<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/NCT01704274</url>
  </required_header>
  <id_info>
    <org_study_id>Protocol # CAUR 09</org_study_id>
    <nct_id>NCT01704274</nct_id>
  </id_info>
  <brief_title>GTN Therapy on Biomarkers of Immune Escape in Men With Biochemical Recurrence of Prostate Cancer After Primary Therapy</brief_title>
  <acronym>GTN</acronym>
  <official_title>A Double-Blind, Randomised, Placebo-Controlled Study of the Effect of Transdermal Nitroglycerin (Glyceryl Trinitrate; GTN) Therapy on Biomarkers of Immune Escape in Men With Biochemical Recurrence of Prostate Cancer After Primary Therapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Queen's University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Queen's University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prostate cancer is the most commonly diagnosed cancer in men in Canada. Over 30% of men over&#xD;
      the age of fifty have histological evidence of prostate cancer on biopsy. Despite the stage&#xD;
      migration afforded by early detection with serum prostate specific antigen (PSA) testing and&#xD;
      an apparent trend toward improved survival over the past several years, prostate cancer&#xD;
      remains a significant cause of morbidity and mortality. Biochemical failure after primary&#xD;
      therapy (surgery or radiation) remains a significant health care burden and strategies to&#xD;
      delay clinical prostate cancer progression and prolong the interval from treatment failure to&#xD;
      systemic therapy would be of significant clinical benefit for those men suffering from a&#xD;
      finding of PSA recurrence.&#xD;
&#xD;
      PSA is widely accepted as the most useful prognostic marker of prostate cancer progression,&#xD;
      particularly after primary therapy with radical surgery or radiation. 5 Despite improved&#xD;
      cancer control rates with definitive management of early stage prostate cancer, a PSA&#xD;
      recurrence is unfortunately a common occurrence (25-50%) in most large case series.&#xD;
&#xD;
      Microenvironmental factors have been demonstrated to play a pivotal role in the selection of&#xD;
      neoplastic cell subpopulations expressing more malignant phenotypes and contributing to the&#xD;
      progression of localized and metastatic disease. Very low levels of O2 (&lt; 10 mmHg) has been&#xD;
      well described in many solid tumours (including prostate cancer) and the extent of hypoxia&#xD;
      has been demonstrated to represent an independent marker of a poor prognosis for patients&#xD;
      with various types of cancers. Tumour hypoxia contributes to numerous adaptive phenotypes&#xD;
      including increased invasion and metastasis, as well as evasion of immune cell surveillance&#xD;
      increased resistance to radiotherapy and chemotherapy. Although cellular adaptive responses&#xD;
      to hypoxia are likely mediated by various mechanisms, our previous preclinical studies&#xD;
      suggest that decreased nitric oxide (NO)-dependent signalling plays a significant role in&#xD;
      this progression of a malignant phenotype.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Researcher's pre-clinical research has demonstrated that hypoxia-induced tumor cell&#xD;
      invasiveness, metastatic ability, resistance to chemotherapeutic agents and evasion of immune&#xD;
      cell recognition are inhibited by molecules that activate the NO signalling pathway involving&#xD;
      cGMP generation (such as glyceryl trinitrate, GTN), and that pharmacological inhibition of NO&#xD;
      signalling results in phenotypes similar to those induced by exposure to hypoxia.&#xD;
&#xD;
      Based on pre-clinical data described above the researchers have recently completed and&#xD;
      published a phase 2 trial in patients with recurrent prostate cancer using a low-dose,&#xD;
      sustained release trasndermal patch of GTN. The GTN was supplied as Minitran™ (nitroglycerin)&#xD;
      transdermal delivery system (3M Company, St. Paul, Minnesota) in an open label, non-blinded&#xD;
      fashion. GTN is a nitrodonor that has been used in the management of angina for over 100&#xD;
      years with a well-documented safety and tolerability record and has never been associated&#xD;
      with carcinogenesis. Their pre-clinical studies have demonstrated that very low molar&#xD;
      concentrations of nitric oxide donors are required to attenuate hypoxia-induced malignant&#xD;
      phenotypes.&#xD;
&#xD;
      Our results suggest a significant inhibition of progressive disease given the effect on PSA&#xD;
      doubling time with GTN treatment compared to their doubling time prior to initiating the&#xD;
      trial. Within 12 months of the trial, 17 of 24 patients had doubling times in the slow&#xD;
