title: A phase 1b dose expansion study of the pan-class I PI3K inhibitor buparlisib (BKM120) plus carboplatin and paclitaxel in PTEN deficient tumors and with dose intensified carboplatin and paclitaxel.
abstract: Purpose We previously reported the phase I dose escalation study of buparlisib, a pan-class 1A PI3K inhibitor, combined with platinum/taxane-based chemotherapy in patients with advanced solid tumors. The combination was well tolerated and promising preliminary efficacy was observed in PTEN deficient tumors. This phase I dose expansion study now evaluates buparlisib plus high dose carboplatin and paclitaxel in unselected patients with advanced solid tumors and buparlisib plus standard dose carboplatin and paclitaxel in patients with PTEN deficient tumors (ClinicalTrials.gov, NCT01297452). Methods There were two expansion cohorts: Cohort A received continuous buparlisib (100 mg/daily) orally plus high dose carboplatin AUC 6 and paclitaxel 200 mg/m2; Cohort B treated patients with PTEN deficient tumors only and they received the recommended phase II dose (RP2D) of continuous buparlisib (100 mg/daily) orally plus standard dose carboplatin AUC 5 and paclitaxel 175 mg/m2. Both cohorts received chemotherapy intravenously on day 1 of the 21-day cycle with pegfilgrastim support. Primary endpoint in Cohort A was to evaluate the safety and tolerability of chemotherapy dose intensification with buparlisib and in Cohort B was to describe preliminary efficacy of the combination among patients with tumors harboring a PTEN mutation or homozygous deletion. Results 14 subjects were enrolled, 7 in Cohort A and 7 in Cohort B. Dose reductions were required in 5 (71%) and 3 (43%) patients, in cohort A and B respectively. Grade 3 adverse events in Cohort A included lymphopenia (n = 5 [71%]), hyperglycemia (n = 2, [29%]), diarrhea (n = 2, [29%]) and rash (n = 2, [29%]) and in cohort B included lymphopenia (n = 5 [71%]), hyperglycemia (n = 4 [57%]) and neutropenia (n = 2 [29%]. The mean number of cycles on protocol was 6. The overall objective response rate was 14% (2 /14). No objective responses were observed in the PTEN deficient cohort. Four out of 6 patients with stable disease (SD) had SD or better for ≥6 cycles, 2 of which had PTEN deficient tumors. Conclusion The addition of buparlisib to high dose carboplatin and paclitaxel was not tolerable. The combination did not reveal significant clinical activity amongst a small and heterogenous group of PTEN deficient tumors.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA. smythl@mskcc.org.
authors.forename: Lillian M
authors.initials: LM
authors.lastname: Smyth
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Kelsey R
authors.initials: KR
authors.lastname: Monson
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Jhaveri
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Bob T
authors.initials: BT
authors.lastname: Li
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Abida
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Mrinal
authors.initials: M
authors.lastname: Gounder
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Harding
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Voss
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Vicky
authors.initials: V
authors.lastname: Makker
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Ho
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Razavi
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: Alexia
authors.initials: A
authors.lastname: Iasonos
authors.affiliation: Department of Psychiatry, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Bialer
authors.affiliation: Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: Mario E
authors.initials: ME
authors.lastname: Lacouture
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: Jerrold B
authors.initials: JB
authors.lastname: Teitcher
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Erinjeri
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: Nora
authors.initials: N
authors.lastname: Katabi
authors.affiliation: Oncology Clinical Sciences, Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Fury
authors.affiliation: Department of Medicine, Weill Cornell Medical College, Memorial Sloan Kettering Cancer Center (MSKCC), 1275 York Avenue, New York, NY, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D017239:Paclitaxel / Q000008:administration & dosage; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D014018:Tissue Distribution
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016190:Carboplatin; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017239:Paclitaxel
keywords: Buparlisib; Carboplatin; PTEN; Paclitaxel; Phase ib