Abstract OT2-6-07: Buparlisib (BKM120), an oral pan-PI3K inhibitor, in combination with paclitaxel in patients with HER2-negative, locally advanced or metastatic breast cancer, with or without PI3K pathway activation: A phase II, randomized, double-blind, placebo-controlled study – BELLE-4
Authors: Martin M , Batista N , Shtivelband M , Chan A , Delaloge S , Dirix L , Lee SC , Le Mouhaer S , Nanni S , DiTomaso E , Urban P , O'Shaughnessy J 
Published: August 2014

Abstract
Background: Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is the most frequently activated signaling pathway in breast cancer. Activation of this pathway has been implicated in tumor growth, progression, and resistance to anticancer therapies. Buparlisib (BKM120) is an oral pan-PI3K inhibitor that targets all four isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in combination with weekly paclitaxel in patients with advanced solid tumors. The maximum tolerated dose of this combination was declared as 100 mg/day and 80 mg/m2/week for buparlisib and paclitaxel, respectively (Dirix et al. ESMO 2012).
Trial design: BELLE-4 (NCT01572727) is a randomized, double-blind, placebo-controlled, Phase II trial of buparlisib or placebo plus weekly paclitaxel in adult women with chemotherapy-naïve, HER2-negative, locally advanced or metastatic breast cancer. Key inclusion criteria are: known PI3K pathway activation status (activated vs non-activated; centrally determined); ECOG performance status ≤1; and adequate bone marrow and organ function. Key exclusion criteria are: no prior treatment with a PI3K or Akt inhibitor; no prior systemic chemotherapy for advanced breast cancer (prior endocrine and adjuvant chemotherapy allowed); and no symptomatic CNS metastases.
Patients are randomized 1:1 to receive oral buparlisib (100 mg once daily) or matching placebo, and IV paclitaxel (80 mg/m2 once weekly) in a 28-day treatment cycle until disease progression, unacceptable toxicity, death or discontinuation from study treatment for any other reason. Stratification at randomization is based upon PI3K pathway activation and hormone receptor status. Tumor assessments are performed locally every 8 weeks from randomization until radiologic progression (RECIST 1.1).
Endpoints: The primary endpoint is progression-free survival* (PFS; per local investigator) in the full and PI3K pathway-activated populations. Secondary endpoints include overall survival (OS), overall response rate (ORR)*, duration of response (DOR)*, clinical benefit rate (CBR)*, time to response*, buparlisib pharmacokinetics, and safety† (*RECIST 1.1, †CTCAE v4.03).
Statistical methods: PFS analysis will be performed in PI3K pathway-activated sub-population, PI3K non-activated sub-population, and the full population, using Bayesian methodology. A stratified Cox proportional hazard model will estimate the hazard ratio of PFS. The Kaplan–Meier method will estimate PFS, OS and DOR (if relevant) for both full and PI3K pathway-activated populations. ORR and CBR will be summarized with exact 95% confidence intervals.
Target accrual: Approximately 200 patients will be randomized onto BELLE-4 at around 80 centers across 18 countries. Recruitment is ongoing across America, Europe, and Asia.
Contact: For further information about the study, contact your local Novartis representative.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-07.