      category or even stable/declining PSA levels. The mean doubling time of the entire cohort&#xD;
      increased to 31.8 months from 13.2 months prior to starting treatment. When compared to a&#xD;
      matched control group of patients with PSA recurrence that did not receive any treatment, a&#xD;
      similar significant difference in PSA doubling time was observed. There were no adverse&#xD;
      effects reported in this trial.&#xD;
&#xD;
      This was the first report of the clinical use of nitric oxide donors in the treatment of&#xD;
      prostate cancer. The role of nitric oxide in malignant progression has been a subject of&#xD;
      controversy, with studies showing either tumor-promoting or tumor-inhibitory roles. These&#xD;
      apparently contradictory effects of NO may be explained by the fact that this molecule can&#xD;
      regulate phenotypes through a variety of mechanisms depending on local concentrations and the&#xD;
      redox state of the cell. Based on our previous findings, the investigators propose that the&#xD;
      observed effect of GTN on the PSA of this patient cohort is related to the 'low&#xD;
      concentration' effects of NO.&#xD;
&#xD;
      The investigators have identified several possible beneficial mechanisms of effect of&#xD;
      low-dose NO donors for cancer management. We have recently published the positive effect of&#xD;
      effect of NO signalling (with GTN as the effector molecule) on cancer immune surveillance.&#xD;
      The major histocompatibility complex class I chain-related (MIC) molecules, MICA and MICB,&#xD;
      play important roles in tumor surveillance by NK cells, lymphokine-activated killer (LAK)&#xD;
      cells, and cytotoxic T cells. While MICA is absent from most normal tissues, they can be&#xD;
      induced by cellular stresses, such as exposure to carcinogens and infection, and are&#xD;
      expressed in a broad range of carcinomas and some haematopoietic malignancies. In humans, the&#xD;
      interaction of cell surface MIC molecules with the C-type lectin-like NKG2D receptor on NK,&#xD;
      LAK and effector T cells leads to the activation of innate and adaptive immune responses with&#xD;
      the subsequent lysis of the tumor cells. Thus, it has been proposed that MIC-NKG2D&#xD;
      interactions are critical to the immune surveillance function of NK, LAK and cytotoxic T&#xD;
      cells.&#xD;
&#xD;
      The investigators have shown that hypoxia contributes to tumor cell shedding of MIC through a&#xD;
      mechanism involving impaired nitric oxide (NO) signalling. While hypoxia increased MIC&#xD;
      shedding in human prostate cancer cells, activation of NO signalling inhibited&#xD;
      hypoxia-mediated MIC shedding. Similar to incubation in hypoxia, pharmacological inhibition&#xD;
      of endogenous NO signalling increased MIC shedding. These findings suggest that the hypoxic&#xD;
      tumor microenvironment contributes to impaired immune surveillance and that activation of NO&#xD;
      signalling is of potential use in cancer immunotherapy.&#xD;
&#xD;
      Based on previous studies it is investigator's hypothesis that low-dose transdermal GTN will&#xD;
      have positive effects on cancer immune surveillance that may translate to therapeutic&#xD;
      benefit. In order to establish proof-of-concept, they propose to initiate the correlative&#xD;
      study described in this protocol, to determine the effect of the GTN treatment on biomarkers&#xD;
      of immune activity in patients with prostate cancer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>April 2012</start_date>
  <completion_date type="Anticipated">December 2013</completion_date>
  <primary_completion_date type="Anticipated">December 2013</primary_completion_date>
  <phase>Phase 3</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>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the following biomarkers: inflammatory/immune markers uPAR, PAI-1, ULBP2, B7-H1, MIF, TGF-β; and PSA compared to placebo.</measure>
    <time_frame>12 months</time_frame>
    <description>All assessments are as per standard of care. The only additional intervention is a 5 mL peripheral vein phlebotomy at each visit. Patients will be followed at 3, 6, 9 and 12 months after initiation of the trial. Clinic visits will assess side effects of drug and include routine follow-up for prostate cancer management. Serum samples for the above-described makers of immune activity will be obtained at the month 3, 6, 9 and 12 visit.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of SR low-dose GTN patches in the proposed patient population.</measure>
    <time_frame>12 months</time_frame>
