<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/NCT03262103</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 15-2081</org_study_id>
    <nct_id>NCT03262103</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Hiltonol® (PolyICLC) for Prostate Cancer</brief_title>
  <official_title>Phase I Study of In Situ Autologous Vaccination Against Prostate Cancer With Intratumoral and Systemic Hiltonol® (Poly-ICLC) Prior To Radical Prostatectomy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ashutosh Kumar Tewari</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Oncovir, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test an approach of stimulating the body's immune system to&#xD;
      attack prostate cancer. This study will test injection of a substance polylysine and&#xD;
      carboxymethylcellulose (Poly-ICLC, Hiltonol®)through a needle guided by MRI (magnetic&#xD;
      resonance imaging) ultrasound fusion technology into the prostate gland. Poly ICLC has been&#xD;
      used to help the body in its fight against cancer. The first aim of the study is to determine&#xD;
      the highest dose of a substance Poly-ICLC (Hiltonol®) that can be safely tolerated by the&#xD;
      study participants. The second aim of the study is to find out the toxicity or side effects&#xD;
      of poly-ICLC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a pilot dose escalation study of IT/IM Poly-ICLC in patients with high risk&#xD;
      clinically localized prostate cancer. The dose and frequency of IT injections will be&#xD;
      increased in successive cohorts to define a safe dose and schedule for further testing.&#xD;
&#xD;
      Intratumoral + intramuscular poly-ICLC in patients with clinical localized prostate cancer.&#xD;
      In the current pilot clinical trial, poly-ICLC will be administered intratumorally (Artemis&#xD;
      guided) and intramuscularly (e.g., deltoid muscle) prior to prostatectomy in patients with&#xD;
      clinically localized prostate cancer. Based on the available preclinical data exploring&#xD;
      intratumoral administration of PAMPs described above, we expect this approach will result in&#xD;
      three immunomodulatory steps26:&#xD;
&#xD;
      Immunomodulatory Step 1: Innate immune local tumor killing induced by intratumoral poly-ICLC&#xD;
      - the initial intratumoral injections are expected to induce activation/recruitment of IL-12,&#xD;
      TNF-α, and other cytokines and NK cells, resulting in early tumor killing and antigen&#xD;
      release.9-11 Poly-ICLC may also have a direct antiproliferative effect on tumor cells&#xD;
      mediated by interferon-inducible nuclear enzyme systems.&#xD;
&#xD;
      Immunomodulatory Step 2: Th1 and cytotoxic T lymphocyte priming as a result of the repeated&#xD;
      in-situ poly-ICLC 'danger signal' combined with the tumor antigens released in step 1 and&#xD;
      further processed and cross-presented by poly-ICLC-activated myeloid dendritic cells.7,8&#xD;
      Poly-ICLC is expected to recruit myeloid dendritic cells and macrophages to the tumor site&#xD;
      where they can load with antigens being released through the innate mechanisms, present them&#xD;
      Th1 cells, and cross-present them to CD8 T cells in the tumor or in the regional lymph nodes,&#xD;
      thus generating antigen specific cytotoxic T lymphocytes.&#xD;
&#xD;
      Immunomodulatory Step 3 (or &quot;Boost&quot; phase): Maintenance of the systemic anti-tumor immune&#xD;
      response and migration of cytotoxic T lymphocytes to remote metastases, through repeated&#xD;
      intramuscular poly-ICLC induction of chemokines, other costimulatory factors, and&#xD;
      inflammasome activation.23-25 The rationale for followup with intramuscular maintenance is&#xD;
      that as part of the comprehensive response, dsRNAs such as poly-ICLC induce various&#xD;
      chemokines and costimulatory factors that help target the response to tumor. For example, one&#xD;
      of these costimulatory factors is OX40, which belongs to the tumor necrosis factor family of&#xD;
      cytokines, and helps maintain cytotoxic lymphocyte longevity and action at the tumor and&#xD;
      metastatic sites.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 16, 2017</start_date>
  <completion_date type="Actual">May 6, 2022</completion_date>
  <primary_completion_date type="Actual">May 6, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose-Limiting Toxicity level</measure>
    <time_frame>Week 6</time_frame>
