Background: Taselisib is an orally bioavailable, potent, selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the alpha isoform showing enhanced activity against PIK3CA mutant cancer cell lines. Clinical data have demonstrated confirmed partial responses in patients with PIK3CA mutant breast cancer (BC) treated with single-agent taselisib. Enhanced antitumor activity has been noted when taselisib is combined with either letrozole or fulvestrant in preclinical and Phase Ib clinical studies. Methods: LORELEI is a Phase II, two-arm, randomized, double-blind, multicenter, study of neoadjuvant letrozole and taselisib versus letrozole and placebo in postmenopausal women with newly diagnosed ER+/HER2-, untreated, Stage I-III operable BC. Other eligibility criteria include tumor size ³ 2 cm by magnetic resonance imaging (MRI), ECOG PS 0-1, and evaluable tumor tissue for PIK3CAgenotyping. Patients treated with anti-diabetic drugs are not eligible. Patients are randomized (1:1) to receive continuous letrozole (2.5 mg) with either taselisib (4 mg on a 5 days on/ 2 days off schedule) or placebo for 16 weeks, followed by surgery. Stratification is based on tumor size and nodal status. The co-primary endpoints are overall objective response rate (ORR) by centrally assessed breast MRI via modified RECIST criteria and pathologic complete response (pCR) rate in breast and axilla at time of surgery in all randomized patients and PIK3CA mutant patients. Secondary endpoints include ORR by centrally-assessed MRI and pCR rate in PIK3CAwild-type patients. The sample size was calculated to detect an absolute percentage increase of 24% in ORR with 80% power at 16% 2-sided alpha and an absolute percentage increase of 18% in pCR rate with 80% power at 4% 2-sided alpha. An interim safety analysis has been conducted by an IDMC with the recommendation of continue the trial without modifications. As of 7 Jan 2016, 198 of the 330 patients have been enrolled, and global enrollment is ongoing. Clinical trial information: NCT02273973