Abstract OT2-6-08: Phase II, randomized, parallel-cohort study of neoadjuvant buparlisib (BKM120) in combination with trastuzumab and paclitaxel in women with HER2-positive, PIK3CA mutant and PIK3CA wild-type primary breast cancer – NeoPHOEBE (2013)

Abstract Background: The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is important for the oncogenic function of HER2. Buparlisib is an oral pan-PI3K inhibitor that targets all 4 isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in patients (pts) with advanced BC as a single agent, and in combination with paclitaxel (Dirix et al. ESMO 2012) or trastuzumab (Pistilli et al. ESMO 2012). Study design: NeoPHOEBE (NCT01816594) is a Phase II, randomized, double-blind, parallel-cohort study of neoadjuvant buparlisib or matched placebo plus trastuzumab and weekly paclitaxel. Upfront stratification of pts into 2 independent cohorts according to PIK3CA mutation status will determine whether pts with PIK3CA-mutant tumors may benefit more from this treatment combination. Adult women with newly diagnosed, HER2-positive, primary non-inflammatory BC who have not previously received systemic therapy for invasive disease are eligible. Other eligibility criteria: tumor size &amp;gt;2 cm; unilateral disease; available tumor tissue for central review of estrogen receptor (ER) and HER2 status, and PIK3CA genotype; known PIK3CA mutation status; and ECOG PS ≤1. Pts in each cohort (PIK3CA mutant or wild-type [wt]) are randomized (1:1) to receive continuous daily buparlisib (100 mg) or placebo and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg) for 6 weeks, followed by continuous daily buparlisib (80 mg) or placebo with weekly trastuzumab (2 mg/kg) and weekly paclitaxel (80 mg/m2) for 12 weeks. Study treatment is followed by surgery within 4 weeks of last paclitaxel dose. Stratification at randomization is based on PIK3CA (mutant vs wt) and ER (positive vs negative) status. Endpoints: All endpoints will be measured in both PIK3CA-mutant and wt cohorts. The primary endpoint is rate of pathologic complete response (pCR; ypT0) at time of surgery. The key secondary endpoint is objective response rate (ORR) at the end of week 6. Other secondary endpoints include pCR by other definitions, ORR prior to surgery, pCR and objective response by ER status, percent of pts with node-negative disease at surgery, rate of breast conserving surgery, and safety. Exploratory objectives include change in standardized uptake value (SUV) at Day 15 by FDG-PET; and ORR and pCR by PTEN expression, Ki67 level, apoptosis rates, percentage of tumor infiltrating lymphocytes (TIL), and by phenotype of 50% TIL at baseline. Statistical methods: The sample size is based on a minimax 2-stage randomized Phase II design with a prospective control. This design allows for early stopping if the desired efficacy is not observed after stage 1. Both cohorts are powered (80%) to detect a clinically meaningful increase in pCR of 18% at a one-sided significance level (α = 0.15). Target accrual: Planned enrollment for NeoPHOEBE is up to 220 pts at 65 sites in 12 countries across South America, Europe, and Asia-Pacific. Contact: For further study information, contact BIG@bordet.be. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-08.