Abstract 1752: A phase I/IIa, first time in human, open-label dose-escalation study of GSK2636771 in subjects with advanced solid tumors with PTEN deficiency

Abstract

Abstract Background: The phosphoinositide 3-kinase (PI3K) pathway is among the most commonly mutated pathways in human cancer. The majority of first-generation PI3K inhibitors currently in clinical trials inhibit multiple PI3K isoforms. The PIK3CB gene encodes p110α isoform, which has been reported to be required for pathway activation in phosphatase and tensin homolog (PTEN) deficient cancer cells [Wee, 2008; Jia 2008]. The observed dependence of PTEN-deficient tumors on p110α provides an opportunity for identification of a novel isoform-selective therapeutic. In addition, as PTEN is commonly mutated, deleted, or epigenetically silenced in a wide range of solid tumors, measurement of PTEN protein expression would provide an identifiable target patient population using a clinically-available biomarker. Methods: GSK2636771 (‘771) is a potent, orally bioavailable, beta isoform-selective inhibitor of PI3K. Study P3B115717 is a Phase I/IIa first-time-in-human dose-escalation study of ‘771. The objectives of the study include the characterization of the safety, tolerability, and pharmacokinetic (PK) profile of ‘771 following single- and repeat-dose administration, evaluation of the pharmacodynamic (PD) effects of ‘771 in tumor and surrogate tissue, and evaluation of the anti-tumor effects of ‘771 in advanced solid tumors with PTEN deficiency. A standard 3+3 dose escalation scheme will be used, however this study incorporates multiple elements designed to accelerate clinical development. These include a single-dose phase for rapid determination of a pharmacokinetically acceptable starting dose, a “backfill” strategy for acquiring parallel samples for PD analyses, mandatory tumor biopsies for select patient cohorts, inclusion of subjects with glioblastoma multiformae, and, importantly, only patients whose tumors lack PTEN expression are eligible for this study, beginning with dose escalation. PD and anti-tumor response will be assessed in-stream to determine biologically effective doses. Anti-tumor efficacy in three tumor types with high prevalence of PTEN loss will be assessed using volumetric imaging in addition to RECIST 1.1, as well as circulating tumor cell enumeration for prostate and breast tumors. Exploratory analyses include evaluation of alterations in tumor growth rates following treatment with ‘771 compared to patient's prior lines of therapy, correlation of serum markers (e.g., IGFBP-2) with tumor PTEN expression, comparison of anti-tumor response to DNA point mutations detected in circulating tumor DNA, and PD assessment in a surrogate tissue (change in pAKT, pGSK3β, and pS6 in platelets). This study initiated in November 2011 and is currently accruing patients (GSK Study P3B115717 - NCT01458067). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1752. doi:1538-7445.AM2012-1752