Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer.

Abstract

PURPOSE:

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: Carolyn D Britten, Alex A Adjei, Robert Millham, Brett E Houk, Gary Borzillo, Kristen Pierce, Zev A Wainberg, Patricia M LoRusso
• Journal: Investigational new drugs (Invest New Drugs) Vol. 32 Issue 3 Pg. 510-7 (Jun 2014) ISSN: 1573-0646 [Electronic] United States
• PMID: 24395457 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
• Antineoplastic Agents
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidines
• MTOR protein, human
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, genetics, metabolism)
• PTEN Phosphohydrolase (metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Pyridones (administration & dosage, adverse effects, pharmacokinetics)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)