Abstract OT1-04-05: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases
Authors: Rugo HS , Drumea KC , Campone M , Barnadas A , Petrenciuc O , Zhang A , Li R , Coleman RE 
Published: March 2017

Abstract
Background: Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223, a first-in-class α emitter with a targeted antitumor effect on bone metastases (mets), was well tolerated and reduced bone biomarker levels in a phase 2 study in patients with bone-dominant MBC (Coleman et al. Breast Cancer Res Treat. 2014). In patients with HER2- estrogen receptor+ (ER+) bone-dominant MBC, everolimus + exemestane (EVE+EXE) improved progression-free survival (PFS) versus EXE alone. Radium-223 combined with EVE+EXE may improve outcomes in patients with HER2- ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of radium-223 versus placebo in these patients (NCT02258451).
Trial design: Patients are randomized to receive (1:1) radium-223 (50 kBq/kg [55 kBq/kg after National Institute of Standards and Technology update] IV) or placebo × 6 cycles q 4 wk + EXE (25 mg PO q d) + EVE (10 mg PO q d) plus best supportive care. EXE+EVE continues until disease progression or unacceptable toxicity. Stratification is by geographic region (EU/N America vs Asia), prior hormone therapy (1 vs ≥ 2), and presence of visceral disease (yes vs no).
Eligibility criteria: Eligible patients are pre- or postmenopausal with HER2- ER+ MBC and have ≥ 2 bone mets or have soft tissue and/or visceral mets. Patients must have measurable disease per RECIST v1.1, ≥ 1 prior line of hormone therapy for MBC, and 1-2 prior skeletal-related events; be on bisphosphonates or denosumab; and have an ECOG score of 0-1. Patients must have had no past or current need for chemotherapy for MBC, no unresolved spinal cord compression, and no prior EVE treatment.
Specific aims: The primary end point is symptomatic skeletal event–free survival (SSE-FS). Secondary end points are overall survival; times to opiate use, pain progression, and cytotoxic chemotherapy; radiologic PFS; and safety. Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination.
Statistical methods: Assuming a 1-sided α of 0.1, 90% power, ∼ 160 SSE-FS events will be required for the analysis. Efficacy will be analyzed by a stratified log-rank test. Safety analysis will be descriptive.
Present and target accrual: Estimated enrollment is ∼ 311 patients. Currently, 74 patients are randomized.
Contact Oana Petrenciuc, Bayer HealthCare Pharmaceuticals, oana.petrenciuc@bayer.com, for more information.
Citation Format: Rugo HS, Drumea KC, Campone M, Barnadas A, Petrenciuc O, Zhang A, Li R, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2-negative, hormone receptor–positive breast cancer and bone metastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-05.