<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03007732</url>
  </required_header>
  <id_info>
    <org_study_id>16703</org_study_id>
    <secondary_id>NCI-2017-01340</secondary_id>
    <nct_id>NCT03007732</nct_id>
  </id_info>
  <brief_title>Pembrolizumab +/- SD-101 in Hormone-Naïve Oligometastatic Prostate Cancer With RT and iADT</brief_title>
  <official_title>Phase 2 Trial Pembrolizumab or Pembrolizumab in Combination With Intratumoral SD-101 Therapy in Patients With Hormone-Naïve Oligometastatic Prostate Cancer Receiving Stereotactic Body Radiation Therapy and Intermittent Androgen Deprivation Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawrence Fong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Prostate Cancer Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>TriSalus Life Sciences, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a non-comparative open-label multicenter Phase 2 clinical trial combining&#xD;
      stereotactic body radiation therapy (SBRT) and pembrolizumab with or without intratumoral&#xD;
      SD-101 in patients with newly diagnosed hormone-naive oligometastatic prostate cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This randomized phase II trial studies how well androgen deprivation therapy, pembrolizumab,&#xD;
      and stereotactic body radiation therapy with or without toll-like receptor 9 (TLR9) agonist&#xD;
      SD-101 in treating patients with prostate cancer and cancer in all oligometastatic sites that&#xD;
      has spread to other places in the body. Androgen can cause the growth of tumor cells.&#xD;
      Androgen deprivation therapy, such as leuprolide acetate, prednisone, and abiraterone acetate&#xD;
      may lessen the amount of androgen made by the body. Monoclonal antibodies, such as&#xD;
      pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Stereotactic&#xD;
      body radiation therapy is a specialized radiation therapy that sends x-rays directly to the&#xD;
      tumor using smaller doses over several days and may cause less damage to normal tissue.&#xD;
      Colony-stimulating factors, such as TLR9 agonist SD-101, may increase the production of blood&#xD;
      cells. It is not yet known whether giving androgen deprivation therapy, pembrolizumab, and&#xD;
      stereotactic body radiation therapy with or without TLR9 agonist SD-101 may work better in&#xD;
      treating patients with prostate cancer and cancer in all oligometastatic sites.&#xD;
&#xD;
      PRIMARY OBJECTIVES&#xD;
&#xD;
        -  Cohort 1 (No longer recruiting)&#xD;
&#xD;
           --To assess the safety associated with giving RT and pembrolizumab with or without&#xD;
           intratumoral SD-101.&#xD;
&#xD;
        -  Cohort 2&#xD;
&#xD;
             -  To continue to assess the safety associated with giving RT and pembrolizumab with&#xD;
                or without intratumoral SD-101.&#xD;
&#xD;
             -  To assess if the rate of PSA &lt; nadir + 2 ng/mL at 15 months in patients with&#xD;
                non-castrate levels of testosterone is greater than the historical control in each&#xD;
                study arm.&#xD;
&#xD;
      SECONDARY OBJECTIVES&#xD;
&#xD;
        -  To determine the rate of testosterone-PSA uncoupling in each study arm in cohort 2.&#xD;
           Testosterone-PSA uncoupling is defined as PSA &lt; 50% baseline and &lt; 20ng/mL for at least&#xD;
           3 months after testosterone recovers to &gt;150 ng/dL. In patients with metastatic hormone&#xD;
           sensitive prostate cancer off hormonal therapy, &gt;90% patient are expected to have PSA&#xD;
           increase to &gt; 50% baseline after 3 months of testosterone recovery.&#xD;
&#xD;
        -  To estimate time to clinical progression&#xD;
&#xD;
        -  To estimate progression-free survival (PFS) in each study arm&#xD;
&#xD;
      EXPLORATORY OBJECTIVE&#xD;
&#xD;
        -  To assess peripheral and tumor-based biomarkers of response and resistance in both&#xD;
           cohorts.&#xD;
&#xD;
        -  To define the treatment-induced effects on circulating immune cells in both cohorts.&#xD;
&#xD;
        -  To explore remodeling of circulating T cell repertoire in both cohorts.&#xD;
&#xD;
        -  To explore the concordance of Prostate-Specific Membrane Antigen (PSMA) - Positron&#xD;
           Emission Tomography (PET) scanning with conventional imaging in oligometastatic prostate&#xD;
           cancer patients in both cohorts.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 17, 2017</start_date>
  <completion_date type="Anticipated">October 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">October 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change Rate of prostate-specific antigen (PSA) &lt; nadir + 2 ng/mL from first day of treatment to 15 months (Cohort 2)</measure>
    <time_frame>Start of treatment and 15 months (approx. 15 months total)</time_frame>
    <description>Only patients in cohort 2, who achieve testosterone recovery to non-castrate levels (&gt;150 ng/dL) at 15 months, will be analyzed for the primary endpoint. The rate of PSA &lt; nadir + 2 ng/mL at 15 months from the start of radiotherapy and cycle 1, day 1 of pembrolizumab, among patients whose testosterone recovers to non-castrate levels (&gt;150 ng/dL). The point estimate of the rate of PSA &lt; nadir + 2 ng/mL will be obtained with its 95% confidence interval for participants by arm in cohort 2 and compared to the historical control rate by one sample binomial test. All patients who receive any part of a dose of RT, SD-101 or pembrolizumab will be analyzed for efficacy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of participants with treatment-related adverse events</measure>
    <time_frame>Up to 15 months</time_frame>
    <description>Adverse events occurring on study will be summarized for all participants that received study intervention (including pembrolizumab, SD-101, SBRT to prostate, SBRT to oligometastatic sites) by maximum toxicity grade for each study arm.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of testosterone-PSA uncoupling (Cohort 2)</measure>
    <time_frame>Up to 15 months</time_frame>
    <description>Testosterone-PSA uncoupling is defined as PSA &lt; 50% baseline and &lt; 20ng/mL for at least 3 months after testosterone recovers to &gt;150 ng/dL. In patients with metastatic hormone-sensitive prostate cancer off hormonal therapy, &gt;90% patients are expected to have PSA increase to &gt; 50% baseline after 3 months of testosterone recovery. Therefore, the presence of PSA testosterone uncoupling in this study may serve as a surrogate of immunotherapeutic responses induced by pembrolizumab combined with RT (arm 1), or RT with SD-101 (arm 2), if a prolonged PSA &lt; nadir + 2 ng/mL is not achieved. The point estimate of testosterone-PSA uncoupling rate will be obtained with its 95% confidence interval for each arm in cohort 2.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to clinical progression (Cohort 2)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The time to clinical progression in each study arm in cohort 2 is defined as the time to radiographic progression by Prostate Specific Antigen Working Group-2 (PSAWG2) criteria, time to symptomatic progressive disease, or PSA progression, whichever comes the first. Kaplan-Meier estimate will be obtained for the time to clinical progression in each study arm in cohort 2</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) (Cohort 2)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Progression-free survival (PFS) will be estimated for each study arm on cohort 2 by Kaplan-Meier estimate, where PFS is a composite endpoint based on PSA progression, radiological progression, clinical deterioration, or death</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">23</enrollment>
  <condition>Prostatic Neoplasms</condition>
  <arm_group>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.&#xD;
Pembrolizumab: Given IV every 21 days for up to 13 doses&#xD;
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.&#xD;
TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1&#xD;
Pembrolizumab: Given IV every 21 days for up to 13 doses&#xD;
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.&#xD;
Pembrolizumab: Given IV every 21 days for up to 13 doses&#xD;
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.&#xD;
TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1&#xD;
Pembrolizumab: Given IV every 21 days for up to 13 doses&#xD;
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>200 mg IV every 21 days for up to 13 doses (Arms 1 and 2)</description>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <other_name>MK-3475</other_name>
    <other_name>Keytruda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SD-101</intervention_name>
    <description>5 mg will be delivered to the dominant prostatic tumor lesion at time of fiducial marker placement (1-5 weeks prior to Cycle 1, Day 1) and and 1-3 weeks after Cycle 1 Day 1</description>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <other_name>Toll-like receptor 9</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leuprolide acetate</intervention_name>
    <description>22.5 mg will be given intramuscularly (IM). First injection 3 months prior to Cycle 1 Day 1. Intermittent androgen deprivation therapy will be given every 3 months starting Cycle 1, Day 1 for 3 additional doses.</description>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <other_name>Intermittent androgen deprivation therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Abiraterone Acetate</intervention_name>