    <description>Participant reported safety and tolerability as per FACT-P questionnaire</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo patch</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Low dose GTN 0.0285 mg/hr</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Low dose GTN</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Dose GTN 0.057 mg/hr</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>High Dose GTN</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Low Dose GTN 0.0285 mg/hr</intervention_name>
    <description>Low Dose GTN</description>
    <arm_group_label>Low dose GTN 0.0285 mg/hr</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>High Dose GTN 0.057 mg/hr</intervention_name>
    <description>High Dose GTN</description>
    <arm_group_label>High Dose GTN 0.057 mg/hr</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males;&#xD;
&#xD;
          -  Legal age of consent (18 years of age);&#xD;
&#xD;
          -  Histological evidence of adenocarcinoma of the prostate;&#xD;
&#xD;
          -  Patients have chosen watchful waiting or active surveillance as preferred management;&#xD;
&#xD;
          -  Patients have biochemical failure (defined below) after primary cancer treatment and&#xD;
             prefer deferred cancer management:&#xD;
&#xD;
               -  Patients with an increasing PSA at least 3 months after surgery (at least two&#xD;
                  values above PSA 0.2 ng/mL);&#xD;
&#xD;
               -  Patients with a PSA 2 ng/ml above their nadir PSA after radiation therapy.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to provide an informed consent;&#xD;
&#xD;
          -  Inability to adhere to the study protocol for any reason;&#xD;
&#xD;
          -  Receiving any other adjuvant therapies for prostate cancer less than 6 months prior to&#xD;
             study entry;&#xD;
&#xD;
          -  Any contraindication to GTN (including concomitant use of nitroglycerin formulations&#xD;
             or phosphodiesterase inhibitors).&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>D. Robert Siemens, MD FRCSC</last_name>
    <role>Principal Investigator</role>
    <affiliation>Queen's University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Angela Black, RN CCRP</last_name>
    <phone>613 549 6666</phone>
    <phone_ext>3848</phone_ext>
    <email>blacka@kgh.kari.net</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Janet Clark-Pereira, BA CCRP</last_name>
    <phone>613 548 7805</phone>
    <email>jmc2@queensu.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Centre for Applied Urological Research/Kingston General Hospital</name>
      <address>
        <city>Kingston</city>
        <state>Ontario</state>
        <zip>K7L 2V7</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joe Downey, MSc CCRP</last_name>
      <phone>613 548 7832</phone>
      <email>downeyj@queensu.ca</email>
    </contact>
    <investigator>
      <last_name>D. Robert Siemens, MD FRCSC</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Michael Leveridge, MD FRCSC</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>November 2013</verification_date>
  <study_first_submitted>October 5, 2012</study_first_submitted>
  <study_first_submitted_qc>October 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 11, 2012</study_first_posted>
  <last_update_submitted>November 5, 2013</last_update_submitted>
  <last_update_submitted_qc>November 5, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 6, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Queen's University</investigator_affiliation>
    <investigator_full_name>Dr. D. Robert Siemens</investigator_full_name>
    <investigator_title>PI</investigator_title>
  </responsible_party>
  <keyword>biochemical</keyword>
  <keyword>recurrence</keyword>
  <keyword>prostate</keyword>
  <keyword>cancer</keyword>
  <keyword>active</keyword>
  <keyword>surveillence</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_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/NCT01704274
org study id: Protocol # CAUR 09
nct id: NCT01704274
lead sponsor: 
has dmc: No
Prostate cancer is the most commonly diagnosed cancer in men in Canada. Over 30% of men over
      the age of fifty have histological evidence of prostate cancer on biopsy. Despite the stage
      migration afforded by early detection with serum prostate specific antigen (PSA) testing and
      an apparent trend toward improved survival over the past several years, prostate cancer
      remains a significant cause of morbidity and mortality. Biochemical failure after primary
      therapy (surgery or radiation) remains a significant health care burden and strategies to
      delay clinical prostate cancer progression and prolong the interval from treatment failure to
      systemic therapy would be of significant clinical benefit for those men suffering from a
      finding of PSA recurrence.

