<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/NCT01683188</url>
  </required_header>
  <id_info>
    <org_study_id>12PLK01</org_study_id>
    <nct_id>NCT01683188</nct_id>
  </id_info>
  <brief_title>HD IL-2 + Vemurafenib in Patients With BRAF Mutation Positive Metastatic Melanoma</brief_title>
  <acronym>PROCLIVITY01</acronym>
  <official_title>A Multi-Center Study of High Dose Aldesleukin (Interleukin-2) + Vemurafenib Therapy in Patients With BRAFV600 Mutation Positive Metastatic Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Clinigen, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Prometheus Laboratories</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Clinigen, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a research study to evaluate treatment of metastatic melanoma patients with a&#xD;
      combination of drugs. The combination being studied is vemurafenib (also known as Zelboraf®)&#xD;
      and High Dose Interleukin-2 (abbreviated as HD IL-2 and known as Proleukin®). The combination&#xD;
      of vemurafenib and HD IL-2 immunotherapy may enhance the response.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be an open-label, uncontrolled two-arm, multi-center study in patients with&#xD;
      metastatic melanoma with BRAFV600 oncogene mutations. Patients will initially receive&#xD;
      treatment with vemurafenib interspersed with two courses of High Dose IL-2 (HD IL-2).&#xD;
      Patients are eligible for the study if they have melanoma positive for the BRAFV600 mutation,&#xD;
      have been on vemurafenib therapy for 0-18 weeks, have responding or stable disease if on&#xD;
      vemurafenib, and meet the requirements for dosing with HD IL-2 and all protocol inclusion and&#xD;
      exclusion criteria.&#xD;
&#xD;
      Two Cohorts will be enrolled, differing only in how they are characterized prior to HD IL-2&#xD;
      treatment:&#xD;
&#xD;
      Cohort 1: will consist of 135 patients naïve to vemurafenib and HD IL-2 therapy. Patients in&#xD;
      Cohort 1 will have an initial evaluation and receive a defined 6 (± 1) week course of&#xD;
      vemurafenib before beginning HD IL-2. This Cohort will be used to define study size and&#xD;
      statistical validity with the comparator being historic controls (using data from the BRAF&#xD;
      positive patients from the Melanoma SELECT study Protocol IIT10PLK06).&#xD;
&#xD;
      Cohort 2: will consist of up to 50 patients who have been on vemurafenib therapy for &gt;7 to 18&#xD;
      weeks with stable or responding disease before starting HD IL-2. Patients in Cohort 2 will&#xD;
      have an initial evaluation and will begin HD IL-2 treatment after &gt;7 to 18 weeks of treatment&#xD;
      with vemurafenib. This Cohort is designed to evaluate whether additive or synergistic&#xD;
      clinical benefit or toxicity is observed in BRAFV600 mutation positive metastatic melanoma&#xD;
      patients treated with vemurafenib as a single agent for &gt;7 to18 weeks prior to the first&#xD;
      course of HD IL-2 therapy in conjunction with continued vemurafenib.&#xD;
&#xD;
      Patients in both cohorts will discontinue dosing vemurafenib prior to each treatment with HD&#xD;
      IL-2 and resume dosing after each discharge. Patients will receive up to two courses (four&#xD;
      cycles) of HD IL-2 and will be evaluated for their disease responses at 10 weeks (±3 weeks)&#xD;
      from the start of HD IL-2 dosing, and 26 weeks (±3 weeks) from the start of HD IL-2 dosing.&#xD;
      QTc intervals will be reviewed daily for changes during each cycle of HD IL-2 dosing.&#xD;
&#xD;
      Administration of vemurafenib and HD IL-2 will be according to the respective Package Inserts&#xD;
      and according to the Institution's standard of care. The investigator will determine the&#xD;
      number of HD IL-2 cycles each patient will receive, according to the investigator's&#xD;
      discretion and medical judgment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    slow accrual led to early closure.&#xD;
  </why_stopped>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">November 2014</completion_date>
  <primary_completion_date type="Actual">November 2014</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Assess Complete Response (CR) rate in BRAFV600 mutation positive metastatic melanoma patients who have received vemurafenib plus HD IL-2 at 10 (±3) weeks from the start of HD IL-2 dosing to assess initial response and 26 (±3) weeks to assess and change</measure>
    <time_frame>10 weeks, 26 weeks</time_frame>
    <description>assessment of tumor response in patients with CR or near CR (&gt; 90%) after discontinuation of vemurafenib, based on RECIST criteria</description>
  </primary_outcome>
  <primary_outcome>
    <measure>compare safety between patients treated with vemurafenib and HD IL-2 versus historical HD IL-2 alone</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>incidence of adverse events</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Compare PFS</measure>
    <time_frame>1 year</time_frame>
    <description>compare progression free survival (PFS) from initiation of vemurafenib between Cohort 1 and Cohort 2 patients, compare overall PFS with the historical data using vemurafenib or HD IL-2 alone,</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">53</enrollment>
  <condition>Metastatic Melanoma</condition>
  <arm_group>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients who have received less than 7 weeks vemurafenib dosing prior to treatment with HD IL-2</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients who have receive &gt;7 weeks to 18 weeks vemurafenib dosing prior to treatment with HD IL-2</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>vemurafenib + HD IL-2</intervention_name>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <other_name>Proleukin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female patients 18 years of age or older.&#xD;
&#xD;
          -  Confirmed and measurable metastatic melanoma with the BRAFV600 mutation.&#xD;
&#xD;
          -  Patients with at least one metastatic melanoma lesion accessible. for biopsy prior to&#xD;
             vemurafenib treatment if no archived tissue is available.&#xD;
&#xD;
          -  Meet the requirements for HD IL-2 therapy per institutional guidelines.&#xD;
&#xD;
          -  Meet the requirements for vemurafenib therapy per institutional guidelines.&#xD;
&#xD;
          -  Patient must be willing to provide written Informed Consent and participate in study&#xD;
             procedures as described in the 12PLK01. Patients consented for 12PLK01 will also be&#xD;