    <description>1000 mg oral dosage will be given daily for 3 months prior to Cycle 1, Day 1 and daily for 9 months starting Cycle 1, Day 1.</description>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <other_name>Intermittent androgen deprivation therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>5 mg oral dosage will be given daily for 3 months prior to Cycle 1 Day 1 and daily for 9 months starting Cycle 1, Day 1.</description>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <other_name>Intermittent androgen deprivation therapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic Body Radiation Therapy</intervention_name>
    <description>7 Gy x 5 fractions (35 Gy total) 1-2 weeks after fiducial marker placement and simulation over 10-14 days.</description>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)</arm_group_label>
    <arm_group_label>Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)</arm_group_label>
    <other_name>SBRT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Be willing and able to provide written informed consent/assent for the trial.&#xD;
&#xD;
          2. Be &gt;=18 years of age on day of signing informed consent.&#xD;
&#xD;
          3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)&#xD;
             Performance Scale.&#xD;
&#xD;
          4. Histologically documented adenocarcinoma of the prostate&#xD;
&#xD;
          5. Oligometastatic disease. In order to be eligible, the patient must have a total of &lt;4&#xD;
             metastatic bone and/or metastatic lymph node sites based on bone and/or soft tissue&#xD;
             lesions as defined by any of the following:&#xD;
&#xD;
               1. Bone metastases will be defined by bone imaging. If the patient has technetium&#xD;
                  bone scan, and/or sodium fluoride (NaF) PET performed, either study may be used&#xD;
                  for documenting metastases; both scans do not need to show the number of&#xD;
                  metastases required for study entry. For patients undergoing PSMA PET, only PSMA&#xD;
                  avid lesions that are consistent with metastasis will be counted as a site of&#xD;
                  metastasis.&#xD;
&#xD;
               2. Distant metastatic lymph node disease. A lymph node ≥1 cm in shortest dimension&#xD;
                  will be noted as involved with disease. Distant metastatic lymph nodes will be&#xD;
                  determined as any lymph nodes outside the confines of the true pelvis. For&#xD;
                  patients undergoing PSMA PET, only PSMA avid lesions that are consistent with&#xD;
                  metastasis will be counted as a site of metastasis.&#xD;
&#xD;
               3. Any other soft tissue lesion deemed by the physician to be consistent with&#xD;
                  distant metastatic disease. For patients undergoing PSMA PET, only PSMA avid&#xD;
                  lesions that have a CT or MRI correlate consistent with metastasis will be&#xD;
                  counted as a site of metastasis.&#xD;
&#xD;
                    -  Note: Radiographic imaging performed as standard of care prior to obtaining&#xD;
                       informed consent and within 60 days of initiating study treatment may be&#xD;
                       used to assess oligometastatic disease during screening, rather than&#xD;
                       repeating scans. For patients who have started on ADT, they must have had&#xD;
                       imaging prior to initiation of hormonal therapy&#xD;
&#xD;
          6. Treatment naïve, defined as less than 2 months of standard of care ADT (e.g. GnRH&#xD;
             agonist or antagonist with or without antiandrogen, including abiraterone) for&#xD;
             metastatic hormone-sensitive prostate cancer prior to enrollment (at the time of&#xD;
             consent)&#xD;
&#xD;
          7. No prior chemotherapy for prostate cancer&#xD;
&#xD;
          8. Not a candidate for or refuse chemotherapy&#xD;
&#xD;
          9. No prior prostatectomy or prostatic radiation&#xD;
&#xD;
         10. PSA &gt;2 ng/mL at baseline or prior to initiation of hormonal therapy&#xD;
&#xD;
         11. Baseline testosterone &gt;150 ng/dL if patient has not initiated hormonal therapy, for&#xD;
             those patients who have already initiated hormonal therapy, baseline testosterone is&#xD;
             not required&#xD;
&#xD;
         12. Consent to undergo mandatory prostatic core biopsies at the time of fiducial marker&#xD;
             placement and 1-3 weeks after Cycle 1 Day 1 of pembrolizumab.&#xD;
&#xD;
         13. The effects of pembrolizumab on the developing human fetus is unknown. Men treated or&#xD;
             enrolled on this protocol must agree to use adequate contraception prior to the first&#xD;
