title: Parallel phase Ib studies of two schedules of buparlisib (BKM120) plus carboplatin and paclitaxel (q21 days or q28 days) for patients with advanced solid tumors.
abstract: OBJECTIVE
  Phosphatidylinositol-3-kinase I (PI3K) inhibition sensitizes a wide range of cancer cell lines to platinum/taxane-based chemotherapy. This phase I study combines buparlisib, a pan-class 1A PI3K inhibitor, with two schedules of carboplatin and paclitaxel for patients with advanced solid tumors (ClinicalTrials.gov, NCT01297452).
  
  
  METHODS
  There were two regimens: Group 1 received carboplatin AUC 5 and paclitaxel 175 mg/m(2), on day 1 of a 21-day cycle with pegfilgrastim support; Group 2 received carboplatin AUC 5 (day 1) and paclitaxel 80 mg/m(2) (days 1, 8, and 15) on a 28-day cycle without growth factor support. In both groups, three dose levels of buparlisib were explored: 50, 80, and 100 mg/day. Primary endpoint was to identify recommended phase II doses of buparlisib in both groups.
  
  
  RESULTS
  Thirty subjects enrolled, 16 in Group 1 and 14 in Group 2. The DLTs were elevated alkaline phosphatase (n = 1) and uncomplicated neutropenia (n = 2). The median numbers of cycles were 5 (Group 1) and 6 (Group 2). The MTDs for buparlisib were 100 mg/day in Group 1 and 80 mg/day in Group 2. Among 25 patients with measurable disease, the confirmed objective response rate was 20% (one complete response, four partial responses). Among three patients with known loss of PTEN expression, all derived clinical benefit from treatment.
  
  
  CONCLUSIONS
  The addition of buparlisib to carboplatin + paclitaxel was well tolerated, and preliminary activity was notable against tumors with loss of PTEN expression.
authors: Developmental Therapeutics Clinic, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors: David M
authors: DM
authors: Hyman
authors: Alexandra E
authors: AE
authors: Snyder
authors: Richard D
authors: RD
authors: Carvajal
authors: John F
authors: JF
authors: Gerecitano
authors: Martin H
authors: MH
authors: Voss
authors: Alan L
authors: AL
authors: Ho
authors: Jason
authors: J
authors: Konner
authors: Jennifer L
authors: JL
authors: Winkelmann
authors: Megan A
authors: MA
authors: Stasi
authors: Kelsey R
authors: KR
authors: Monson
authors: Alexia
authors: A
authors: Iasonos
authors: David R
authors: DR
authors: Spriggs
authors: Philip
authors: P
authors: Bialer
authors: Mario E
authors: ME
authors: Lacouture
authors: Jerrold B
authors: JB
authors: Teitcher
authors: Nora
authors: N
authors: Katabi
authors: Matthew G
authors: MG
authors: Fury
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D016190:Carboplatin; D017239:Paclitaxel; D000069585:Filgrastim