NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With Weekly Paclitaxel in HER2-positive Primary Breast Cancer

This randomized, parallel cohort, two stage, double-blind, placebo-controlled study evaluated the oral PI3K inhibitor BKM120 in combination with trastuzumab and paclitaxel in HER2-positive, PIK3CA wild-type and PIK3CA mutant primary breast cancer prior to surgery (neo-adjuvant setting).

NeoPHOEBE evaluated the efficacy (as defined by pCR) of BKM120 (an oral PI3K inhibitor) in combination with trastuzumab and paclitaxel in a randomized, placebo-controlled, neo-adjuvant study in women diagnosed with primary breast cancer \>1.5 cm (by US or MRI) with centrally confirmed HER2 overexpression or amplification, who have not previously undergone treatment for invasive breast cancer.

Prior to the initiation of paclitaxel, there was a 6-week "biologic window" with trastuzumab plus BKM120 or placebo only. The study was conducted separately in two cohorts (PIK3CA mutated and PI3K3CA wild-type) using a two-stage approach. Within each cohort patients were randomized into one of the following treatment arms:

Arm 1: BKM120 plus trastuzumab for 6 weeks followed by BKM120 and trastuzumab plus weekly paclitaxel for an additional 12 weeks.

Arm 2: BKM120 placebo plus trastuzumab for 6 weeks followed by BKM120 placebo plus trastuzumab plus weekly paclitaxel for an additional 12 weeks.

After completion of study treatment, patients were to have undergone definitive surgery.

Eligibility Criteria:
Inclusion Criteria:

* Patient had provided a signed study ICF prior to any screening procedure
* Patient was a female ≥ 18 years of age
* Patient has an ECOG performance status of 0-1
* Patient has a unilateral (multifocal or multicentric disease allowed), histologically confirmed, newly diagnosed early breast cancer \>2cm by clinical examination and/or \>1.5 cm confirmed by ultrasound or by MRI
* Patient has tumor tissue available for central review of ER, HER2 and PI3K status with centrally confirmed HER2-positive disease and known PI3KCA mutation status
* Patient has adequate bone marrow, renal and liver function
* Patient is able to swallow and retain oral medication

Exclusion Criteria:

* Patient has received prior systemic treatment for currently diagnosed disease
* Patient has a known contraindications, hypersensitivity or intolerance to trastuzumab, paclitaxel or products containing cremophor
* Patient has bilateral breast cancer or metastatic disease or inflammatory breast cancer
* LVEF below 50% as determined by MUGA scan or ECHO
* Patient has active cardiac disease or a history of cardiac abnormalities as defined in the protocol
* Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of BKM120
* Patient is currently receiving warfarin or other coumarin derived anti-coagulants
* Patient is currently receiving chronic treatment with corticosteroids or another immunosuppressive agents (standard premedication for paclitaxel and local applications allowed)
* Patient is currently receiving treatment with drugs known to be strong inhibitors or inducers of CYP3A
* Patient has certain scores on an anxiety and depression mood questionnaires
* Pregnant or nursing (lactating) women or patients not willing to apply apply highly effective contraception as defined in the protocol