    <description>3+3 dose escalation rules to define a safe dose of preoperative intratumoral (IT) plus intramuscular (IM) Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC, Hiltonol®) prior to radical prostatectomy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of adverse events</measure>
    <time_frame>Week 6</time_frame>
    <description>Safety as determined by the frequency of adverse events as per the Common Terminology for Adverse Events (CTCAE) version 4.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to PSA progression</measure>
    <time_frame>up to Week 12</time_frame>
    <description>The time to prostate-specific antigen (PSA) progression will be defined as the time to PSA &gt; 0.2 ng/mL</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intratumoral (IT) Poly ICLC 0.5 mg IT once/week (week 1) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intratumoral (IT) Poly ICLC 0.5 mg IT once/week (week 1+2) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intratumoral (IT) Poly ICLC 1.0 mg IT once/week (week 1) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intratumoral (IT) Poly ICLC 1.0 mg IT once/week (week 1+2) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Intratumoral (IT) Poly ICLC 0.5 mg</intervention_name>
    <description>0.5 mg IT once/week (week 1)</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Intratumoral (IT) Poly ICLC 1.0 mg</intervention_name>
    <description>1.0 mg IT once/week (week 1)</description>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
    <other_name>Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Intramuscular (IM) Poly ICLC</intervention_name>
    <description>1 mg IM twice weekly (weeks 3-6)</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
    <other_name>Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Radical Prostatectomy</intervention_name>
    <description>as per standard care</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent and HIPAA authorization for release of personal health&#xD;
             information.&#xD;
&#xD;
          -  Age &gt; 18 years at the time of consent.&#xD;
&#xD;
          -  ECOG Performance Status of 0-1 within 14 days prior to being registered for protocol&#xD;
             therapy (Study Procedure Manual).&#xD;
&#xD;
          -  Histologically confirmed adenocarcinoma of the prostate (with previous diagnostic&#xD;
             tissue available for tumor marker analysis).&#xD;
&#xD;
          -  Gleason 7 - 10, cT2a - cT3b adenocarcinoma of the prostate with plans for radical&#xD;
             prostatectomy&#xD;
&#xD;
          -  PSA ≥ 4 ng/ml&#xD;
&#xD;
          -  Tumor visible on multiparametric MRI&#xD;
&#xD;
          -  Tolerated previous transrectal ultrasound guided biopsy procedure under local&#xD;
             anesthetic&#xD;
&#xD;
          -  Uncomplicated previous TRUS biopsy procedure (i.e., no prior hospitalization due to&#xD;
             sepsis, prostatic abscess or severe hemorrhage following TRUS prostate biopsy)&#xD;
&#xD;
          -  Willing to undergo the intra-tumoral (IT) injection of the Poly-ICLC into the&#xD;
             prostatic tumor as per the protocol&#xD;
&#xD;
          -  No prior hormonal therapy with the exception of oral 5-alpha-reductase inhibitors&#xD;
             (finasteride, dutasteride, etc.). Patients who have received prior oral anti-androgen&#xD;
             therapies (bicalutamide, flutamide, nilutamide, etc.) must be off treatment for at&#xD;
             least 6 weeks prior to enrollment. Patients who have received prior LHRH agonist or&#xD;
             antagonist therapy (leuprolide, goserelin acetate, etc.) are eligible provided serum&#xD;
             testosterone is &gt; 50 mg/dl.&#xD;
&#xD;
          -  No prior radiation therapy (external beam or brachytherapy) to the pelvis or prostate.&#xD;
&#xD;
          -  No clinically significant infections as judged by the treating investigator.&#xD;
&#xD;
          -  No characteristics suggesting a potential higher risk of infection with intraprostatic&#xD;
             injections:&#xD;
&#xD;
               -  Recurrent urinary tract infections or history of prostatitis within 3 months&#xD;
                  prior to enrollment into the study.&#xD;
&#xD;
               -  Urine analysis positive for nitrites and leucocyte esterase. Such patients could&#xD;
                  be considered for the study after treatment and resolution of the infection.&#xD;
&#xD;
               -  Active proctitis&#xD;
&#xD;
               -  History of prostatic abscess&#xD;
&#xD;
               -  Taking immunosuppressive medication including systemic corticosteroids&#xD;
&#xD;
               -  Active hematologic malignancy&#xD;
&#xD;
          -  No uncontrolled angina, congestive heart failure or MI within 6 months.&#xD;