             dose of study therapy, for the duration of the study participation, and for 120 days&#xD;
             after the last dose of study therapy. Their partners should also be encouraged to use&#xD;
             proper method of contraception. Their partners should also be encouraged to use proper&#xD;
             method of contraception.&#xD;
&#xD;
         14. Demonstrate adequate organ function defined as: Adequate Organ Function Laboratory&#xD;
             Values (Performed within 10 days of treatment initiation):&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥1,500 /microliter (mcL)&#xD;
&#xD;
               -  Platelets &gt;=100,000 / mcL&#xD;
&#xD;
               -  Hemoglobin &gt;=9 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin (EPO)&#xD;
                  dependency (within 7 days of assessment)&#xD;
&#xD;
               -  Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be&#xD;
                  used in place of creatinine or CrCl) &lt;=1.5 X upper limit of normal (ULN) OR ≥60&#xD;
                  mL/min for subject with creatinine levels &gt; 1.5 X institutional ULN. Creatinine&#xD;
                  clearance should be calculated per institutional standard&#xD;
&#xD;
               -  Serum total bilirubin &lt;= 1.5 X ULN OR Direct bilirubin &lt;= ULN for subjects with&#xD;
                  total bilirubin levels &gt; 1.5 ULN&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (ALT) (SGPT)&#xD;
                  ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases&#xD;
&#xD;
               -  Albumin &gt;2.5 mg/dL&#xD;
&#xD;
               -  International Normalized Ratio (INR) or Prothrombin Time (PT)&#xD;
&#xD;
               -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is&#xD;
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range&#xD;
                  of intended use of anticoagulants ≤1.5 X ULN unless subject is receiving&#xD;
                  anticoagulant therapy as long as PT or PTT is within therapeutic range of&#xD;
                  intended use of anticoagulants&#xD;
&#xD;
               -  Creatinine clearance should be calculated per institutional standard.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients who are not appropriate candidates for prostate or oligometastasis-directed&#xD;
             SBRT&#xD;
&#xD;
          2. Patients with neuroendocrine or small cell features are not eligible.&#xD;
&#xD;
          3. Patients with evidence of liver metastasis are excluded.&#xD;
&#xD;
          4. Gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists (e.g., leuprorelin,&#xD;
             degarelix) for &gt; 2 months prior to consenting&#xD;
&#xD;
          5. Antiandrogens (e.g., bicalutamide, flutamide, nilutamide, abiraterone, enzalutamide)&#xD;
             for &gt; 2 months prior to consenting. Patients on 5-alpha reductase inhibitors are&#xD;
             allowed on study.&#xD;
&#xD;
          6. Estrogen containing compounds for &gt; 2 months prior to consenting&#xD;
&#xD;
          7. PC-SPES or PC-x products. Other herbal therapies or supplements will be considered by&#xD;
             the Principle Investigator on a case-by-case basis based on their potential for&#xD;
             hormonal or anti-cancer therapies.&#xD;
&#xD;
          8. Prior immunotherapy or chemotherapy for prostate cancer&#xD;
&#xD;
          9. Prior radiation therapy to the prostate&#xD;
&#xD;
         10. Prior prostatectomy&#xD;
&#xD;
         11. Is currently participating and receiving study therapy or has participated in a study&#xD;
             of an investigational agent and received study therapy or used an investigational&#xD;
             device within 4 weeks of the first dose of treatment.&#xD;
&#xD;
         12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any&#xD;
             other form of systemic immunosuppressive therapy within 7 days prior to the first dose&#xD;
             of trial treatment, with the exception of steroids for adrenal insufficiency in which&#xD;
             case prednisone =&lt;10mg/day or its equivalent is allowed.&#xD;
&#xD;
         13. Has a known history of active Bacillus Tuberculosis (TB)&#xD;
&#xD;
         14. Hypersensitivity to pembrolizumab or any of its excipients.&#xD;
&#xD;
         15. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study&#xD;
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events&#xD;
             due to agents administered more than 4 weeks earlier.&#xD;
&#xD;
         16. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy&#xD;
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at&#xD;
             baseline) from adverse events due to a previously administered agent.&#xD;
&#xD;
               -  Note: Subjects with &lt;= Grade 2 neuropathy are an exception to this criterion and&#xD;
                  may qualify for the study.&#xD;
