Abstract Introduction While therapies for metastatic breast cancer (MBC) are improving duration and quality of life, treatment remains palliative in intent, and long-term survival is infrequent. Improvements in systemic therapy are required. In this multinational, placebo-controlled, ran- domized phase III trial, Translational Research In Oncology (TRIO) and ImClone Systems will evaluate the effects of combining IMC- 1121B (ramucirumab), a humanized monoclonal antibody (MoAb) directed against a key angiogenesis-promoting receptor, to standard first-line docetaxel chemotherapy for women with HER2-negative MBC. Here, we describe the rationale for combining these agents, and the resulting study design and conduct. Rationale Angiogenesis Angiogenesis is the physiologic process by which new blood ves- sels are formed, and inhibition of tumor-associated angiogenesis is among the most promising emerging approaches for the treatment of breast cancer. Although a number of growth factors are consid- ered possible regulators of the angiogenic process (including basic fibroblast growth factor, transforming growth factor-α, transform- ing growth factor-β, tumor necrosis factor, platelet-derived endo- thelial cell growth factor, hepatocyte growth factor, angiogenin, interleukin-8, and placental growth factor), vascular endothelial growth factor (VEGF) appears to be the most important of these. VEGF is distinct in that it is the only identified endothelial cell– specific mitogen during angiogenesis, and intratumoral levels of VEGF are strong and independent prognostic markers in breast cancer. 1 Furthermore, in women with MBC, adding anti-VEGF antibodies to taxane chemotherapy improves progression-free sur- vival (PFS) and response rates. 2,3 Vascular endothelial growth factor interacts with endothelial cell surface receptors to mediate its effects. Among the relevant recep- tors, it is VEGF receptor-2 (VEGFR-2) that is normally expressed exclusively on endothelial and hematopoietic cells and is commonly overexpressed in human breast cancers and tumorigenic breast can- TRIO-012: A Multicenter, Multinational, Randomized, Double-Blind Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients With HER2-Negative, Unresectable, Locally Recurrent or Metastatic Breast Cancer John Mackey, 1 Karen Gelmon, 2 Miguel Martin, 3 Nicole McCarthy, 4 Tamas Pinter, 5 Mathieu Rupin, 6 Hagop Youssoufian 7 In this multinational, placebo-controlled, randomized phase III trial, Translational Research In Oncology (TRIO) will define the efficacy and safety of adding a novel antiangiogenic agent, IMC-1121B (ramucirumab), to standard first-line do- cetaxel chemotherapy for women with HER2-negative metastatic breast cancer. We will evaluate whether the addition of IMC-1121B prolongs progression-free survival and whether its use improves overall survival. Accrual is under way. Clinical Breast Cancer, Vol. 9, No. 4, 258-261, 2009; DOI: 10.3816/CBC.2009.n.044 Keywords: Angiogenesis inhibitor, Bevacizumab, Ramucirumab, Vascular endothelial growth factor receptor Current฀Trial 1 University of Alberta and Cross Cancer Institute, Edmonton, Canada 2 British Columbia Cancer Agency and University of Vancouver, Canada 3 San Carlos University Hospital, Madrid, Spain 4 Royal Brisbane and Women’s Hospital, Brisbane, Australia 5 Petz Alador Country Hospital, Gyor, Hungary 6 Cancer International Research Group, Paris 7 ImClone Systems, New York, NY Submitted: May 11, 2009; Accepted: May 22, 2009 Address for correspondence: John Mackey, Department of Medical Oncology, University of Alberta, Cross Cancer Institute, 11560-University Ave, Edmonton, Alberta, Canada T6G 1Z2 Fax: 780-432-8888; e-mail: john.mackey@cirg.org This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1526-8209 provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400. 258 | Clinical Breast Cancer November 2009