<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/NCT03276832</url>
  </required_header>
  <id_info>
    <org_study_id>MC1578</org_study_id>
    <secondary_id>NCI-2017-01591</secondary_id>
    <secondary_id>MC1578</secondary_id>
    <nct_id>NCT03276832</nct_id>
  </id_info>
  <brief_title>Imiquimod and Pembrolizumab in Treating Patients With Stage IIIB-IV Melanoma</brief_title>
  <official_title>Pilot Study to Test the Safety and Efficacy of the Combination of Imiquimod and Pembrolizumab for the Treatment of Metastatic Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mayo Clinic</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot trial studies the side effects and how well imiquimod and pembrolizumab work in&#xD;
      treating patients with stage IIIB-IV melanoma. Imiquimod may stimulate the immune system.&#xD;
      Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells&#xD;
      to grow and spread. Giving imiquimod and pembrolizumab may work better at treating melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To gain preliminary data of the anti-tumor activity and safety profile of the combination&#xD;
      of imiquimod and pembrolizumab in patients with unresectable cutaneous melanoma.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To compare and contrast (in a hypothesis generating manner) the biomarker profiles of&#xD;
      patients who have a confirmed complete response (CR) or partial response (PR) by Response&#xD;
      Evaluation Criteria in Solid Tumors (RECIST) criteria with patients who do not.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive pembrolizumab intravenously (IV) on day 1 and apply imiquimod cutaneously on&#xD;
      days 1-5 (Monday - Friday). Courses repeat every 21 days for up to 2 years (approximately 35&#xD;
      courses) in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 12 weeks for 2 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">December 20, 2017</start_date>
  <completion_date type="Anticipated">December 15, 2023</completion_date>
  <primary_completion_date type="Actual">October 1, 2021</primary_completion_date>
  <phase>Early 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>Duration of response</measure>
    <time_frame>From registration to disease progression, assessed up to 2 years</time_frame>
    <description>Will be estimated using the Kaplan-Meier method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of adverse events graded using Common Terminology Criteria for Adverse Events version 4.0</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>For each type of toxicity reported, the proportion of patients experiencing a severe level of that toxicity will be determined.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From registration to death due to any cause, assessed up to 2 years</time_frame>
    <description>Will be estimated using the Kaplan-Meier method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>From registration to documentation of first disease progression or death due to any cause, assessed up to 2 years</time_frame>
    <description>Will be estimated using the Kaplan-Meier method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Tumor response rate defined as percentage of patients whose objective disease status meets the criteria for Response Evaluation Criteria in Solid Tumors (RECIST) criteria for partial or complete response on two consecutive disease evaluations</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>If there are no tumor responses documented among these 10 patients, then upper bound of a one-sided 95% confidence interval for the tumor response rate would be 25.9%.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Biomarker changes during treatment</measure>
    <time_frame>Baseline up to 12 weeks</time_frame>
    <description>For each patient and each biomarker, a times-series plot of biomarker value will be constructed. These graphs will be visually examined for trends within and between the group of patients whose tumor responded to treatment and the group of patients whose tumor did not respond to treatment. Will include assessing total tumor RNA through RNA seq and PDL1 expression through the use of immunohistochemistry.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Metastatic Melanoma</condition>
  <condition>Stage IIIB Cutaneous Melanoma AJCC v7</condition>
  <condition>Stage IIIC Cutaneous Melanoma AJCC v7</condition>
  <condition>Stage IV Cutaneous Melanoma AJCC v6 and v7</condition>
  <arm_group>
    <arm_group_label>Treatment (pembrolizumab, imiquimod)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive pembrolizumab IV on day 1 and apply imiquimod cutaneously on days 1-5 (Monday - Friday). Courses repeat every 21 days for up to 2 years (approximately 35 courses) in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Imiquimod</intervention_name>
    <description>Applied cutaneously</description>
    <arm_group_label>Treatment (pembrolizumab, imiquimod)</arm_group_label>
    <other_name>Aldara</other_name>
    <other_name>R 837</other_name>
    <other_name>S 26308</other_name>
    <other_name>Zyclara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (pembrolizumab, imiquimod)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (pembrolizumab, imiquimod)</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>Lambrolizumab</other_name>
    <other_name>MK-3475</other_name>
    <other_name>SCH 900475</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological confirmation of stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c that is not&#xD;
             suitable for surgical resection&#xD;
&#xD;
          -  Patients must not have received prior pembrolizumab or other anti-PD1/PDL1 therapies&#xD;
             for their metastatic disease&#xD;
&#xD;
          -  At least one cutaneous lesion that is amenable to treatment with topical imiquimod&#xD;
&#xD;
          -  Measurable disease by RECIST&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1500/mm^3&#xD;
&#xD;
          -  Platelet count &gt;= 100,000/mm^3&#xD;
&#xD;
          -  Hemoglobin &gt; 9.0 g/dL or &gt;= 5.6 mmol/L without transfusion or (EPO) erythropoietin&#xD;
             dependency (within 7 days of assessment)&#xD;
&#xD;
          -  Serum total bilirubin =&lt; 1.5 X upper limit of normal (ULN) or direct bilirubin =&lt;&#xD;
             (ULN) for subjects with total bilirubin levels &gt; 1.5 ULN&#xD;
&#xD;
          -  Aspartate transaminase (AST) =&lt; 2.5 x ULN or =&lt; 5 x ULN for subjects with liver&#xD;
             metastases&#xD;
&#xD;
          -  Albumin &gt;= 2.5mg/dL&#xD;
&#xD;
          -  International normalized ratio (INR) or prothrombin time (PT) =&lt; 1.5 X ULN unless&#xD;
             subject is receiving anticoagulant therapy as long as PT or partial thromboplastin&#xD;
             time (PTT) is within therapeutic range of intended use of anticoagulants&#xD;
&#xD;
          -  Activated partial thromboplastin time (aPTT) =&lt; 1.5 ULN unless subject is receiving&#xD;
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use&#xD;
