<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/NCT02215512</url>
  </required_header>
  <id_info>
    <org_study_id>RRx001-22-01</org_study_id>
    <nct_id>NCT02215512</nct_id>
  </id_info>
  <brief_title>Dose-Escalation Study of RRx-001 in Combination With Whole Brain Radiation in Subjects With Brain Metastases</brief_title>
  <acronym>BRAINSTORM</acronym>
  <official_title>A Phase 1 Dose-Escalation Study of RRx-001 in Combination With Whole Brain Radiation in Subjects With Brain Metastases (BRAINSTORM)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>EpicentRx, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>EpicentRx, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In this dose-escalation study, the safety and tolerability of escalating dose levels of&#xD;
      RRx-001 administered intravenously twice a week in subjects with brain metastases receiving&#xD;
      whole brain radiation therapy (WBRT) will be assessed. Once a maximum tolerated dose is&#xD;
      identified, further (up to approximately 30) participants will be recruited. The study will&#xD;
      use MRI to monitor changes in tumor blood flow associated with RRx-001.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this research study is to test the safety and activity of whole brain&#xD;
      radiation therapy with RRx-001, an experimental radiation sensitizer, in participants with&#xD;
      brain metastases. As a radiation sensitizer, RRx-001 may increase the effect of whole brain&#xD;
      radiation, the standard of care for brain metastases, on cancer cells in a specific target&#xD;
      area while reducing damage to normal healthy cells. The ability to sensitize the cancer cells&#xD;
      to radiation sets off a 'domino effect' of free radical damage in the tumor from a given&#xD;
      amount or dose of radiation.&#xD;
&#xD;
      This study, which is called BRAINSTORM, since RRx-001 is associated with the development of a&#xD;
      &quot;free radical storm&quot; in the brain tumors, is divided into two stages. In the first stage,&#xD;
      approximately 3 participants at a time will be entered at a particular dose level of RRx-001&#xD;
      and then observed in order to see whether that dose results in side effects with radiation.&#xD;
      If no bad side effects are observed, a second group of approximately 3 subjects will be given&#xD;
      a slightly higher dose of RRx-001 and also monitored for side effects with radiation. This&#xD;
      process will be repeated until a dose is reached, which has the most activity against the&#xD;
      cancer cells without unacceptable side effects. At this point, more participants will be&#xD;
      entered at this dose level until a maximum enrollment of approximately 30 participants has&#xD;
      been reached.&#xD;
&#xD;
      RRx-001 releases a gas called nitric oxide, which widens the diameter of blood vessels, and&#xD;
      allows the delivery of more oxygen to tumors. The presence of oxygen in tumors is critical&#xD;
      for the effectiveness of radiation therapy, since cancer cells are about two to three times&#xD;
      more vulnerable to radiation when oxygen is present. The reason that cancer cells are so much&#xD;
      more vulnerable to the effects of radiation when oxygen is present is that radiation relies&#xD;
      on the formation of harmful molecules known as free radicals that damage proteins and genetic&#xD;
      material (DNA); without oxygen lower levels of free radicals are produced. Changes in the&#xD;
      diameter go blood vessels will be studied by magnetic resonance imaging.&#xD;
&#xD;
      Unlike chemotherapies or other radiation sensitizers, RRx-001 does not have to enter the&#xD;
      tumor to be effective because nitric oxide, as a gas, is able to spread or diffuse from the&#xD;
      bloodstream into cancer cells.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 6, 2015</start_date>
  <completion_date type="Actual">November 12, 2020</completion_date>
  <primary_completion_date type="Actual">November 28, 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number, frequency and type of adverse events</measure>
    <time_frame>42 days</time_frame>
    <description>To identify the maximum tolerated dose (MTD) of RRx-001 in combination with WBRT, defined as the dose of RRx-001 associated with a 20% probability of dose-limiting toxicity (DLT) in subjects with brain metastases</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>4 months</time_frame>
    <description>To assess the Objective Response Rate of RRx-001 in combination with WBRT using modified Response Evaluation Criteria in Solid Tumors</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate</measure>
    <time_frame>4 months</time_frame>
    <description>To assess the Clinical Benefit Rate of RRx-001 in combination with WBRT using modified Response Evaluation Criteria in Solid Tumors</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intracranial Progression Free Survival</measure>
    <time_frame>4 months</time_frame>
    <description>To obtain a preliminary estimate of the efficacy of RRx-001 in combination with WBRT in prolonging intracranial Progression Free Survival in subjects with brain metastases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>10 months</time_frame>
    <description>Overall Survival in subjects with brain metastases treated with WBRT and RRx-001</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain Imaging Parameters</measure>
    <time_frame>6 weeks</time_frame>
    <description>To evaluate changes in imaging parameters of the brain as a surrogate measure of pharmacologic activity and neurocognitive outcome</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Brain Metastases</condition>
  <arm_group>
    <arm_group_label>RRx-001 + WBRT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>RRx-001 administered intravenously twice a week (10, 17, 33, 55 mg) in subjects with brain metastases receiving whole brain radiation therapy (WBRT).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RRx-001 + WBRT</intervention_name>
    <description>Subjects will receive a combination of RRx-001 and whole brain radiotherapy.</description>
    <arm_group_label>RRx-001 + WBRT</arm_group_label>
    <other_name>Whole brain radiotherapy and RRx-001</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  One or more brain metastases&#xD;
&#xD;
          -  Prior radiation therapy to the brain is allowed with the exception of whole brain&#xD;
             irradiation&#xD;
&#xD;
          -  Subjects must be neurologically stable for at least 14 days prior to first dose of&#xD;
             study drug;&#xD;
&#xD;
          -  Male and female subjects who are not surgically sterile or post-menopausal must agree&#xD;
             to use reliable methods of birth control for the duration of the study and for 90 days&#xD;
             after the last dose of study drug administration; male partners of female subjects&#xD;
             should use condoms for the duration of the study, and for 90 days after the last dose&#xD;
             of study drug administration&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Any evidence of severe or uncontrolled diseases&#xD;
&#xD;
          -  Inadequate bone marrow reserve&#xD;
&#xD;
          -  Previous whole brain radiotherapy&#xD;
&#xD;
          -  Prior RRx-001 therapy&#xD;
&#xD;
          -  Insufficient recovery from all side effects of previous anticancer therapies&#xD;
&#xD;
          -  Evidence of blood clotting or bleeding abnormalities&#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>Michelle Kim, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Providence Saint John's Health Center</name>
      <address>
        <city>Santa Monica</city>
        <state>California</state>
        <zip>90404</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Allegiance Health</name>
      <address>
        <city>Jackson</city>
        <state>Michigan</state>
        <zip>49201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Cancer Institute of New Jersey (Rutgers University)</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>August 11, 2014</study_first_submitted>
  <study_first_submitted_qc>August 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2014</study_first_posted>
  <last_update_submitted>November 1, 2021</last_update_submitted>
  <last_update_submitted_qc>November 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</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/NCT02215512
org study id: RRx001-22-01
nct id: NCT02215512
lead sponsor: 
has dmc: No
In this dose-escalation study, the safety and tolerability of escalating dose levels of
      RRx-001 administered intravenously twice a week in subjects with brain metastases receiving
      whole brain radiation therapy (WBRT) will be assessed. Once a maximum tolerated dose is
      identified, further (up to approximately 30) participants will be recruited. The study will
      use MRI to monitor changes in tumor blood flow associated with RRx-001.
The purpose of this research study is to test the safety and activity of whole brain
      radiation therapy with RRx-001, an experimental radiation sensitizer, in participants with
      brain metastases. As a radiation sensitizer, RRx-001 may increase the effect of whole brain
      radiation, the standard of care for brain metastases, on cancer cells in a specific target
      area while reducing damage to normal healthy cells. The ability to sensitize the cancer cells
      to radiation sets off a 'domino effect' of free radical damage in the tumor from a given
      amount or dose of radiation.