             asked to participate in the 10PLK13 PROCLAIM (Proleukin®) registry study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A patient will not be considered eligible for study participation if any of the&#xD;
             following exclusion criteria are met:&#xD;
&#xD;
          -  Prior therapy of metastatic disease with any of the following: IL-2, Ipilimumab, or&#xD;
             other highly selective BRAF, MEK, NRAS, cMET inhibitors (e.g. GSK2118436 or&#xD;
             GSK1120212) and TKIs.&#xD;
&#xD;
               -  Exception: with a 6 week washout the following are allowed:&#xD;
&#xD;
                    -  Adjuvant Ipilimumab,&#xD;
&#xD;
                    -  Anti PD-1, Anti PD L-1&#xD;
&#xD;
          -  Exclusion for Cohort 1 only: vemurafenib treatment &gt;7 weeks.&#xD;
&#xD;
          -  Exclusion for Cohort 2 only: vemurafenib treatment &lt;7 weeks. (eligible for Cohort 1)&#xD;
             or &gt;18 weeks.&#xD;
&#xD;
          -  QTc interval of &gt;500ms.&#xD;
&#xD;
          -  Patients with known or suspected infection with human immunodeficiency virus (HIV),&#xD;
             hepatitis C virus (HCV), hepatitis B virus (HBV) or other infectious hepatitis.&#xD;
&#xD;
          -  Pregnant, nursing or planning to become pregnant.&#xD;
&#xD;
          -  Untreated brain metastases. (Brain metastases that have been treated, which no longer&#xD;
             require corticosteroid therapy and are without progression by MRI assessment at least&#xD;
             6 weeks after definitive therapy are acceptable.)&#xD;
&#xD;
          -  Received investigational drug within 30 days prior to study dosing. Patients may&#xD;
             participate in non-interventional or observational clinical study (ies)&#xD;
&#xD;
          -  Concomitant disease or condition that would interfere with the conduct of the study or&#xD;
             that would, in the opinion of the Investigator, pose an unacceptable risk to the&#xD;
             patient in this study.&#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>Tharak Rao, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Prometheus Laboratories</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Arizona Cancer Center</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85719</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moores UCSD Cancer Center</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MSMC Research Program</name>
      <address>
        <city>Miami Beach</city>
        <state>Florida</state>
        <zip>33140</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory University School of Medicine</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Loyola University Medical Center, Div of Hematology/Oncology</name>
      <address>
        <city>Maywood</city>
        <state>Illinois</state>
        <zip>60153</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Luther General Cancer Care Institute</name>
      <address>
        <city>Park Ridge</city>
        <state>Illinois</state>
        <zip>60068</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Iowa Hospitals and Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Kansas</name>
      <address>
        <city>Kansas City</city>
        <state>Kansas</state>
        <zip>66160-0003</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hematology/Oncology Clinic</name>
      <address>
        <city>Baton Rouge</city>
        <state>Louisiana</state>
        <zip>70809</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan, Comprehensive Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karmanos Cancer Institute</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota Masonic Cancer Center</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dartmouth-Hitchcock Medical Center</name>
      <address>
        <city>Lebanon</city>
        <state>New Hampshire</state>
        <zip>03756</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>John Theurer Cancer Center at Hackensack University Medical Center</name>
      <address>
        <city>Hackensack</city>
        <state>New Jersey</state>
        <zip>07601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Columbia University Medical Center, Herbert Irving Comprehensive Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10032</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Christ Hospital Cancer Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45219</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Case Comprehensive Cancer Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Providence Cancer Center</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Luke's Hospital, Anderson Campus</name>
      <address>
        <city>Easton</city>
        <state>Pennsylvania</state>
        <zip>18045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Cancer Centers</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>September 7, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2012</study_first_posted>
  <last_update_submitted>January 28, 2021</last_update_submitted>
  <last_update_submitted_qc>January 28, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>melanoma</keyword>
  <keyword>skin cancer</keyword>
  <keyword>Stage IV</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vemurafenib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>August 3, 2021</submitted>
    <returned>August 26, 2021</returned>
    <submitted>April 26, 2023</submitted>
    <returned>May 25, 2023</returned>
  </pending_results>
  <!-- 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/NCT01683188
org study id: 12PLK01
nct id: NCT01683188
lead sponsor: 
collaborator: 
has dmc: Yes
This is a research study to evaluate treatment of metastatic melanoma patients with a
      combination of drugs. The combination being studied is vemurafenib (also known as Zelboraf®)
      and High Dose Interleukin-2 (abbreviated as HD IL-2 and known as Proleukin®). The combination
      of vemurafenib and HD IL-2 immunotherapy may enhance the response.
This will be an open-label, uncontrolled two-arm, multi-center study in patients with
      metastatic melanoma with BRAFV600 oncogene mutations. Patients will initially receive
      treatment with vemurafenib interspersed with two courses of High Dose IL-2 (HD IL-2).
      Patients are eligible for the study if they have melanoma positive for the BRAFV600 mutation,
      have been on vemurafenib therapy for 0-18 weeks, have responding or stable disease if on
      vemurafenib, and meet the requirements for dosing with HD IL-2 and all protocol inclusion and
      exclusion criteria.

