Abstract OT2-3-08: Phase III randomized study of the oral pan-PI3K inhibitor BKM120 with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer, treated with aromatase inhibitor, and progressed on or after mTOR inhibitor-based treatment – BELLE-3
Authors: Di Leo A , Germa C , Weber D , Di Tomaso E , Dharan B , Massacesi C , Hirawat S 
Published: August 2014

Abstract
Background: The PI3K/AKT/mTOR pathway is frequently activated in breast cancer (BC), and has been implicated in resistance to endocrine therapies and mTOR inhibitors (mTORi). BKM120 is an oral inhibitor of all 4 isoforms of class I PI3K (α, β, γ, δ). In combination with fulvestrant, BKM120 has demonstrated pro-apoptotic effects in vitro and anti-tumor activity in vivo. Preliminary clinical activity was observed with BKM120 in pts with BC, both as a single agent and in combination with letrozole (Mayer, et al. ASCO 2012: #510), or trastuzumab (Saura, et al. SABCS 2011: #PD09-03). Use of the pan-PI3K inhibitor BKM120 may overcome resistance to mTORi in BC by targeting the PI3K pathway upstream; this will be explored in the current study. Stratification of pts according to PI3K activation status will definitively conclude whether this biomarker is predictive of response.
Study design: This is a Phase III randomized, double-blind, placebo-controlled trial of BKM120 or placebo in combination with fulvestrant (BELLE-3; CBKM120F2303). Postmenopausal women with HR+/HER2– locally advanced or metastatic BC whose disease has been treated with aromatase inhibitor (AI), and is refractory to endocrine and mTORi combination therapy (progression while on mTORi and endocrine therapy or within 30 days of end of treatment) are eligible for enrollment. Other eligibility criteria include: ≤1 previous line of chemotherapy for advanced disease; and available archival tumor tissue for analysis of PI3K-related biomarkers. Pts are randomized (2:1) to receive continuous BKM120 (100 mg) or placebo daily, and fulvestrant (500 mg). Randomization is stratified according to PI3K pathway activation (PIK3CA mut and/or PTEN mut and/or loss of PTEN protein expression by immunohistochemistry), and visceral disease status. Study treatment is given until disease progression or until study discontinuation for any reason.
Co-primary endpoints are progression-free survival (PFS) in both full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints are overall survival (OS) in both full and PI3K pathway-activated populations. Other secondary endpoints are PFS and OS (PI3K non-activated/unknown population), overall response rate and clinical benefit rate, safety (CTCAE 4.03), pharmacokinetics of BKM120, and patient-reported quality of life (EORTC QLQ-C30 and QLQ-BR23).
Statistical methods: PFS and OS will be estimated using the Kaplan–Meier method for full and PI3K pathway-activated populations. Both primary and key secondary endpoints will be tested using a stratified log-rank test at levels α governed by a graphical gate-keeping procedure. A stratified Cox regression will be used to estimate the hazard ratio, along with two-sided 95% CI.
Target accrual: Estimated enrollment for BELLE-3 is 615 pts. Recruitment in this Global study is ongoing with planned enrollment of patients in North America, South America, Europe and Asia.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-08.