&#xD;
               -  Note: If subject received major surgery, they must have recovered adequately from&#xD;
                  the toxicity and/or complications from the intervention prior to starting&#xD;
&#xD;
         17. Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include carcinoid, basal cell carcinoma of the skin or squamous cell&#xD;
             carcinoma of the skin that has undergone potentially curative therapy or in situ&#xD;
             cervical cancer.&#xD;
&#xD;
         18. Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis. Subjects with previously treated brain metastases may participate provided&#xD;
             they are stable (without evidence of progression by imaging for at least four weeks&#xD;
             prior to the first dose of trial treatment and any neurologic symptoms have returned&#xD;
             to baseline), have no evidence of new or enlarging brain metastases, and are not using&#xD;
             steroid treatment for at least 14 days prior to the first dose of study treatment.&#xD;
             This exception does not include carcinomatous meningitis which is excluded regardless&#xD;
             of clinical stability.&#xD;
&#xD;
         19. Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment.&#xD;
&#xD;
         20. Has known history of, or any evidence of active, non-infectious pneumonitis.&#xD;
&#xD;
         21. Has an active infection requiring systemic therapy.&#xD;
&#xD;
         22. Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator.&#xD;
&#xD;
         23. Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
         24. Expecting to father children within the projected duration of the trial, starting with&#xD;
             the pre-screening or screening visit through 120 days after the last dose of trial&#xD;
             treatment.&#xD;
&#xD;
         25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.&#xD;
&#xD;
         26. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).&#xD;
&#xD;
         27. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (HCV) (i.e. HCV RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
         28. Has received a live vaccine within 30 days of planned start of study therapy. a. Note:&#xD;
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and&#xD;
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live&#xD;
             attenuated vaccines, and are not allowed within 30 days.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lawrence Fong, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>August 5, 2016</study_first_submitted>
  <study_first_submitted_qc>December 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <last_update_submitted>September 12, 2023</last_update_submitted>
  <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Lawrence Fong</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ascorbic Acid</mesh_term>
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Leuprolide</mesh_term>
    <mesh_term>Abiraterone Acetate</mesh_term>
    <mesh_term>Methyltestosterone</mesh_term>
    <mesh_term>Estrogens, Conjugated (USP)</mesh_term>
    <mesh_term>Androgens</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03007732
org study id: 16703
secondary id: NCI-2017-01340
nct id: NCT03007732
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This is a non-comparative open-label multicenter Phase 2 clinical trial combining
      stereotactic body radiation therapy (SBRT) and pembrolizumab with or without intratumoral
      SD-101 in patients with newly diagnosed hormone-naive oligometastatic prostate cancer.
This randomized phase II trial studies how well androgen deprivation therapy, pembrolizumab,
      and stereotactic body radiation therapy with or without toll-like receptor 9 (TLR9) agonist
      SD-101 in treating patients with prostate cancer and cancer in all oligometastatic sites that
      has spread to other places in the body. Androgen can cause the growth of tumor cells.
      Androgen deprivation therapy, such as leuprolide acetate, prednisone, and abiraterone acetate
      may lessen the amount of androgen made by the body. Monoclonal antibodies, such as
      pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Stereotactic
      body radiation therapy is a specialized radiation therapy that sends x-rays directly to the
      tumor using smaller doses over several days and may cause less damage to normal tissue.
      Colony-stimulating factors, such as TLR9 agonist SD-101, may increase the production of blood
      cells. It is not yet known whether giving androgen deprivation therapy, pembrolizumab, and
      stereotactic body radiation therapy with or without TLR9 agonist SD-101 may work better in
      treating patients with prostate cancer and cancer in all oligometastatic sites.

