41 Appendi x “B”................................................................................................................................. 42 Page 9 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 A ppendix “C”: Multicenter Guidelines ........................................................................... 49 Page 10 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 Abbreviations Abbreviation Meaning AE Adverse Event CFR Code of Federal Regulations COH City of Hope CR Complete Response CRA Clinical Research Associate CRF Case Report Form CRPC Castration Resistant Prostate Cancer CTCAE Common Terminology Criteria for Adverse Events CTEP Cancer Therapy Evaluation Program DSMC Data Safety Monitoring Committee FDA Food and Drug Administration GCP Good Clinical Practice IB Investigator Brochure ICF Informed Consent Form IDS Investigational Drug Services IND Investigational New Drug IRB Institutional Review Board NCI National Cancer Institute PD Progressive Disease PI Principal Investigator PMT Protocol Monitoring Team PR Partial Response SAE Serious Adverse Event SD Stable Disease Page 11 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 1.0 Goals and Objectives (Scientific Aims) 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 fus ion 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 assess 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. 2.0 Background 2.1 Introduction/Rationale for Development Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer- related death in men in the United States1. Androgen deprivation therapy is effective in the initial management of advanced prostate cancer but eventually cancer evolves into the aggressive phenotype referred to as castration resistant prostate cancer (CRPC) which is usually fatal within 12-22 months2. Sipuleucel-T is an active cellular immunotherapy consisting of autologous, peripheral blood mononuclear cells (PBMC’s), including antigen presenting cells (APC’s) that have been activated in vivo with a recombinant fusion protein (PA2024). PA2024 consists of a prostate antigen, prostatic acid phosphatase (PAP) that is fused to granulocyte-macrophage colony-stimulating factor (GMCSF), an immune cell activator3. Sipuleucel-T was evaluated in a randomized placebo-controlled Phase III trial in patients with asymptomatic and minimally symptomatic CRPC and demonstrated statistically significant survival advantage of 4.1 months4. Main eligibility criteria included the presence of metastatic CRPC, lack of visceral metastases, and lack of significant pain defined by the use of narcotic analgesics. The compound was well-tolerated with brief febrile infusion reactions constituting the main side effect. Sipuleucel-T did not induce significant PSA or objective responses but there was evidence of immune activation targeting prostate antigens. Specifically titers against PA2024 that exceeded 400 at any time after baseline were observed in 66.2 % of patients in the Sipuleucel-T and 2.9% in the placebo group. Patients with positive antibody titer against PA2024 had improved survival as compared to patients who did not generate such response. Antibodies against PAP were observed in 28.5% of patients treated with Sipuleucel-T and 1.4 % in patients in a placebo group. At week 6 , T-cell proliferation responses (stimulation index>5) to PA2024 were seen in 73% of patients in the Sipuleucel-T group and 12.1% in the placebo arm. Responses to PAP were observed in 27.3 % in the Sipuleucel-T group and 8.0% in the placebo group. Based on the results of this trial Sipuleucel-T was approved by Food and Drug Administration for the treatment of patients with metastatic CRPC. 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 Page 12 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 enhanc e or broaden antitumor immune responses, in part, because of radiation-induced phenotypic alterations of tumor cells that render them more susceptible to immune-mediated killing. Our internal City of Hope data indicates synergistic effect of immunotherapy and radiation in murine model utilizing anti- CEA antibody (Dr Raubitschek-personnel communication.) 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. Our proposal is based on the hypothesis that applying sensitizing radiotherapy t o selected metastatic site prior to immunotherapy will enhance immune response in patients treated with Sipuleucel- T. 2.2 Overview of Proposed Study This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory requirements. Sipuleucel-T (APC8015, Provenge ®) is an autologous cell product consisting of antigen presenting cells (APCs) loaded with prostate antigen PA2024, a recombinant fusion protein composed of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF acts as a targeting molecule that directs the PAP antigen to APCs and promotes antigen uptake and processing. A dose of sipuleucel-T is prepared from cells from a single leukapheresis procedure, with a minimum of 20 million CD54 + cells (the biologically active component of sipuleucel-T), which is administered via a single intravenous infusion at Weeks 0, 2, and 4. Sipuleucel-T has been approved based on the demonstration of 4.1 months survival advantaged when applied to patients with asymptomatic or minimally symptomatic CRPC. Eligible patients will meet the standard 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 metastatic site w ill 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 have 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 following fractionation schemes: 1) 300 cGy/day to 3000 cGy. Approximately 7 days after completion of radiation therapy, patients will begin therapy with Sipul eucel-T autologous vaccine. 2.3 Preclinical Studies Sipuleucel-T-Pre-clinical studies in rats demonstrated that APCs loaded with a fusion protein consisting of rat prostatic acid phosphatase (rPAP) coupled to a targeting molecule, rat granulocyte-macrophage colony-stimulating factor (rGM-CSF), induced strong cellular immune responses in vivo to tissues and tumors that express PAP (Laus 2001). Based on these observations, an APC product, designated APC8015 (sipuleucel-T), was developed for the treatment of men with prostate cancer 2.4 Human Studies Sipuleucel- T Separate Phase 1 and Phase 2 trials of sipuleucel-T were performed at the University of California, San Francisco (UCSF) (Small 2000) and the Mayo Clinic (Burch 2000, Burch 2004). Data from the Phase 1 and Phase 2 trials demonstrated that intravenous infusions of sipuleucel-T were generally well tolerated and effectively stimulated T cell responses to the immunogen. In addition, following therapy with sipuleucel-T, several subjects had decreases in PSA levels or objective tumor regressions suggesting anti-tumor activity. A dose of 3 million CD54+ cells was adequate to generate an immune response. There were no apparent dose related or dose limiting toxicities, warranting the conclusion that the maximum cell dose that could be manufactured from a single leukapheresis product was safe. PR-0292.08, 03 JAN 2008 Page 14 of 55 Dendreon Corporation Sipuleucel-T (APC8015) Page 13 of 50 IRB Protocol No. 12367 Version Date: 10/24/2017 Version: 09 A randomized, placebo-controlled, Phase 3 trial (D9901, n = 127 subjects) was subsequently conducted. A statistically significant survival benefit was demonstrated, with the relative risk of death 70% greater for subjects randomized to placebo ( P = 0.010, 2-sided log rank; HR = 1.71). The median survival was 25.9 months for subjects randomized to sipuleucel-T compared to 21.4 months for those randomized to placebo. At 36 months from randomization, the survival rate for subjects receiving sipuleucel-T was 3.1 times higher than the survival rate for subjects receiving placebo (34% vs. 11%; P = 0.0046, chi square) (Small 2006). In addition, when the Kaplan-Meier curves for time to disease progression were compared, there was a delay in the time from randomization to disease progression in the sipuleucel-T group compared with the placebo group (HR = 1.45 [95% CI: 0.99, 2.11], P = 0.052). A second smaller, randomized, placebo-controlled Phase 3 trial (D9902A, n = 98 subjects) with the same design as D9901 demonstrated a 20% improvement in median survival for subjects who were randomized to receive sipuleucel-T compared to placebo. Furthermore, at the 3-year follow-up, the percentage of subjects alive in the sipuleucel-T treated group was substantially greater than the percentage of subjects alive who received placebo. The results from this study did not reach statistical significance based on the log rank test.