title: Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors.
abstract: OBJECTIVE
  This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), safety, preliminary activity, pharmacokinetics (PK), and pharmacodynamics of BKM120, a potent and highly specific oral pan-Class I PI3K inhibitor.
  
  
  METHODS
  Thirty-five patients with advanced solid tumors received daily BKM120 12.5 to 150 mg. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Assessments included archival tumor molecular status, response by Response Evaluation Criteria in Solid Tumors (RECIST), positron emission tomography tracer uptake ([(18)F]fluorodeoxyglucose positron emission tomography [FDG-PET]), fasting plasma C-peptide, and phosphorylated ribosomal protein S6 (pS6) in skin biopsies.
  
  
  RESULTS
  Overall, treatment was well tolerated. Dose-limiting toxicities were grade 2 mood alteration (80 mg), grade 3 epigastralgia, grade 3 rash, grade 2 and grade 3 mood alteration (100 mg), and two grade 4 hyperglycemia (150 mg). The MTD was 100 mg/d. Frequent treatment-related adverse events included rash, hyperglycemia, diarrhea, anorexia, and mood alteration (37% each); nausea (31%); fatigue (26%); pruritus (23%); and mucositis (23%). BKM120 demonstrated rapid absorption, half-life of ∼40 hours, ∼three-fold steady-state accumulation, dose-proportional exposure, and moderate interpatient variability. One patient demonstrated a confirmed partial response (triple-negative breast cancer); seven patients (20%) were on study for ≥ 8 months. BKM120 demonstrated dose-dependent pharmacodynamic effects on [(18)F]FDG-PET, fasting C-peptide, fasting blood glucose, and pS6. No significant trends were seen to correlate tumor molecular alterations with clinical activity.
  
  
  CONCLUSIONS
  This study demonstrates feasibility and proof-of-concept of class I PI3K inhibition in patients with advanced cancers. BKM120, at the MTD of 100 mg/d, is safe and well tolerated, with a favorable PK profile, clear evidence of target inhibition, and preliminary antitumor activity.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Maja
authors.initials: M
authors.lastname: de Jonge
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Diana
authors.initials: D
authors.lastname: Birle
authors.forename: David
authors.initials: D
authors.lastname: Demanse
authors.forename: Stefan S
authors.initials: SS
authors.lastname: De Buck
authors.forename: Qinhua C
authors.initials: QC
authors.lastname: Ru
authors.forename: Malte
authors.initials: M
authors.lastname: Peters
authors.forename: Michael
authors.initials: M
authors.lastname: Goldbrunner
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage* / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; 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* / Q000201:enzymology / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors