title: Phase I dose-escalation and -expansion study of buparlisib (BKM120), an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy.
  
  
  METHODS
  Patients with advanced solid tumors (N = 83) enrolled in a Phase I dose-escalation and -expansion study of single-agent buparlisib. Patients in the dose-expansion arm (n = 43) had tumor samples with PIK3CA and/or PTEN alterations.
  
  
  RESULTS
  The most common cancers were colorectal (n = 31) and breast cancer (n = 21). Median number of prior antineoplastic regimens was four (range: 1-12). Grade 3/4 adverse events (AEs) included asthenia (12.0 %) and performance status decrease (9.6 %). Treatment-related AEs (all grades) included decreased appetite, diarrhea, nausea (each in 33 % of patients), hyperglycemia (31 %) and rash (29 %). One confirmed partial response (PR; triple-negative breast cancer) and three unconfirmed PRs (parotid gland carcinoma, epithelioid hemangiothelioma, ER + breast cancer) were reported. Tumor molecular status did not predict clinical benefit in the full study cohort, or among the colorectal or breast cancer subpopulations. Pharmacodynamic biomarkers ((18)F-FDG-PET, C-peptide, pS6) demonstrated dose-dependent changes; however, tumor heterogeneity precluded a clear correlation with clinical benefit.
  
  
  CONCLUSIONS
  Buparlisib was well tolerated up to the 100 mg/day dose and showed preliminary activity in patients with advanced cancers. Future studies in more homogeneous patient populations will evaluate buparlisib in combination with other agents and further investigate the use of predictive biomarkers.
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain, jrodon@vhio.net.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Irene
authors.initials: I
authors.lastname: Braña
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Maja J
authors.initials: MJ
authors.lastname: De Jonge
authors.forename: Natasha
authors.initials: N
authors.lastname: Homji
authors.forename: David
authors.initials: D
authors.lastname: Mills
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Di Tomaso
authors.forename: Celine
authors.initials: C
authors.lastname: Sarr
authors.forename: Lucia
authors.initials: L
authors.lastname: Trandafir
authors.forename: Cristian
authors.initials: C
authors.lastname: Massacesi
authors.forename: Ferry
authors.initials: F
authors.lastname: Eskens
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; 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* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000631:Aminopyridines; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D009025:Morpholines; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C571178:NVP-BKM120; C484760:PIK3CA protein, human; C494929:PTEN protein, human