Abstract OT2-3-09: 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 resistant to aromatase inhibitor – BELLE-2
Authors: Baselga J , Campone M , Cortes J , Iwata H , de Laurentiis M , Jonat W , Di Tomaso E , Hachemi S , Goteti S , Germa C , Massacesi C , Arteaga C 
Published: August 2014

Abstract
Background: The PI3K/AKT/mTOR pathway has been reported altered in up to 40% of hormone receptor-positive (HR+) breast cancers (BC). Furthermore, pathway activation has been implicated in resistance to endocrine therapy, including aromatase inhibitors (AI). 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 achieved near-complete tumor regression in HR+ PIK3CA-mutated estrogen-independent xenografts. Preliminary clinical activity was observed with BKM120 in patients 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).
Study design: This is a Phase III randomized, double-blind, placebo-controlled trial of BKM120 or placebo in combination with fulvestrant in postmenopausal women with HR+/HER2– locally advanced or metastatic BC that progressed on or after AI treatment (BELLE-2; CBKM120F2302; NCT01610284). After a 14-day fulvestrant run-in phase to allow determination of tumor PI3K pathway activation status, patients are randomized (1:1) to receive continuous BKM120 (100 mg/d) or placebo, and fulvestrant 500 mg at C1D15, and D1 of all cycles thereafter; 1 cycle=28 days. Randomization is stratified according to PI3K pathway activation (PIK3CA mut and/or PTEN mut and/or loss of PTEN protein expression by IHC), and visceral disease status. Study treatment is given until disease progression or until study discontinuation for any reason.
Eligibility criteria include: postmenopausal women with HR+/HER2– locally advanced or metastatic BC refractory to AI (progression while on AI, or within 4 wks [metastatic] or 12 mos [adjuvant] of last AI dose); no more than 1 previous line of chemotherapy for advanced disease; and available archival tumor tissue for analysis of PI3K-related biomarkers.
Co-primary endpoints: PFS in the full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in both full and PI3K pathway-activated populations. Other secondary endpoints: PFS and OS (PI3K non-activated/unknown population), overall response rate and clinical benefit rate (both in full, PI3K-activated, PI3K non-activated/unknown populations), safety (CTCAE 4.03), pharmacokinetics of BKM120 and fulvestrant, 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 both 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% confidence interval.
Target accrual: Estimated enrollment for BELLE-2 is 842 patients. Recruitment in this Global study is ongoing with planned enrollment of patients in North America, South America, Europe, Asia and Africa.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-09.