      PSA is widely accepted as the most useful prognostic marker of prostate cancer progression,
      particularly after primary therapy with radical surgery or radiation. 5 Despite improved
      cancer control rates with definitive management of early stage prostate cancer, a PSA
      recurrence is unfortunately a common occurrence (25-50%) in most large case series.

      Microenvironmental factors have been demonstrated to play a pivotal role in the selection of
      neoplastic cell subpopulations expressing more malignant phenotypes and contributing to the
      progression of localized and metastatic disease. Very low levels of O2 (< 10 mmHg) has been
      well described in many solid tumours (including prostate cancer) and the extent of hypoxia
      has been demonstrated to represent an independent marker of a poor prognosis for patients
      with various types of cancers. Tumour hypoxia contributes to numerous adaptive phenotypes
      including increased invasion and metastasis, as well as evasion of immune cell surveillance
      increased resistance to radiotherapy and chemotherapy. Although cellular adaptive responses
      to hypoxia are likely mediated by various mechanisms, our previous preclinical studies
      suggest that decreased nitric oxide (NO)-dependent signalling plays a significant role in
      this progression of a malignant phenotype.
Researcher's pre-clinical research has demonstrated that hypoxia-induced tumor cell
      invasiveness, metastatic ability, resistance to chemotherapeutic agents and evasion of immune
      cell recognition are inhibited by molecules that activate the NO signalling pathway involving
      cGMP generation (such as glyceryl trinitrate, GTN), and that pharmacological inhibition of NO
      signalling results in phenotypes similar to those induced by exposure to hypoxia.

      Based on pre-clinical data described above the researchers have recently completed and
      published a phase 2 trial in patients with recurrent prostate cancer using a low-dose,
      sustained release trasndermal patch of GTN. The GTN was supplied as Minitran™ (nitroglycerin)
      transdermal delivery system (3M Company, St. Paul, Minnesota) in an open label, non-blinded
      fashion. GTN is a nitrodonor that has been used in the management of angina for over 100
      years with a well-documented safety and tolerability record and has never been associated
      with carcinogenesis. Their pre-clinical studies have demonstrated that very low molar
      concentrations of nitric oxide donors are required to attenuate hypoxia-induced malignant
      phenotypes.

      Our results suggest a significant inhibition of progressive disease given the effect on PSA
      doubling time with GTN treatment compared to their doubling time prior to initiating the
      trial. Within 12 months of the trial, 17 of 24 patients had doubling times in the slow
      category or even stable/declining PSA levels. The mean doubling time of the entire cohort
      increased to 31.8 months from 13.2 months prior to starting treatment. When compared to a
      matched control group of patients with PSA recurrence that did not receive any treatment, a
      similar significant difference in PSA doubling time was observed. There were no adverse
      effects reported in this trial.

      This was the first report of the clinical use of nitric oxide donors in the treatment of
      prostate cancer. The role of nitric oxide in malignant progression has been a subject of
      controversy, with studies showing either tumor-promoting or tumor-inhibitory roles. These
      apparently contradictory effects of NO may be explained by the fact that this molecule can
      regulate phenotypes through a variety of mechanisms depending on local concentrations and the
      redox state of the cell. Based on our previous findings, the investigators propose that the
      observed effect of GTN on the PSA of this patient cohort is related to the 'low
      concentration' effects of NO.