&#xD;
          -  Patients with history of HIV (if CD4+ T cell counts are ≥350 cells/µL on established&#xD;
             ART therapy), Hepatitis B (with viral load below limits of quantification) or&#xD;
             Hepatitis C (who have completed a curative therapy and have a viral load below the&#xD;
             limit of quantification) are eligible for this study.&#xD;
&#xD;
          -  No treatment with any investigational agent for any medical condition within 28 days&#xD;
             prior to being registered for protocol therapy.&#xD;
&#xD;
               -  Adequate end organ function as determined by the following laboratory values:&#xD;
&#xD;
                    -  White blood cell count (WBC) &gt; 2.5 k/mm3&#xD;
&#xD;
                    -  Absolute neutrophil count (ANC) &gt; 1.5 k/mm3&#xD;
&#xD;
                    -  Hemoglobin (Hgb) &gt; 8.0 g/dL&#xD;
&#xD;
                    -  Platelets &gt; 100 k/mm3&#xD;
&#xD;
                    -  Calculated creatinine clearance of &gt; 60 cc/min using the Cockcroft-Gault&#xD;
                       formula:&#xD;
&#xD;
        Males: (140 - Age in years) × Actual Body Weight in kg 72 × Serum Creatinine (mg/dL)&#xD;
&#xD;
          -  Bilirubin &lt; 2.0 x ULN&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) &lt; 2.5 x ULN&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) &lt; 2.5 x ULN 18) Able to speak, read and write in&#xD;
             English.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ashutosh K. Tewari, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sujit S Nair, Ph.D.</last_name>
    <role>Study Director</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>September 2022</verification_date>
  <study_first_submitted>August 23, 2017</study_first_submitted>
  <study_first_submitted_qc>August 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <last_update_submitted>September 8, 2022</last_update_submitted>
  <last_update_submitted_qc>September 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 10, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>Ashutosh Kumar Tewari</investigator_full_name>
    <investigator_title>Professor, System Chairman of the Department of Urology</investigator_title>
  </responsible_party>
  <keyword>Prostate Cancer</keyword>
  <keyword>Gleason 7-10</keyword>
  <keyword>Immunotherapy</keyword>
  <keyword>Neoadjuvant</keyword>
  <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>Poly I-C</mesh_term>
    <mesh_term>Carboxymethylcellulose Sodium</mesh_term>
    <mesh_term>Poly ICLC</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03262103
org study id: GCO 15-2081
nct id: NCT03262103
lead sponsor: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to test an approach of stimulating the body's immune system to
      attack prostate cancer. This study will test injection of a substance polylysine and
      carboxymethylcellulose (Poly-ICLC, Hiltonol®)through a needle guided by MRI (magnetic
      resonance imaging) ultrasound fusion technology into the prostate gland. Poly ICLC has been
      used to help the body in its fight against cancer. The first aim of the study is to determine
      the highest dose of a substance Poly-ICLC (Hiltonol®) that can be safely tolerated by the
      study participants. The second aim of the study is to find out the toxicity or side effects
      of poly-ICLC.
This is a pilot dose escalation study of IT/IM Poly-ICLC in patients with high risk
      clinically localized prostate cancer. The dose and frequency of IT injections will be
      increased in successive cohorts to define a safe dose and schedule for further testing.

      Intratumoral + intramuscular poly-ICLC in patients with clinical localized prostate cancer.
      In the current pilot clinical trial, poly-ICLC will be administered intratumorally (Artemis
      guided) and intramuscularly (e.g., deltoid muscle) prior to prostatectomy in patients with
      clinically localized prostate cancer. Based on the available preclinical data exploring
      intratumoral administration of PAMPs described above, we expect this approach will result in
      three immunomodulatory steps26:

      Immunomodulatory Step 1: Innate immune local tumor killing induced by intratumoral poly-ICLC
      - the initial intratumoral injections are expected to induce activation/recruitment of IL-12,
      TNF-α, and other cytokines and NK cells, resulting in early tumor killing and antigen
      release.9-11 Poly-ICLC may also have a direct antiproliferative effect on tumor cells
      mediated by interferon-inducible nuclear enzyme systems.

