title: A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.
abstract: OBJECTIVE
  MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.
  
  
  METHODS
  This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer.
  
  
  RESULTS
  Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.
  
  
  CONCLUSIONS
  At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Philippe L
authors.initials: PL
authors.lastname: Bedard
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: UCLA-University of California, Los Angeles, California.
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.affiliation: Hospital Universitario Virgen del Rocio, Seville, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.affiliation: Respiratory Oncology, University Hospital KU Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Vansteenkiste
authors.affiliation: Digestive Oncology, University Hospital KU Leuven, Leuven, Belgium.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Pérez-García
authors.affiliation: Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Stathis
authors.affiliation: UCLA-University of California, Los Angeles, California.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Britten
authors.affiliation: GlaxoSmithKline Oncology R&D, Collegeville, Pennsylvania.
authors.forename: Ngocdiep
authors.initials: N
authors.lastname: Le
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Carter
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Demanse
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Denes
authors.initials: D
authors.lastname: Csonka
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Malte
authors.initials: M
authors.lastname: Peters
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Zubel
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Nauwelaerts
authors.affiliation: Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. Cristiana.Sessa@eoc.ch.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage* / Q000009:adverse effects; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib