title: Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer.
abstract: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor.
  
  
  
  Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer.
  
  
  
  In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients.
  
  
  
  BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: U A
authors.initials: UA
authors.lastname: Matulonis
authors.affiliation: Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Wulf
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: W T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Department of Hematology and Oncology, Massachusetts General Hospital, Boston, USA.
authors.forename: M
authors.initials: M
authors.lastname: Birrer
authors.affiliation: Department of Gynecologic Oncology, MD Anderson Cancer Center, Houston, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Westin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: S
authors.initials: S
authors.lastname: Farooq
authors.affiliation: Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Bell-McGuinn
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: E
authors.initials: E
authors.lastname: Obermayer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: C
authors.initials: C
authors.lastname: Whalen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: T
authors.initials: T
authors.lastname: Spagnoletti
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: W
authors.initials: W
authors.lastname: Luo
authors.affiliation: Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Hok
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: C
authors.initials: C
authors.lastname: Aghajanian
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: D B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Systems Biology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: H
authors.initials: H
authors.lastname: Won
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: S
authors.initials: S
authors.lastname: Palakurthi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Weill Cornell Medical College, New York, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,USA.
authors.forename: E
authors.initials: E
authors.lastname: Winer
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010793:Phthalazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics
chemical_list: D000631:Aminopyridines; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
keywords: BKM120; PARP-inhibitors; breast cancer; olaparib; ovarian cancer