title: Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity of the PI3K/mTOR inhibitor PF-04691502, administered orally once daily.
  
  
  METHODS
  Escalating doses of PF-04691502 were administered to 23 patients with advanced solid tumors in sequential cohorts across the following dose levels: 2 mg, 4 mg, 8 mg, and 11 mg. 14 additional patients were enrolled in an expansion cohort at the MTD to ensure at least five matched pre- and post-treatment biopsies for biomarkers of PI3K activity.
  
  
  RESULTS
  The MTD of PF-04691502 was 8 mg orally once daily. There were three dose-limiting toxicities: one grade 3 fatigue at 8 mg, one grade 3 rash at 11 mg, and one intolerable grade 2 fatigue at 11 mg. Among 37 patients enrolled, treatment-related adverse events included fatigue, decreased appetite, nausea, hyperglycemia, rash, and vomiting. Across all dose levels, average steady-state plasma PF-04691502 concentrations approximated or exceeded the target concentration of 16.2 ng/mL required for ≥75 % tumor growth inhibition in preclinical models. PF-04691502 resulted in increased mean fasting serum glucose, insulin, and c-peptide levels, and produced partial blockade of PI3K signalling in five paired tumor biopsies, as demonstrated by reductions in phosphorylated Akt, FKHR/FKHRL1, and STAT3. No objective anti-tumor responses were observed.
  
  
  CONCLUSIONS
  Daily oral administration of PF-04691502 was tolerable at 8 mg orally once daily, with a safety profile similar to other PI3K/mTOR inhibitors. PF-04691502 demonstrated PI3K pathway inhibition by changing glucose homeostasis, and by decreasing phosphorylation of downstream molecules in tumor tissue.
authors.affiliation: UCLA Medical Center, Los Angeles, CA, USA, britten@musc.edu.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Britten
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Robert
authors.initials: R
authors.lastname: Millham
authors.forename: Brett E
authors.initials: BE
authors.lastname: Houk
authors.forename: Gary
authors.initials: G
authors.lastname: Borzillo
authors.forename: Kristen
authors.initials: K
authors.lastname: Pierce
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; C546842:MTOR protein, human; C494929:PTEN protein, human