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|Ref Type||Journal Article|
|Authors||Britten CD, Adjei AA, Millham R, Houk BE, Borzillo G, Pierce K, Wainberg ZA, LoRusso PM|
|Title||Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer.|
|Journal||Investigational new drugs|
|Abstract Text||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.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.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.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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||PF-04691502||Phase I||Actionable||In a Phase I trial, PF-04691502 demonstrated safety and efficacy in patients with advanced solid tumors (PMID: 24395457).||24395457|