Page 2 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 PARTICIPATING INSTITUTIONS: City of Hope National Medical Center 1500 East Duarte Road Duarte, CA 91010 (626) 256 -4673 Huntsman Cancer Institute, University of Utah 2000 Circle of Hope, Ste 2123, Salt Lake City, Utah 84112 Phone: 801 -585-0255 Pager: 801 -339-2041 Fax: 801 -585-0124 City of Hope National Medical Center – South Pasadena 209 Fair Oaks South Pasadena, CA 91030 (626) 396 -2900 DATA COORDINATING CENTER City of Hope National Medical Center 1500 East Dua rte Road Duarte, CA 91010 (626) 256 -4673 Page 3 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 Experimental Design Schema Registration Randomization Arm A (Sipuleucel-T) Arm B (Sipuleucel-T and radiation therapy) Study Schema for Arm A patients: (to simplify comparison between both groups, the start of therapy in group A will be counted as week 3) Week 1-2 Week 3 (Day 19) Week 4 (Day 22) Week 5 (Day 33) Week 6 (Day 36) rest Sipuleucel-T Sipuleucel- T Sipuleucel-T Sipuleucel -T collection infusion collection infusion Week 7 (Day 47) Week 8 (Day 50) Week 4 (Day22), and weeks 12, 24, 36, 48, 60 Sipuleucel-T Sipuleucel- T Assays for immune correlates collection Infusion Study Schema for Arm B patients: Week 1-2 Week 3 Week 3 (Day 19) Week 4 (Day 22) Week 5 (Day 33) Week 6 (Day 36) EBR T to Rest Sipuleucel-T Sipuleucel-T Sipuleucel-T Sipuleucel -T sing le met collection infusion collection infusion Week 7 (Day 47) Week 8 (Day 50) Week 4 (Day22), and weeks 12, 24, 36, 48, 60 Sipul eucel-T Sipuleucel-T Assays for immune correlates collection Infusion Page 4 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 P rotocol Synopsis Protocol Title: RANDOMIZED PHASE II TRIAL OF SIPULEUCEL T IMMUNOTHERAPY PRECEDED BY SENSITIZING RADIATION THERAPY AND SIPULEUCEL -T ALONE IN PATIENTS WITH CASTRATE RESISTANT METASTATIC PROSTATE CANCER Brief Protocol Title for the Lay Public (if applicable): Sipuleucel -T preceded by sensiti zing radiation therapy in patients with metastatic castration resistant prostate cancer Study Phase: Phase II Participating Sites: City of Hope Cancer Center City of Hope South Pasadena Huntsman Cancer Institute, University of Utah Rationale for this Study: The combination of radiation therapy and immunotherapy holds promise as a strategy for cancer treatment. Preclinical studies have shown that radiation may act synergistically with immunotherapy to enhance or broaden antitumor immune responses, in p art, because of radiation -induced phenotypic alterations of tumor cells that render them more susceptible to immune -mediated killing(1). Clinical trials utilizing the combination of therapeutic vaccines with radiation have supported many of these findings, and other clinical trials are both ongoing and planned. Sipuleucel -T is an active cellular immunotherapy approved for treatment of patients with castrate - resistant, asymptomatic or minimally symptomatic metastatic prostate cancer (2). Our proposal is ba sed on the hypothesis that applying sensitizing radiotherapy to selected metastatic site prior to immunotherapy will enhance immune response in patients treated with Sipuleucel -T. Objectives: Primary Objective : To assess the feasibility, based on percent able or willing to receive all three infusions of Sipuleucel -T immunotherapy, when combining Sipuleucel -T with radiation therapy to a single site of metastasis delivered one week prior to beginning of Sipuleucel -T therapy Secondary Objectives: 1. To assess the effect of radiation therapy to single metastasis on immune response (antibody and T -cell proliferation to prostate acid phosphatase PAP and fusion protein PA2024) generated by Sipuleucel -T immunotherapy. 2. To assess the effect of external beam radiotherapy to single metastasis on PSA response to therapy with Sipuleucel -T. 3. To assess the effect of external beam radiation therapy to single metastasis on radiographic response rate to therapy with Sipuleucel -T. 4. To asses s the time from the onset of therapy with Sipuleucel -T +/- radiation to the need for subsequent therapy for prostate cancer. 5. To assess the toxicity associated with Sipuleucel -T +radiation. Page 5 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 Study Design: Eligible patients will meet the st andard criteria for approved use of Sipuleucel -T. Patients will be randomized to receive standard Sipuleucel -T regimen (Arm A) or Sipuleucel -T preceded by radiation therapy to single site of metastatic disease (Arm B). In patients assigned to Arm B one me tastatic site will be selected for radiation based primarily on the safety of radiation in that location. Radiation to bone metastases from L3 down to pelvis and femurs will be excluded provided that patients have other areas of metastases. Patients who ha ve metastases only in the above locations (L3 down to pelvis and femurs) will be allowed provided that they have normal WBC and they will not receive radiation to more than 20% of the bone marrow. Patients will be treated with 300 cGy/day to 3000 cGy. Approximately 7 days after completion of radiation therapy patients will begin therapy with Sipuleucel -T autologous vaccine. Endpoints: Primary Endpoint: The primary endpoint in this trial will be percent of patients able to receive all three infusions of Sipuleucel -T following radiation therapy . This endpoint reflects both tolerability and the ability to collect adequate numbers of CD54+ cells for the generation of Sipuleucel -T. Secondary Endpoint: Secondary endpoints will include measurements of immune responses to PAP, PA2024 and PSA and radiologic responses to therapy with Sipuleucel -T +/- external beam radiation therapy to single metastasis. Toxicity comparison between the two arms is also a secondary endpoint. Sample Size: Total Sample size is 50 randomized in a 1:1 fashion to Arm A and B. Anticipated accrual is 2 -3 patients a month . Estimated Duration of the Study 24 months Summary of Subject Eligibility Criteria: Inclusion Criteria: Patients with metastatic castration -resistant p rostate cancer who are candida tes for Sipuleucel -T immunotherapy . Metastatic, minimally symptomatic or asymptomatic disease, ECOG PS 0 -2 Exclusion Criteria: Liver metastases, known brain metastases, > 2 prior chemotherapy regimens Page 6 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 Investigational Produ ct Dosage and Administration: Not Applicable. Radiation therapy constitutes investigational component of this study Clinical Observations and Tests to be Performed: Evaluation for toxicity will be performed at week 4, 6, 8, 12 and every 12 weeks thereafter. PSA will be performed at week 4 and 12, radiologic evaluation will be performed at week 12, and immune assays will be performed at week 4, 12, 24, 36, 48, 60 Statistical Considerations: This is a randomized Phase II study . The primary end point in this trial will be the ability to safely combine Sipuleucel -T with radiation therapy and collect adequate numbers of CD54+ cells for the generation of Sipuleucel -T. This is measured by the percent of patients able to receive all three infusions o f Sipuleucel -T. Secondary endpoints will include toxicity, and measurements of immune responses to PAP, PA2024 and PSA and radiologic responses to therapy with Sipuleucel -T +/- external beam radiation therapy to single metastasis. Sponsor/Licensee: City of Hope Cancer Center Case Report Forms Not applicable Page 7 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 Table of Contents SECTION ..............................................................................................................................