Brown, MD Department of Urology Tel: 319-356-2273 e-mail: james -brown-2@uiowa.edu Mark C. Smith, MD Department of Radiation Oncology Tel: 319-384-6135 e-mail: mark-c-smith@uiowa.edu Michael O’Donnell, MD Department of Urology Tel: 319-384-6981 e-mail: michael -odonnell@uiowa.edu Sundeep Deorah , MD Department of Urology Tel: 319-384-5418 e-mail: sundeep-deora@uiowa.edu Amit Gupta, MD Department of Urology Tel: 319-384-5251 e-mail: amit-gupta-1@uiowa.edu Kenneth Nepple , MD Department of Urology Tel: 319-35-2114 e-mail: kenneth-nepple@uiowa.edu Pamela Zehr, RN , MA Holden Comprehensive Cancer Center tel: 319-353-8914 e-mail: pamela-zehr@uiowa.edu Mary Schall , RN, BSN Holden Comprehensive Cancer Center tel: 319-356-3516 e-mail: mary-schall@uiowa.edu 1 Please send all communications to this investigator. Karen Clark Griffith, RN, PhD Iowa City Veterans Affairs Health Care System Tel: 319-338-0581, ext. 7519 e-mail: karen.clarkgriffith@va.gov Erica Brown , ARNP Department of Urology Tel: 319-467-5072 e-mail: erica-brown@uiowa.edu Gideon Zamba, PhD Department of Biostatistics Tel: 319 384 5020 e-mail: gideon-zamba@uiowa.edu Steven Varga, PhD Department of Microbiology Tel: 319-335-774 e-mail: steven-varga@uiowa.edu Lyse Norian, PhD Department of Urology Tel: 319-335-3013 e-mail: lyse-norian@uiowa.edu Nicole Miller, PA -C Department of Urology Tel: 319-356-3850 e-mail: nicole- miller@uiowa.edu Roseanne Rath, PA -C Department of Urology Tel: 319-353-6972 e-mail: roseanne-rath@uiowa.edu PROTOCOL #1 Lubaroff, page 2 Lubaroff Investigational Pharmacist Kristine Johnson, BS, RPh Pharmacy Department Tel: 319-353-7077 e-mail: kristine-johnson@uiowa.edu Medical Monitor Daniel Berg, MD Holden Comprehensive Cancer Center Tel: 319-353-7800 e-mail: daniel -j-berg@uiowa.edu The Principal Investigator is funding this clinical trial through a award from the Department of Defense Prostate Cancer Research Program. Lubaroff Ad/PSA Phase II, protocol #2, page 3 INDEX Section Pages Introduction 4-14 Objectives 14 Patient Selection 14,15 Registration Procedures 15,16 Research Intervention Plan 16,17 Adverse Events 17-19 Measurement of Clinical and Immunological Efficacy 19-22 Study Parameters 23-26 Drug Formulation and Procurement 27,28 Statistical plan 28,29 Addendum 30 Roles and Responsibilities of Study Personnel 31,32 Literature References 32-36 Lubaroff Ad/PSA Phase II, protocol #2, page 4 1. INTRODUCTION 1.1 Background - Immunotherapy in Prostate Cancer Prostate cancer is the second leading cause of cancer death among males in the United States. There will be an estimated 234,460 new diagnoses of prostate cancer made in the United States in 2006 (1). Treatments for organ-confined prostate cancer include radical prostatectomy and radiation therapy . When the cancer presents de novo, or recurs outside the prostate, first- line systemic treatments typically include hormonal blockade (with LHRH agonists or bilateral orchiectomy), which suppress testosterone levels , limit the growth of androgen-dependent cancer cells, and result in clinical tumor control. After a median time of 2 years, patients progress into a clinical hormone-refractory state, when the prostate specific antigen (PSA) levels rise despite castration, there is proliferation of androgen-independent cancer cells, and there is continued clinical tumor growth that becomes fatal. Therapeutic measures in this situation include further hormonal manipulation s or the use of systemic chemotherapy, which has recently shown a small survival benefit in phase III trials. Approximately 30,000 Americans die from prostate cancer each year. Immunotherapeutic approaches against prostate cancer have been investigated for several years. Most of these studies have concentrated on active non-specific therapy and adoptive or passive therapy, with only recent focus on the induction of antigen-specific immune responses. Viral vectors have been used successfully in both gene transfer and vaccine therapy studies (2). Replication- competent and replication-defici ent adenoviruses expressing foreign proteins have been used to elicit immune responses to a variety of tumor antigens (3-7). We have demonstrated that immunizations with adenovirus, carrying the human PSA gene, can induce vigorous anti -PSA T -cell responses and cause the destruction of PSA -secreting tumors in a pre-clinical mouse model of prostate cancer (8,9). Such a ctive immunization against prostate-cancer associated antigens might be more effective than active non-specific or adoptive/passive immunotherapy. Therefore, we have pursu ed a vaccination strategy based on an adenovirus that carries the gene for prostate specific antigen (PSA). Results from our Phase I trial of adenovirus/PSA (Ad/PSA) vaccine (section 1.4, below) demonstrated that a single immunization of men with metastatic prostate cancer was able to induce anti -PSA T cell responses. The trial design was a dose escalation study with the vaccine administered subcutaneously (sc) either in an aqueous solution or in a collagen matrix (Gelfoam ®). We now propose a Phase II clinical trial using the Ad/PSA vaccine, administered in multiple injections to prostate cancer patients with minimal disease burden. 1.2 Adenovirus v ector s Recombinant adenoviral vectors transduce a wide range of dividing and nondividing cells types, making this gene delivery system valuable as a tool for studying diseases, for vaccine therapy, and for potential clinical use (10). Recombinant adenovirus can be prepared and purified in high titers. In addition, wild-type adenovirus infections are extremely common in the general population, giving adenovirus a well -documented safety record ( 11). Moreover, adenoviruses are structurally stable and no adverse effects have been reported following the vaccination of US military recruits with wild types, demonstrating their safety for human use ( 11). Adenoviral vectors for gene therapy and vaccine therapy are adenoviruses which have been genetically modified to allow insertion of foreign genes and to render the virus replication-defective. Current vectors have a deletion in the E1 region or in both the E1 and E2 regions. Adenoviral gene transfer has been Lubaroff Ad/PSA Phase II, protocol #2, page 5 used in a variety of experimental conditions that include transfers to the liver ( 12), lung ( 13), central nervous system ( 14,15), and to cancer cells ( 16). There is evidence that the introduction of foreign transgenes by adenovirus induces immune responses to the transgene product, which become ultimately responsible for the elimination of the virus (17,18). While this is disadvantageous for insertion of functional genes into host cells, it is advantageous in the use of viruses carrying foreign genes as immunogens. In the vaccine therapy of cancer, active immunization against a murine colon cancer, breast cancer, and melanoma antigens have been induced by adenoviral vaccines (19-26). The Ad/PSA vaccine used our laboratory and in our Phase I clinical trial was produced by inserting the gene for the full length pre-pro form of human PSA into a replication deficient adenovirus seroty pe 5. Replication deficiency was induced by deletion of the E1a and E1b genes of the virus. Details of the vaccine can be found in section 9 of this protocol.