Cancer Therapy: Clinical Vaccination of Metastatic Renal Cancer Patients with MVA-5T4: A Randomized, Double-Blind, Placebo-Controlled Phase III Study Robert J. Amato 1 , Robert E. Hawkins 2 , Howard L. Kaufman 3 , John A. Thompson 4 , Piotr Tomczak 5 , Cezary Szczylik 6 , Mike McDonald 7 , Sarah Eastty 7 , William H. Shingler 7 , Jackie de Belin 7 , Madusha Goonewardena 7 , Stuart Naylor 7 , and Richard Harrop 7 Abstract Purpose: The TroVax Renal Immunotherapy Survival Trial was a randomized, placebo-controlled phase III study that investigated whether modified vaccinia Ankara encoding the tumor antigen 5T4 (MVA-5T4) prolonged survival of patients receiving first-line standard-of-care (SOC) treatment for meta- static renal cell cancer. Experimental Design: Patients with metastatic clear cell renal cancer, prior nephrectomy, and good or intermediate prognosis were randomized 1:1 to receive up to 13 immunizations of MVA-5T4/placebo in combination with either sunitinib, interleukin-2 or interferon-α. The primary end point was overall sur- vival. Secondary end points included progression-free survival, overall response rate, and safety. Results: Seven hundred thirty-three patients were recruited (365 MVA-5T4 and 368 placebo). Treat- ment arms were well balanced for SOC and prognosis. No significant difference in the incidence of adverse events or serious adverse events was observed. No significant difference in overall survival was evident in the two treatment arms (median 20.1 months MVA-5T4 versus 19.2 months placebo; P = 0.55). The magnitude of the 5T4-specific antibody response induced by vaccination with MVA-5T4 was asso- ciated with enhanced patient survival. Furthermore, exploratory analyses suggested a number of pretreat- ment hematologic factors that could identify patients who derive significant benefit from this vaccine. Conclusion: MVA-5T4 in combination with SOC was well tolerated, but no difference in survival was observed in the overall study population. Exploratory analyses indicate that there may be subsets of patients who could gain significant benefit from MVA-5T4, but such results would need to be confirmed in future randomized clinical studies. Clin Cancer Res; 16(22); 5539–47. ©2010 AACR. Renal cell carcinoma (RCC) represents 5% of epithelial cancers diagnosed annually in the United States, the majority being of clear cell histology (1, 2). Approximately 20% to 30% of RCC patients present with metastatic disease, which has a poor prognosis. Conventional cyto- toxic chemotherapeutic agents and hormonal therapies have little impact on survival, and response rates are usually <10%. Until recently, cytokine therapy using interleukin-2 (IL-2) or interferon- α (IFN- α) was the mainstay of treatment; however, it yielded low response rates of <30% and median survival times of ∼1 year (3). However, a better understanding of the mechanisms un- derlying RCC tumorigenesis has led to the development of new targeted agents. Indeed, the Food and Drug Adminis- tration has recently approved sunitinib, sorafenib, temsir- olimus, everolimus, pazopanib, and bevacizumab for use against advanced RCC. Despite these advances, the man- agement of metastatic RCC remains a challenge. The abil- ity to add a new therapeutic moiety to an existing therapy without increasing toxicity or reducing efficacy would be valuable. Cancer vaccines offer one possible approach to achieve this goal. Although there have been several failed phase III trials, a number of cancer vaccine/immunother- apy products have shown encouraging data in late-stage clinical studies and the Food and Drug Administration has recently approved the first therapeutic vaccine (Pro- venge) for the treatment of prostate cancer. Even with this encouraging breakthrough, it is critical that we continue to gain a better understanding of the nature of the efficacious Authors' Affiliations: 1 The University of Texas/Memorial Hermann Hospital, Houston, Texas; 2 Christie Hospital, Withington, Manchester, United Kingdom; 3 Rush University Medical Center, Chicago, Illinois; 4 University of Washington, Seattle, Washington; 5 Lord's Transfiguration Independent Public Clinical Hospital, Poznan, Poland; 6 Military Institute of Medicine, Department of Oncology, Warsaw, Poland; and 7 Oxford BioMedica (UK) Ltd., The Medawar Centre, Oxford, United Kingdom Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Richard Harrop, Oxford BioMedica, Robert Robinson Avenue, Oxford Science Park, Oxford OX4 4GA, United Kingdom. Phone: 44-1865-783000; Fax: 44-1865-783001; E-mail: r.harrop@ oxfordbiomedica.co.uk. doi: 10.1158/1078-0432.CCR-10-2082 ©2010 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 5539