310TiP - A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in patients with HER2–negative...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Breast Cancer
Presenter Hope Rugo
Citation Annals of Oncology (2016) 27 (6): 68-99. 10.1093/annonc/mdw365
Authors H. Rugo1, O. Petrenciuc2, A. Zhang3, R. Li4, R.E. Coleman5
  • 1Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, 94115 - San Francisco/US
  • 2Global Clinical Development, Pharmaceuticals Division of Bayer, Whippany/US
  • 3Global Development, Pharmaceuticals Division of Bayer, Whippany/US
  • 4Global Research And Development Statistics, Pharmaceuticals Division of Bayer, Whippany/US
  • 5Oncology, University of Sheffield, Weston Park Hospital, S10 2SJ - Sheffield/GB



Treatment options for bone-dominant metastatic breast cancer (MBC) are limited. Radium-223 (Ra-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. Ra-223 plus EVE + EXE may improve outcomes in patients with HER2 ER+ bone-dominant MBC; this trial will evaluate efficacy and safety of Ra-223 versus placebo in these patients (NCT02258451).

Trial design

Eligible patients are pre- or postmenopausal with HER2 ER+ MBC and ≥ 2 bone or soft tissue 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. Patients are randomized to receive (1:1) Ra-223 (50 kBq/kg [55 kBq/kg after National Institute of Standards and Technology update] IV) or placebo × 6 cycles q 4 wk plus 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 Amer vs Asia), prior hormone therapy (1 vs ≥ 2), and presence of visceral disease (yes vs no). Safety and efficacy are assessed every 4 weeks. Long-term safety is assessed until study termination. 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 chemotherapy; radiologic PFS; and safety. 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. Estimated enrollment is ∼ 311 patients. Currently, 72 patients are randomized.

Clinical trial identification


Legal entity responsible for the study

Pharmaceuticals Division of Bayer


Pharmaceuticals Division of Bayer


H. Rugo: Speakers bureau, honoraria: Genomic Health; research funding: Plexxikon, Macrogenics, OBI, Eisai, Pfizer, Novartis, Lilly, GlaxoSmithKline, Genentech, Celsion, Nektar, Merck; travel, accommodations, expenses: Novartis, Nektar, Roche/Genentech, OBI, Mylan. O. Petrenciuc: Employed by and travel, accommodations, expenses from Bayer. A. Zhang, R. Li: Employed by Bayer. R.E. Coleman: Expert testimony for Novartis; research funding from Bayer.