title: Phase Ib dose-finding study of abiraterone acetate plus buparlisib (BKM120) or dactolisib (BEZ235) in patients with castration-resistant prostate cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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°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).
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: BC Cancer Agency, Vancouver, Canada.
authors.forename: Kim Nguyen
authors.initials: KN
authors.lastname: Chi
authors.affiliation: University Hospital 12 de Octubre, CIBER-ONC, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Institute of Cancer Research, London, UK.
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Gravis
authors.affiliation: St. Augustinus Hospital, Antwerp, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Pascal
authors.initials: JP
authors.lastname: Machiels
authors.affiliation: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Mita
authors.affiliation: Medical Oncology Department, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Mellado
authors.affiliation: Novartis Pharma S.A.S, Rueil-Malmaison, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Turri
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Joan
authors.initials: J
authors.lastname: Maier
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Denes
authors.initials: D
authors.lastname: Csonka
authors.affiliation: Novartis Healthcare Pvt. Ltd., Hyderabad, India.
authors.forename: Arunava
authors.initials: A
authors.lastname: Chakravartty
authors.affiliation: Department of Cancer Medicine, Gustave Roussy, University of Paris Sud, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
mesh_terms: D000069501:Abiraterone Acetate / Q000008:administration & dosage / Q000493:pharmacokinetics; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001247:Asthenia / Q000139:chemically induced; D023341:Chills / Q000139:chemically induced; D003967:Diarrhea / Q000139:chemically induced; D005334:Fever / Q000139:chemically induced; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D007610:Kallikreins / Q000097:blood; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000493:pharmacokinetics; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy*; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics; D013280:Stomatitis / Q000139:chemically induced; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000631:Aminopyridines; D007093:Imidazoles; D009025:Morpholines; C571178:NVP-BKM120; D011804:Quinolines; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D000069501:Abiraterone Acetate; C531198:dactolisib
keywords: Abiraterone acetate (AA); Buparlisib (BKM120); Castration-resistant prostate cancer (CRPC); Dactolisib (BEZ235)