      This study, which is called BRAINSTORM, since RRx-001 is associated with the development of a
      "free radical storm" in the brain tumors, is divided into two stages. In the first stage,
      approximately 3 participants at a time will be entered at a particular dose level of RRx-001
      and then observed in order to see whether that dose results in side effects with radiation.
      If no bad side effects are observed, a second group of approximately 3 subjects will be given
      a slightly higher dose of RRx-001 and also monitored for side effects with radiation. This
      process will be repeated until a dose is reached, which has the most activity against the
      cancer cells without unacceptable side effects. At this point, more participants will be
      entered at this dose level until a maximum enrollment of approximately 30 participants has
      been reached.

      RRx-001 releases a gas called nitric oxide, which widens the diameter of blood vessels, and
      allows the delivery of more oxygen to tumors. The presence of oxygen in tumors is critical
      for the effectiveness of radiation therapy, since cancer cells are about two to three times
      more vulnerable to radiation when oxygen is present. The reason that cancer cells are so much
      more vulnerable to the effects of radiation when oxygen is present is that radiation relies
      on the formation of harmful molecules known as free radicals that damage proteins and genetic
      material (DNA); without oxygen lower levels of free radicals are produced. Changes in the
      diameter go blood vessels will be studied by magnetic resonance imaging.

      Unlike chemotherapies or other radiation sensitizers, RRx-001 does not have to enter the
      tumor to be effective because nitric oxide, as a gas, is able to spread or diffuse from the
      bloodstream into cancer cells.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number, frequency and type of adverse events
time frame: 42 days
description: To identify the maximum tolerated dose (MTD) of RRx-001 in combination with WBRT, defined as the dose of RRx-001 associated with a 20% probability of dose-limiting toxicity (DLT) in subjects with brain metastases
measure: Objective Response Rate
time frame: 4 months
description: To assess the Objective Response Rate of RRx-001 in combination with WBRT using modified Response Evaluation Criteria in Solid Tumors
measure: Clinical Benefit Rate
time frame: 4 months
description: To assess the Clinical Benefit Rate of RRx-001 in combination with WBRT using modified Response Evaluation Criteria in Solid Tumors
measure: Intracranial Progression Free Survival
time frame: 4 months
description: To obtain a preliminary estimate of the efficacy of RRx-001 in combination with WBRT in prolonging intracranial Progression Free Survival in subjects with brain metastases
measure: Overall Survival
time frame: 10 months
description: Overall Survival in subjects with brain metastases treated with WBRT and RRx-001
measure: Brain Imaging Parameters
time frame: 6 weeks
description: To evaluate changes in imaging parameters of the brain as a surrogate measure of pharmacologic activity and neurocognitive outcome
arm group label: RRx-001 + WBRT
arm group type: Experimental
description: RRx-001 administered intravenously twice a week (10, 17, 33, 55 mg) in subjects with brain metastases receiving whole brain radiation therapy (WBRT).
intervention type: Drug
intervention name: RRx-001 + WBRT
description: Subjects will receive a combination of RRx-001 and whole brain radiotherapy.
arm group label: RRx-001 + WBRT
other name: Whole brain radiotherapy and RRx-001
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michelle Kim, MD
role: Principal Investigator
affiliation: University of Michigan
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms