Abstract OT1-1-01: LORELEI: A Phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer
Authors: Saura Cristina , de Azambuja Evandro , Dubsky Peter , Oliveira Mafalda , Saini Kamal S , Fes Christian , Lin Ray S , Wilson Timothy R , Fredickson Jill , Parmar Hema , Hsu Jerry Y , Piccard Martine , Gnant Michael , Baselga Jose 
Published: May 2015

Abstract
Background: Taselisib (GDC-0032) is an orally bioavailable, potent, and 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 PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PIK3CA mutant cancer cell lines. Clinical data have also demonstrated confirmed partial responses in patients with PIK3CA mutant breast cancer treated with single-agent taselisib. Preclinical and clinical data also show enhanced antitumor activity when taselisib is combined with either letrozole or fulvestrant.
Study design: LORELEI is a phase II, two-arm, randomized, double-blind, multicenter, neoadjuvant study of letrozole and taselisib versus letrozole and placebo in postmenopausal women with newly diagnosed ER+/HER2-, untreated, stage I-III operable breast cancer. Other relevant eligibility criteria include tumor size ≥ 2 cm, unilateral disease, ECOG PS ≤1, and available and evaluable tumor tissue for central review of PIK3CA mutation analysis. Patients will be randomized (1:1) to receive continuous daily letrozole (2.5 mg) with either placebo or taselisib (4mg on a 5 days on/ 2 days off schedule) for 16 weeks. Study treatment is followed by surgery. Adjuvant treatment will be given as per physician’s discretion. Stratification at randomization is based on tumor size and nodal status.
Endpoints: The co-primary endpoints are overall objective response rate (ORR) by centrally assessed breast magnetic resonance imaging (MRI) via modified RECIST criteria and pathologic complete response (pCR) rate in breast and axilla at time of surgery in all enrolled patients and PIK3CA mutant (MT) patients. Secondary endpoints include ORR by centrally assessed MRI and pCR rate in PIK3CA wild-type (WT) patients. Other secondary endpoints performed in all enrolled patients and separately as per PIK3CA mutation status include: assessment of ORR using breast ultrasound, clinical breast exam (i.e. palpation) and mammography; changes in Ki67 levels from baseline to week 3, baseline to surgery and week 3 to surgery; centrally assessed preoperative endocrine prognostic index (PEPI) score; changes in enhancing tumor volume from baseline to surgery as measured by breast MRI via central assessment. Exploratory analyses include expression of biomarkers predictive of response to letrozole plus taselisib from tumor tissue or blood.
Statistical methods:
The sample size was calculated to detect an absolute percentage increase of 24% in ORR via MRI (40% in the letrozole-placebo arm vs. 64% in the letrozole-taselisib arm in the PIK3CA MT cohort) with 80% power at 16% two-sided significance level. The sample size will also detect an absolute percentage increase of 18% in pCR rate (1% in the letrozole-placebo arm vs 19% in the letrozole-taselisib arm in the PIK3CA MT cohort) with 80% power at 4% two-sided significance level.
Target accrual: Approximately 330 pts at 110 global sites across Europe, North and South America, and Asia-Pacific.
Reference Study ID Numbers: GO28888/BIG-3-13/SOLTI 1205/ABCSG 38.
Citation Format: Cristina Saura, Evandro de Azambuja, Peter Dubsky, Mafalda Oliveira, Kamal S Saini, Christian Fes, Ray S Lin, Timothy R Wilson, Jill Fredickson, Hema Parmar, Jerry Y Hsu, Martine Piccard, Michael Gnant, Jose Baselga. LORELEI: A Phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib (GDC-0032) versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative, early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-01.