Abstract B163: First-in-patient study of PF-04691502, a small molecule intravenous dual inhibitor of PI3K and mTOR in patients with advanced cancer: Update on safety, efficacy, and pharmacology.
Authors: Millham Robert , Houk Brett , Borzillo Gary , LoRusso Patricia , Marburg Lisa , Britten Carolyn , Wainberg Zev , Adjei Alex , Dy Grace 
Published: June 2012

Abstract
Background: Activation of the PI3K pathway has been implicated in the growth and survival of a wide variety of human cancers. Mutations in PIK3CA, the gene encoding the catalytic subunit of PI3K, are very common in human cancers, having been observed in prostate, breast and colorectal tumors, among others. Phosphatase and tensin homolog (PTEN) deletion, leading to the activation of Akt signaling has been observed in many types of malignancies including prostate cancer, breast cancer, and glioma. PF-04691502 is an orally available dual-specificity inhibitor of PI3K and mTOR which is being evaluated for the treatment of human cancers.
Methods: PF-04691502 is evaluated in a Phase 1 dose escalation study at doses ranging from 2 to 11 mg once daily (QD) using the standard 3+3 dose escalation method. Assessments include safety (NCI CTC AE v4.0), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. A maximum tolerated dose (MTD) of 8 mg QD has been determined. PD assessments include blood glucose and immunohistochemistry analysis of phosphoproteins in tumor and surrogate tissue (hair follicles). Antitumor activity is assessed per RECIST version 1.1.
Results: As of 15 August 2011, a total of 30 patients have been dosed at 2, 4, 8 and 11 mg QD. The median age of patients was 62; median baseline ECOG PS was 0. Represented tumor types have included CRC (8), NSCLC (4), and breast (2), among others. Analysis of archived tumor biopsies revealed PI3K pathway alterations in 7/13 evaluable patients; alterations included PTEN loss, PIK3CA mutation or amplification. PF-04691502 has been well tolerated with the most common treatment-related AEs being fatigue, nausea, vomiting, decreased appetite and rash. One patient has experienced DLT (Fatigue) at the 8 mg QD dose level, and two patients experienced DLT at 11 mg (Fatigue, Rash). Preliminary PK data indicate that PF-04691502 is eliminated with a half life of approximately 11–15 hours, with low clearance and a relatively high volume of distribution. Eleven patients have experienced hyperglycemia, a known effect of PI3K/Akt pathway suppression. No objective tumor response has been observed; 5 patients have experienced stable disease (SD) in excess of 16 weeks, with one patient (CRC) remaining on study for 39 weeks and one patient (HER2+ BC) for 27 weeks. Enrollment to MTD expansion cohorts is ongoing.
Conclusions: Daily oral administration of PF-04691502 appears safe and tolerable across multiple dose levels, with multiple patients deriving clinical benefit with prolonged SD. Multiple observations of hyperglycemia are suggestive of target modulation. Updated data for safety, PK, PD and antitumor activity will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B163.