      PRIMARY OBJECTIVES

        -  Cohort 1 (No longer recruiting)

           --To assess the safety associated with giving RT and pembrolizumab with or without
           intratumoral SD-101.

        -  Cohort 2

             -  To continue to assess the safety associated with giving RT and pembrolizumab with
                or without intratumoral SD-101.

             -  To assess if the rate of PSA < nadir + 2 ng/mL at 15 months in patients with
                non-castrate levels of testosterone is greater than the historical control in each
                study arm.

      SECONDARY OBJECTIVES

        -  To determine the rate of testosterone-PSA uncoupling in each study arm in cohort 2.
           Testosterone-PSA uncoupling is defined as PSA < 50% baseline and < 20ng/mL for at least
           3 months after testosterone recovers to >150 ng/dL. In patients with metastatic hormone
           sensitive prostate cancer off hormonal therapy, >90% patient are expected to have PSA
           increase to > 50% baseline after 3 months of testosterone recovery.

        -  To estimate time to clinical progression

        -  To estimate progression-free survival (PFS) in each study arm

      EXPLORATORY OBJECTIVE

        -  To assess peripheral and tumor-based biomarkers of response and resistance in both
           cohorts.

        -  To define the treatment-induced effects on circulating immune cells in both cohorts.

        -  To explore remodeling of circulating T cell repertoire in both cohorts.

