Chemotherapy Protocols/*administration & dosage/pharmacokinetics MH - Area Under Curve MH - Asthenia/chemically induced MH - Chills/chemically induced MH - Diarrhea/chemically induced MH - Fever/chemically induced MH - Humans MH - Hyperglycemia/chemically induced MH - Imidazoles/administration & dosage/pharmacokinetics MH - Kallikreins/blood MH - Male MH - Maximum Tolerated Dose MH - Middle Aged MH - Morpholines/administration & dosage/pharmacokinetics MH - Prostate-Specific Antigen/blood MH - Prostatic Neoplasms, Castration-Resistant/blood/*drug therapy MH - Quinolines/administration & dosage/pharmacokinetics MH - Stomatitis/chemically induced MH - Vomiting/chemically induced OTO - NOTNLM OT - Abiraterone acetate (AA) OT - Buparlisib (BKM120) OT - Castration-resistant prostate cancer (CRPC) OT - Dactolisib (BEZ235) EDAT- 2017/03/11 06:00 MHDA- 2017/08/08 06:00 CRDT- 2017/03/11 06:00 PHST- 2017/01/10 00:00 [received] PHST- 2017/01/23 00:00 [accepted] PHST- 2017/03/11 06:00 [pubmed] PHST- 2017/08/08 06:00 [medline] PHST- 2017/03/11 06:00 [entrez] AID - S0959-8049(17)30085-0 [pii] AID - 10.1016/j.ejca.2017.01.024 [doi] PST - ppublish SO - Eur J Cancer. 2017 May;76:36-44. doi: 10.1016/j.ejca.2017.01.024. Epub 2017 Mar 20.