Abstract P4-13-27: A phase Ib dose de-escalation study of combined tamoxifen and goserelin acetate with alpelisib (BYL719) or buparlisib (BKM120) in premenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer
Authors: Lu Y-S , Ro J , Tseng L-M , Chao T-Y , Chitapanarux I , Valenti R , Canatar A , Salomon H , Park YH 
Published: May 2016

Abstract
Background: Growing evidence suggests that concomitant inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway could enhance and extend the clinical benefit of endocrine therapies in hormone receptor-positive (HR+) metastatic breast cancer (mBC). In this Phase Ib study (NCT02058381), alpelisib (a p110α-selective inhibitor) or buparlisib (a pan-PI3K inhibitor) was combined with tamoxifen and goserelin acetate in premenopausal women with mBC, a more prevalent patient population in Asian vs Western countries.
Methods: Premenopausal women with HR+/human epidermal growth factor receptor 2-negative (HER2–) locally advanced or mBC and no prior endocrine therapy for metastatic disease were recruited in Taiwan, Republic of Korea, and Thailand. Patients (pts) received tamoxifen (20 mg once daily [QD]) and goserelin (3.6 mg Q28D) with either alpelisib (350 mg QD; Group 1) or buparlisib (100 mg QD; Group 2) on a continuous dosing schedule in 28-day cycles. The primary objective was to define the recommended Phase II dose (RP2D) for each combination, based on dose-limiting toxicities (DLTs) observed during Cycle 1, using a dose de-escalation design. Secondary objectives included pharmacokinetics, safety and tolerability (per Common Terminology Criteria for Adverse Events v4.03), efficacy (per Response Evaluation Criteria In Solid Tumors v1.1), and impact on quality of life.
Results: As of February 2, 2015, 12 pts, all Asian, have been treated in the first cohort. In Group 1, 6 pts with a median age of 43 were treated with alpelisib (350 mg starting dose), and no DLTs were observed in Cycle 1. In Group 2, 6 pts with a median age of 47 were treated with buparlisib (100 mg starting dose), and 1 DLT of Grade (G) 3 alanine aminotransferase/aspartate aminotransferase elevation was observed. In Group 1, significant toxicities included hypokalemia (G3: 1 pt), rash (G3: 1 pt; G1/2: 2 pts), anemia (G3: 1 pt), leukopenia (G3: 1 pt), and infections (G3: 1 pt; G1/2: 1 pt); no G4 toxicities were reported. In Group 2, significant toxicities included liver toxicity (G4: 1 pt; G3: 1 pt; G1/2: 2 pts), psychiatric disorders (G4: 1 pt; G3: 1 pt; G1/2: 1 pt), rash (G3: 1 pt; G1/2: 2 pts), hypertension (G3: 1 pt; G1/2: 1 pt), and hyperglycemia (G3: 1 pt). No pts in Group 1, and 5/6 pts in Group 2, have discontinued treatment due to adverse events (AEs). Median treatment duration was 110 days in Group 1 and 71 days in Group 2.
Conclusions: The combination of alpelisib (350 mg) with tamoxifen and goserelin resulted in a manageable toxicity profile. Meanwhile, the same combination with full-dose buparlisib (100 mg) was less well tolerated; despite the appearance of only one DLT during Cycle 1, the majority of pts subsequently stopped treatment due to AEs. An expansion phase is ongoing, and results will be integrated with safety, tolerability, and efficacy results for the first 15 pts enrolled in each group. PIK3CA status at baseline will also be assessed.
Citation Format: Lu Y-S, Ro J, Tseng L-M, Chao T-Y, Chitapanarux I, Valenti R, Canatar A, Salomon H, Park YH. A phase Ib dose de-escalation study of combined tamoxifen and goserelin acetate with alpelisib (BYL719) or buparlisib (BKM120) in premenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-27.