        -  To explore the concordance of Prostate-Specific Membrane Antigen (PSMA) - Positron
           Emission Tomography (PET) scanning with conventional imaging in oligometastatic prostate
           cancer patients in both cohorts.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change Rate of prostate-specific antigen (PSA) < nadir + 2 ng/mL from first day of treatment to 15 months (Cohort 2)
time frame: Start of treatment and 15 months (approx. 15 months total)
description: Only patients in cohort 2, who achieve testosterone recovery to non-castrate levels (>150 ng/dL) at 15 months, will be analyzed for the primary endpoint. The rate of PSA < nadir + 2 ng/mL at 15 months from the start of radiotherapy and cycle 1, day 1 of pembrolizumab, among patients whose testosterone recovers to non-castrate levels (>150 ng/dL). The point estimate of the rate of PSA < nadir + 2 ng/mL will be obtained with its 95% confidence interval for participants by arm in cohort 2 and compared to the historical control rate by one sample binomial test. All patients who receive any part of a dose of RT, SD-101 or pembrolizumab will be analyzed for efficacy
measure: Number of participants with treatment-related adverse events
time frame: Up to 15 months
description: Adverse events occurring on study will be summarized for all participants that received study intervention (including pembrolizumab, SD-101, SBRT to prostate, SBRT to oligometastatic sites) by maximum toxicity grade for each study arm.
measure: Rate of testosterone-PSA uncoupling (Cohort 2)
time frame: Up to 15 months
description: Testosterone-PSA uncoupling is defined as PSA < 50% baseline and < 20ng/mL for at least 3 months after testosterone recovers to >150 ng/dL. In patients with metastatic hormone-sensitive prostate cancer off hormonal therapy, >90% patients are expected to have PSA increase to > 50% baseline after 3 months of testosterone recovery. Therefore, the presence of PSA testosterone uncoupling in this study may serve as a surrogate of immunotherapeutic responses induced by pembrolizumab combined with RT (arm 1), or RT with SD-101 (arm 2), if a prolonged PSA < nadir + 2 ng/mL is not achieved. The point estimate of testosterone-PSA uncoupling rate will be obtained with its 95% confidence interval for each arm in cohort 2.
measure: Time to clinical progression (Cohort 2)
time frame: Up to 3 years
description: The time to clinical progression in each study arm in cohort 2 is defined as the time to radiographic progression by Prostate Specific Antigen Working Group-2 (PSAWG2) criteria, time to symptomatic progressive disease, or PSA progression, whichever comes the first. Kaplan-Meier estimate will be obtained for the time to clinical progression in each study arm in cohort 2
measure: Progression-free survival (PFS) (Cohort 2)
time frame: Up to 3 years
description: Progression-free survival (PFS) will be estimated for each study arm on cohort 2 by Kaplan-Meier estimate, where PFS is a composite endpoint based on PSA progression, radiological progression, clinical deterioration, or death
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)
arm group type: Experimental
description: Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.
Pembrolizumab: Given IV every 21 days for up to 13 doses
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group type: Experimental
description: Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.
TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1
Pembrolizumab: Given IV every 21 days for up to 13 doses
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
arm group type: Experimental
description: Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.
Pembrolizumab: Given IV every 21 days for up to 13 doses
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group type: Experimental
description: Three month androgen deprivation therapy (ADT) run-in followed by leuprolide injected intramuscularly every 3 months for 3 doses (or another FDA approved gonadotropin-releasing hormone agent for 9 months) + abiraterone by mouth daily with prednisone by mouth daily (or equivalent medication per local standard practice) for 9 months starting on Day 1.
TLR9 agonist SD-101: Injected into the dominant prostatic tumor lesion at time of fiducial marker placement (1-5weeks prior to Cycle 1 Day 1) and 1-3 weeks after Cycle 1 Day 1
Pembrolizumab: Given IV every 21 days for up to 13 doses
Radiotherapy: Given every other day over 10-14 days delivered to the whole prostate gland and oligometastatic sites via stereotactic body radiation therapy (SBRT) starting 1-2 weeks after marker placement.
intervention type: Drug
intervention name: Pembrolizumab
description: 200 mg IV every 21 days for up to 13 doses (Arms 1 and 2)
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
other name: MK-3475
other name: Keytruda
intervention type: Drug
intervention name: SD-101
description: 5 mg will be delivered to the dominant prostatic tumor lesion at time of fiducial marker placement (1-5 weeks prior to Cycle 1, Day 1) and and 1-3 weeks after Cycle 1 Day 1
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
other name: Toll-like receptor 9
intervention type: Drug
intervention name: Leuprolide acetate
description: 22.5 mg will be given intramuscularly (IM). First injection 3 months prior to Cycle 1 Day 1. Intermittent androgen deprivation therapy will be given every 3 months starting Cycle 1, Day 1 for 3 additional doses.
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
other name: Intermittent androgen deprivation therapy
intervention type: Drug
intervention name: Abiraterone Acetate
description: 1000 mg oral dosage will be given daily for 3 months prior to Cycle 1, Day 1 and daily for 9 months starting Cycle 1, Day 1.
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
other name: Intermittent androgen deprivation therapy
intervention type: Drug
intervention name: Prednisone
description: 5 mg oral dosage will be given daily for 3 months prior to Cycle 1 Day 1 and daily for 9 months starting Cycle 1, Day 1.
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
other name: Intermittent androgen deprivation therapy
intervention type: Radiation
intervention name: Stereotactic Body Radiation Therapy
description: 7 Gy x 5 fractions (35 Gy total) 1-2 weeks after fiducial marker placement and simulation over 10-14 days.
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 1: Prostate Only Sites (ADT, SBRT, Pembrolizumab, SD-101)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab)
arm group label: Cohort 2: Prostate and Oligometastatic sites (ADT, SBRT, Pembrolizumab, SD-101)
other name: SBRT
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lawrence Fong, MD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Lawrence Fong
investigator title: Professor
mesh term: Prostatic Neoplasms
mesh term: Ascorbic Acid
mesh term: Prednisone
mesh term: Pembrolizumab
mesh term: Leuprolide
mesh term: Abiraterone Acetate
mesh term: Methyltestosterone
mesh term: Estrogens, Conjugated (USP)
mesh term: Androgens
sharing ipd: No