      Two Cohorts will be enrolled, differing only in how they are characterized prior to HD IL-2
      treatment:

      Cohort 1: will consist of 135 patients naïve to vemurafenib and HD IL-2 therapy. Patients in
      Cohort 1 will have an initial evaluation and receive a defined 6 (± 1) week course of
      vemurafenib before beginning HD IL-2. This Cohort will be used to define study size and
      statistical validity with the comparator being historic controls (using data from the BRAF
      positive patients from the Melanoma SELECT study Protocol IIT10PLK06).

      Cohort 2: will consist of up to 50 patients who have been on vemurafenib therapy for >7 to 18
      weeks with stable or responding disease before starting HD IL-2. Patients in Cohort 2 will
      have an initial evaluation and will begin HD IL-2 treatment after >7 to 18 weeks of treatment
      with vemurafenib. This Cohort is designed to evaluate whether additive or synergistic
      clinical benefit or toxicity is observed in BRAFV600 mutation positive metastatic melanoma
      patients treated with vemurafenib as a single agent for >7 to18 weeks prior to the first
      course of HD IL-2 therapy in conjunction with continued vemurafenib.

      Patients in both cohorts will discontinue dosing vemurafenib prior to each treatment with HD
      IL-2 and resume dosing after each discharge. Patients will receive up to two courses (four
      cycles) of HD IL-2 and will be evaluated for their disease responses at 10 weeks (±3 weeks)
      from the start of HD IL-2 dosing, and 26 weeks (±3 weeks) from the start of HD IL-2 dosing.
      QTc intervals will be reviewed daily for changes during each cycle of HD IL-2 dosing.

      Administration of vemurafenib and HD IL-2 will be according to the respective Package Inserts
      and according to the Institution's standard of care. The investigator will determine the
      number of HD IL-2 cycles each patient will receive, according to the investigator's
      discretion and medical judgment.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Assess Complete Response (CR) rate in BRAFV600 mutation positive metastatic melanoma patients who have received vemurafenib plus HD IL-2 at 10 (±3) weeks from the start of HD IL-2 dosing to assess initial response and 26 (±3) weeks to assess and change
time frame: 10 weeks, 26 weeks
description: assessment of tumor response in patients with CR or near CR (> 90%) after discontinuation of vemurafenib, based on RECIST criteria
measure: compare safety between patients treated with vemurafenib and HD IL-2 versus historical HD IL-2 alone
time frame: through study completion, an average of 1 year
description: incidence of adverse events
measure: Compare PFS
time frame: 1 year
description: compare progression free survival (PFS) from initiation of vemurafenib between Cohort 1 and Cohort 2 patients, compare overall PFS with the historical data using vemurafenib or HD IL-2 alone,
arm group label: Cohort 1
arm group type: Other
description: Patients who have received less than 7 weeks vemurafenib dosing prior to treatment with HD IL-2
arm group label: Cohort 2
arm group type: Other
description: Patients who have receive >7 weeks to 18 weeks vemurafenib dosing prior to treatment with HD IL-2
intervention type: Drug
intervention name: vemurafenib + HD IL-2
arm group label: Cohort 1
arm group label: Cohort 2
other name: Proleukin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Tharak Rao, MD
role: Principal Investigator
affiliation: Prometheus Laboratories
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country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Vemurafenib
sharing ipd: No
submitted: August 3, 2021
returned: August 26, 2021
submitted: April 26, 2023
returned: May 25, 2023