      The investigators have identified several possible beneficial mechanisms of effect of
      low-dose NO donors for cancer management. We have recently published the positive effect of
      effect of NO signalling (with GTN as the effector molecule) on cancer immune surveillance.
      The major histocompatibility complex class I chain-related (MIC) molecules, MICA and MICB,
      play important roles in tumor surveillance by NK cells, lymphokine-activated killer (LAK)
      cells, and cytotoxic T cells. While MICA is absent from most normal tissues, they can be
      induced by cellular stresses, such as exposure to carcinogens and infection, and are
      expressed in a broad range of carcinomas and some haematopoietic malignancies. In humans, the
      interaction of cell surface MIC molecules with the C-type lectin-like NKG2D receptor on NK,
      LAK and effector T cells leads to the activation of innate and adaptive immune responses with
      the subsequent lysis of the tumor cells. Thus, it has been proposed that MIC-NKG2D
      interactions are critical to the immune surveillance function of NK, LAK and cytotoxic T
      cells.

      The investigators have shown that hypoxia contributes to tumor cell shedding of MIC through a
      mechanism involving impaired nitric oxide (NO) signalling. While hypoxia increased MIC
      shedding in human prostate cancer cells, activation of NO signalling inhibited
      hypoxia-mediated MIC shedding. Similar to incubation in hypoxia, pharmacological inhibition
      of endogenous NO signalling increased MIC shedding. These findings suggest that the hypoxic
      tumor microenvironment contributes to impaired immune surveillance and that activation of NO
      signalling is of potential use in cancer immunotherapy.

      Based on previous studies it is investigator's hypothesis that low-dose transdermal GTN will
      have positive effects on cancer immune surveillance that may translate to therapeutic
      benefit. In order to establish proof-of-concept, they propose to initiate the correlative
      study described in this protocol, to determine the effect of the GTN treatment on biomarkers
      of immune activity in patients with prostate cancer.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in the following biomarkers: inflammatory/immune markers uPAR, PAI-1, ULBP2, B7-H1, MIF, TGF-β; and PSA compared to placebo.
time frame: 12 months
description: All assessments are as per standard of care. The only additional intervention is a 5 mL peripheral vein phlebotomy at each visit. Patients will be followed at 3, 6, 9 and 12 months after initiation of the trial. Clinic visits will assess side effects of drug and include routine follow-up for prostate cancer management. Serum samples for the above-described makers of immune activity will be obtained at the month 3, 6, 9 and 12 visit.
measure: Safety and tolerability of SR low-dose GTN patches in the proposed patient population.
time frame: 12 months
description: Participant reported safety and tolerability as per FACT-P questionnaire
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo patch
arm group label: Low dose GTN 0.0285 mg/hr
arm group type: Experimental
description: Low dose GTN
arm group label: High Dose GTN 0.057 mg/hr
arm group type: Experimental
description: High Dose GTN
intervention type: Other
intervention name: Low Dose GTN 0.0285 mg/hr
description: Low Dose GTN
arm group label: Low dose GTN 0.0285 mg/hr
intervention type: Other
intervention name: High Dose GTN 0.057 mg/hr
description: High Dose GTN
arm group label: High Dose GTN 0.057 mg/hr
intervention type: Other
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: D. Robert Siemens, MD FRCSC
role: Principal Investigator
affiliation: Queen's University
last name: Angela Black, RN CCRP
phone: 613 549 6666
phone ext: 3848
email: blacka@kgh.kari.net
last name: Janet Clark-Pereira, BA CCRP
phone: 613 548 7805
email: jmc2@queensu.ca
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Queen's University
investigator full name: Dr. D. Robert Siemens
investigator title: PI
mesh term: Prostatic Neoplasms
mesh term: Recurrence