Abstract OT2-1-01: Fulvestrant alone versus fulvestrant and everolimus versus fulvestrant, everolimus and anastrozole: A Phase III randomized, placebo-controlled trial in postmenopausal patients with hormone-receptor-positive stage IV breast cancer: SWOG-Clinical Trials Ini
Authors: Somlo George , Barlow William , Moore Halle , Gralow Julie , Schott Anne , Hayes Daniel , Kuhn Peter , Hicks James , Lew Danika , Tripathy Debu , Hortobagyl Gabriel 
Published: May 2015

Abstract
BACKGROUND: The median survival for women with hormone-receptor-positive (HR+) stage IV metastatic breast cancer (MBC) is 36 months. Strategies to improve outcome for postmenopausal women, include combinations of aromatase inhibitors (AIs) with either the estrogen receptor downregulator fulvestrant, or with the PI3kinase/AKT/mTOR signal inhibitor everolimus, as this pathway has been implicated as a mediator of resistance to endocrine therapies. However,fulvestrant 500 mg has not been tested in combination with everolimus alone, or in combination with everolimus and an AI.
SPECIFIC AIMS/TRIAL DESIGN: S1222 (NCT02137837) is a randomized phase III double-blinded, placebo-controlled clinical trial and is currently accruing. Patients receive fulvestrant (500 mg IM every 2 weeks for 3 doses, then monthly) on all arms, everolimus 10 PO daily (Arms 2 and 3, placebo Arm 1), and anastrozole 1 mg daily (Arm 3), or placebo (Arms 2 and 1). The co-primary objectives are to compare progression-free survival (PFS) between fulvestrant and everolimus (Arm 2) vs. fulvestrant (Arm 1), and fulvestrant, everolimus, and anastrozole (Arm 3) vs. fulvestrant (Arm 1). Additional objectives include comparison of PFS between Arms 2 and 3, and overall survival (OS), response and clinical benefit rates, toxicities, feasibility, compliance, and OS among the study arms.
Translational research goals are to test molecular determinants of response in circulating tumor cells (CTCs), assess a previously piloted CTC-Endocrine Therapy Index (CTC ETI), perform CTC-Next Generation Sequencing Analysis (CTC-NGS), and NGS on cancer tissue and germ line DNA.
ELIGIBILITY CRITERIA: Postmenopausal women with histologically confirmed de novo or newly relapsed stage IV MBC, with HER2-negative and HR-positive (&gt;1% positive nuclear staining) features, with either measurable, or evaluable disease are eligible. Previous neoadjuvant/adjuvant therapy allowed, but adjuvant anti-HR therapy must have been completed ≥ 12 months prior to enrollment.
STATISTICAL METHODS/TARGET ACCRUAL: This is a parallel randomized design with equal allocation to the three arms: (1) fulvestrant + placebo for everolimus + placebo for anastrozole; (2) fulvestrant + everolimus + placebo for anastrozole; (3) fulvestrant, everolimus, and anastrozole. PFS is the primary outcome. There are two coprimary hypotheses: (1) Arm 2 versus Arm 1; and (2) Arm 3 versus Arm 1, each will be tested at α = 0.025 (2-sided) .Arm 2 versus Arm 3 is a secondary comparison. Sample size computations are based on accrual of 33 patients per month for 24 months resulting in a computed accrual total of 792. We estimate that the final analysis will occur 24 months after the last patient is accrued, an average followup of 36 months at the time of the final analysis with an expected trial duration of 4 years.
*SWOG-CTI manages the non-federally funded components of SWOG under The Hope Foundation. The study is supported by AstraZeneca and Novartis Pharmaceuticals Corp.
Citation Format: George Somlo, William Barlow, Halle Moore, Julie Gralow, Anne Schott, Daniel Hayes, Peter Kuhn, James Hicks, Danika Lew, Debu Tripathy, Gabriel Hortobagyl. Fulvestrant alone versus fulvestrant and everolimus versus fulvestrant, everolimus and anastrozole: A Phase III randomized, placebo-controlled trial in postmenopausal patients with hormone-receptor-positive stage IV breast cancer: SWOG-Clinical Trials Ini [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 OT2-1-01.