      Immunomodulatory Step 2: Th1 and cytotoxic T lymphocyte priming as a result of the repeated
      in-situ poly-ICLC 'danger signal' combined with the tumor antigens released in step 1 and
      further processed and cross-presented by poly-ICLC-activated myeloid dendritic cells.7,8
      Poly-ICLC is expected to recruit myeloid dendritic cells and macrophages to the tumor site
      where they can load with antigens being released through the innate mechanisms, present them
      Th1 cells, and cross-present them to CD8 T cells in the tumor or in the regional lymph nodes,
      thus generating antigen specific cytotoxic T lymphocytes.

      Immunomodulatory Step 3 (or "Boost" phase): Maintenance of the systemic anti-tumor immune
      response and migration of cytotoxic T lymphocytes to remote metastases, through repeated
      intramuscular poly-ICLC induction of chemokines, other costimulatory factors, and
      inflammasome activation.23-25 The rationale for followup with intramuscular maintenance is
      that as part of the comprehensive response, dsRNAs such as poly-ICLC induce various
      chemokines and costimulatory factors that help target the response to tumor. For example, one
      of these costimulatory factors is OX40, which belongs to the tumor necrosis factor family of
      cytokines, and helps maintain cytotoxic lymphocyte longevity and action at the tumor and
      metastatic sites.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose-Limiting Toxicity level
time frame: Week 6
description: 3+3 dose escalation rules to define a safe dose of preoperative intratumoral (IT) plus intramuscular (IM) Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC, Hiltonol®) prior to radical prostatectomy
measure: Number of adverse events
time frame: Week 6
description: Safety as determined by the frequency of adverse events as per the Common Terminology for Adverse Events (CTCAE) version 4.0.
measure: Time to PSA progression
time frame: up to Week 12
description: The time to prostate-specific antigen (PSA) progression will be defined as the time to PSA > 0.2 ng/mL
arm group label: Cohort 1
arm group type: Experimental
description: Intratumoral (IT) Poly ICLC 0.5 mg IT once/week (week 1) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10
arm group label: Cohort 2
arm group type: Experimental
description: Intratumoral (IT) Poly ICLC 0.5 mg IT once/week (week 1+2) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10
arm group label: Cohort 3
arm group type: Experimental
description: Intratumoral (IT) Poly ICLC 1.0 mg IT once/week (week 1) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10
arm group label: Cohort 4
arm group type: Experimental
description: Intratumoral (IT) Poly ICLC 1.0 mg IT once/week (week 1+2) Intramuscular (IM) Poly ICLC 1 mg IM twice weekly (weeks 3-6) Followed by Radical Prostatectomy at Week 10
intervention type: Biological
intervention name: Intratumoral (IT) Poly ICLC 0.5 mg
description: 0.5 mg IT once/week (week 1)
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Biological
intervention name: Intratumoral (IT) Poly ICLC 1.0 mg
description: 1.0 mg IT once/week (week 1)
arm group label: Cohort 3
arm group label: Cohort 4
other name: Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose
intervention type: Biological
intervention name: Intramuscular (IM) Poly ICLC
description: 1 mg IM twice weekly (weeks 3-6)
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
other name: Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose
intervention type: Procedure
intervention name: Radical Prostatectomy
description: as per standard care
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
criteria: 
gender: Male
gender based: Yes
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ashutosh K. Tewari, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
last name: Sujit S Nair, Ph.D.
role: Study Director
affiliation: Icahn School of Medicine at Mount Sinai
facility: 
country: United States
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citation: Nair SS…. Salazar A, Galsky M, Bhardwaj N and Tewari A. Phase I study of in situ autologous vaccination for prostate cancer in a neo-adjuvant setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT096
responsible party type: Sponsor-Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: Ashutosh Kumar Tewari
investigator title: Professor, System Chairman of the Department of Urology
mesh term: Prostatic Neoplasms
mesh term: Poly I-C
mesh term: Carboxymethylcellulose Sodium
mesh term: Poly ICLC