Abstract OT3-06-07: A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer
Authors: Pluard T , Oh SY , Oliveira M , Cescon D , Tan-Chiu E , Wu Y , Carpenter C , Cunningham E , Ballas M , Dhar A , Sparano J 
Published: February 2018

Abstract
Background:
Advanced or metastatic ER+BC (estrogen receptor positive breast cancer) is an incurable illness that will prove fatal for most afflicted women. Current standards of care include endocrine, targeted, and chemotherapy. Preclinical data suggest that altering the expression of the estrogen receptor (ER) as well as other ER-responsive genes may provide therapeutic benefit for women for whom endocrine therapy alone has proven inadequate. The bromodomain (BRD) and extra-terminal (BET) family of proteins (BRD2, BRD3, BRD4 and BRDT) bind to acetyl-histone residues and epigenetically control transcription of genes driving cell survival and proliferation. BET proteins have been implicated in carcinogenesis and treatment resistance in multiple tumors including ER+BC, and are a novel target for therapy in breast cancer. GSK525762 is a pan-BET inhibitor that has shown strong synergistic activity with fulvestrant in killing ER+BC cells in vitro and in xenograft models. The combination of BET agents with endocrine therapy may provide therapeutic benefit and restore sensitivity to ER targeting agents like fulvestrant.
Trial Design & Specific Aims:
This study is a Phase I/II dose-escalation, expansion (Phase I) and randomized control (Phase II) study with oral administration of GSK525762 in combination with fulvestrant in advanced or metastatic ER+BC subjects, whose disease has progressed on prior treatment with at least one line of endocrine therapy.
Phase I of the study is designed as parallel single arms to determine a recommended Phase 2 dose (RP2D) based on safety, tolerability, pharmacokinetic, and efficacy profiles in two distinct populations of ER+ breast cancer:
Subjects with disease that relapsed during treatment or within 12 months of adjuvant therapy with an AI, OR disease that progressed during treatment with an AI for advanced/metastatic disease.
OR
Subjects with disease that progressed during treatment with the combination of a CDK4/6 inhibitor plus letrozole for advanced or metastatic disease.
Phase II of the study is a randomized, double-blind, placebo-controlled cohort, designed to evaluate the efficacy of the combination.
Key Eligibility Criteria: Patients must have received &lt;3 lines of systemic anti-cancer therapy (≤1 line of chemo), measurable disease, and PS 0-1.
Statistical Methods: A modified toxicity probability interval (mTPI) design will be used to monitor safety. A Bayesian adaptive design will be used to evaluate efficacy in Phase 1.
Present and Target Accrual: Target enrolment will be ˜300 subjects across ˜50 sites worldwide. To date, 2 subjects have been enrolled.
Contact Information: Elizabeth Cunningham, Elizabeth.A.Cunningham@GSK.com.
NCT02964507
Funding: GSK
Citation Format: Pluard T, Oh SY, Oliveira M, Cescon D, Tan-Chiu E, Wu Y, Carpenter C, Cunningham E, Ballas M, Dhar A, Sparano J. A phase I/II dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with fulvestrant in subjects with ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-06-07.