             of anticoagulants&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 X upper limit of normal (ULN)&#xD;
&#xD;
               -  NOTE: measured or calculated (per institutional standard) creatinine clearance is&#xD;
                  acceptable &gt;= 60 mL/min for subject with creatinine levels &gt; 1.5 X institutional&#xD;
                  ULN&#xD;
&#xD;
          -  Negative urine or serum pregnancy test done =&lt; 72 hours prior to first treatment, for&#xD;
             women of childbearing potential only&#xD;
&#xD;
               -  If the urine test is positive or cannot be confirmed as negative, a serum&#xD;
                  pregnancy test will be required&#xD;
&#xD;
          -  Provide informed written consent&#xD;
&#xD;
          -  Willing to return to enrolling institution for follow-up&#xD;
&#xD;
          -  Willing to provide tissue from a newly obtained core or excisional biopsy of a tumor&#xD;
             lesion in appropriate low risk cutaneous lesions&#xD;
&#xD;
               -  NOTE: if the tissue biopsy is deemed to be of increased risk for the patient, the&#xD;
                  biopsy should not be performed and is optional&#xD;
&#xD;
               -  NOTE: newly-obtained is defined as a specimen obtained up to 42 days prior to&#xD;
                  registration where no anti-cancer therapy after the specimen was obtained and&#xD;
                  registration&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any of the following:&#xD;
&#xD;
               -  Pregnant women&#xD;
&#xD;
               -  Nursing women&#xD;
&#xD;
               -  Men or women of childbearing potential who are unwilling to employ adequate&#xD;
                  contraception&#xD;
&#xD;
                    -  NOTE: female subjects of childbearing potential should be willing to use 2&#xD;
                       methods of birth control or be surgically sterile, or abstain from&#xD;
                       heterosexual activity for the course of the study through 120 days after the&#xD;
                       last dose of study medication; subjects of childbearing potential are those&#xD;
                       who have not been surgically sterilized or have not been free from menses&#xD;
                       for &gt; 1 year; male subjects should agree to use an adequate method of&#xD;
                       contraception starting with the first dose of study therapy through 120 days&#xD;
                       after the last dose of study therapy; abstain from heterosexual activity is&#xD;
                       also acceptable method of contraception for males&#xD;
&#xD;
          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment&#xD;
             of the investigator, would make the patient inappropriate for entry into this study or&#xD;
             interfere significantly with the proper assessment of safety and toxicity of the&#xD;
             prescribed regimens&#xD;
&#xD;
          -  Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Receiving any other investigational agent which would be considered as a treatment for&#xD;
             the primary neoplasm or used an investigational device =&lt; 4 weeks from registration&#xD;
&#xD;
          -  History of myocardial infarction =&lt; 6 months, or congestive heart failure requiring&#xD;
             use of ongoing maintenance therapy for life-threatening ventricular arrhythmias&#xD;
&#xD;
          -  Known history of active TB (Bacillus tuberculosis)&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients&#xD;
&#xD;
          -  Prior anti-cancer monoclonal antibody (mAb) =&lt; 4 weeks prior to registration or who&#xD;
             has not recovered (i.e., =&lt; grade 1 or at baseline) from adverse events due to agents&#xD;
             administered more than 4 weeks prior to registration&#xD;
&#xD;
          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy =&lt; 2 weeks&#xD;
             prior to registration or who has not recovered (i.e., =&lt; grade 1 or at baseline) from&#xD;
             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 therapy&#xD;
&#xD;
          -  Known secondary malignancy that has progressed within the last 3 years or requires&#xD;
             active treatment; exceptions include 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;
          -  Known central nervous system (CNS) metastases and/or carcinomatous meningitis&#xD;
&#xD;
          -  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 (eg., 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;
          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis&#xD;
&#xD;
          -  Active infection requiring systemic therapy&#xD;
&#xD;
          -  History or current evidence of any condition, therapy, or laboratory abnormality that&#xD;
             might confound the results of the trial, interfere with the subject?s participation&#xD;
             for the full duration of the trial, or is not in the best interest of the subject to&#xD;
             participate, in the opinion of the treating investigator&#xD;
&#xD;
          -  Known psychiatric or substance abuse disorders that would interfere with cooperation&#xD;
             with the requirements of the trial&#xD;
&#xD;
          -  Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent&#xD;
&#xD;
          -  Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or&#xD;
             hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is&#xD;
             detected)&#xD;
&#xD;
          -  Received a live vaccine =&lt; 30 days prior to registration&#xD;
&#xD;
               -  Note: seasonal influenza vaccines for injection are generally inactivated flu&#xD;
                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist)&#xD;
                  are live attenuated vaccines, and are not allowed&#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>Richard Joseph</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Florida</name>
      <address>
        <city>Jacksonville</city>
        <state>Florida</state>
        <zip>32224-9980</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>September 7, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <last_update_submitted>August 31, 2023</last_update_submitted>
  <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2023</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>Melanoma</mesh_term>
    <mesh_term>Skin Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>Imiquimod</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/NCT03276832
org study id: MC1578
secondary id: NCI-2017-01591
secondary id: MC1578
nct id: NCT03276832
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This pilot trial studies the side effects and how well imiquimod and pembrolizumab work in
      treating patients with stage IIIB-IV melanoma. Imiquimod may stimulate the immune system.
      Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells
      to grow and spread. Giving imiquimod and pembrolizumab may work better at treating melanoma.
PRIMARY OBJECTIVES:

      I. To gain preliminary data of the anti-tumor activity and safety profile of the combination
      of imiquimod and pembrolizumab in patients with unresectable cutaneous melanoma.

      SECONDARY OBJECTIVES:

      I. To compare and contrast (in a hypothesis generating manner) the biomarker profiles of
      patients who have a confirmed complete response (CR) or partial response (PR) by Response
      Evaluation Criteria in Solid Tumors (RECIST) criteria with patients who do not.

      OUTLINE:

      Patients receive pembrolizumab intravenously (IV) on day 1 and apply imiquimod cutaneously on
      days 1-5 (Monday - Friday). Courses repeat every 21 days for up to 2 years (approximately 35
      courses) in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 12 weeks for 2 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Duration of response
time frame: From registration to disease progression, assessed up to 2 years
description: Will be estimated using the Kaplan-Meier method.
measure: Incidence of adverse events graded using Common Terminology Criteria for Adverse Events version 4.0
time frame: Up to 2 years
description: For each type of toxicity reported, the proportion of patients experiencing a severe level of that toxicity will be determined.
measure: Overall survival
time frame: From registration to death due to any cause, assessed up to 2 years
description: Will be estimated using the Kaplan-Meier method.
measure: Progression free survival
time frame: From registration to documentation of first disease progression or death due to any cause, assessed up to 2 years
description: Will be estimated using the Kaplan-Meier method.
measure: Tumor response rate defined as percentage of patients whose objective disease status meets the criteria for Response Evaluation Criteria in Solid Tumors (RECIST) criteria for partial or complete response on two consecutive disease evaluations
time frame: Up to 2 years
description: If there are no tumor responses documented among these 10 patients, then upper bound of a one-sided 95% confidence interval for the tumor response rate would be 25.9%.
measure: Biomarker changes during treatment
time frame: Baseline up to 12 weeks
description: For each patient and each biomarker, a times-series plot of biomarker value will be constructed. These graphs will be visually examined for trends within and between the group of patients whose tumor responded to treatment and the group of patients whose tumor did not respond to treatment. Will include assessing total tumor RNA through RNA seq and PDL1 expression through the use of immunohistochemistry.
arm group label: Treatment (pembrolizumab, imiquimod)
arm group type: Experimental
description: Patients receive pembrolizumab IV on day 1 and apply imiquimod cutaneously on days 1-5 (Monday - Friday). Courses repeat every 21 days for up to 2 years (approximately 35 courses) in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Imiquimod
description: Applied cutaneously
arm group label: Treatment (pembrolizumab, imiquimod)
other name: Aldara
other name: R 837
other name: S 26308
other name: Zyclara
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (pembrolizumab, imiquimod)
intervention type: Biological
intervention name: Pembrolizumab
description: Given IV
arm group label: Treatment (pembrolizumab, imiquimod)
other name: Keytruda
other name: Lambrolizumab
other name: MK-3475
other name: SCH 900475
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Richard Joseph
role: Principal Investigator
affiliation: Mayo Clinic
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Skin Neoplasms
mesh term: Pembrolizumab
mesh term: Imiquimod