<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/NCT03772899</url>
  </required_header>
  <id_info>
    <org_study_id>MIMic</org_study_id>
    <nct_id>NCT03772899</nct_id>
  </id_info>
  <brief_title>Fecal Microbial Transplantation in Combination With Immunotherapy in Melanoma Patients (MIMic)</brief_title>
  <official_title>Fecal Microbial Transplantation in Combination With Immunotherapy in Melanoma Patients (MIMic)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawson Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Lawson Health Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Immunotherapy has helped many cancer patients in the last 5 years by enhancing a patient's&#xD;
      immune system to fight cancer. Anti-Programmed Death (PD-1) immunotherapy drugs such as&#xD;
      pembrolizumab and nivolumab remove the breaks from cancer-fighting immune cells and have been&#xD;
      effective in treating some melanoma patients. Despite the major breakthrough of immunotherapy&#xD;
      in oncology treatment, many patients do not respond to this new class of anti-cancer drugs.&#xD;
      Recently, evidence suggests that the microorganisms living in a patient's intestines play a&#xD;
      major role in modifying the response to anti-PD-1drugs. Patients who respond to these drugs&#xD;
      have a unique and healthy group of microorganisms in their gut. Therefore, positive&#xD;
      modification of a cancer patient's gut microorganisms to create a more diverse and healthy&#xD;
      microbiome may improve the response to immunotherapy. One method of modifying the microbiome&#xD;
      is Fecal Microbial Transplantation (FMT) that is already being successfully used in the&#xD;
      clinic to treat non-cancer patients with persistent bacterial infections.&#xD;
&#xD;
      In this study, the investigators will combine FMT with the approved immunotherapy drugs&#xD;
      pembrolizumab or nivolumab that are the standard of care for the treatment of advanced&#xD;
      melanoma. The purpose of this study is to examine the safety of combining these two therapies&#xD;
      in melanoma patients. The investigator will use fecal material from a healthy donor selected&#xD;
      via our stringent protocol that is Health Canada approved. In addition to assessing the&#xD;
      safety of the combination, the investigator will also study the effect of FMT on the immune&#xD;
      system and microbial ecosystem of the gut.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 27, 2019</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</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>To evaluate the safety of combining Fecal Microbial Transplantation (FMT) using intestinal bacteria existing in the stool of healthy donors with immunotherapy in melanoma patients.</measure>
    <time_frame>60 months</time_frame>
    <description>Toxicity assessments and concurrent medication review will occur at every visit throughout immunotherapy treatment. Any adverse events after FMT administration will be followed until resolution or until judged stable by the investigator.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assess Objective Response Rate</measure>
    <time_frame>At baseline and every 12 weeks thereafter up to 60 months</time_frame>
    <description>To evaluate whether combination of FMT and immunotherapy can enhance antitumor effect in melanoma patients by assessing the objective response rate (ORR; the rate of complete response plus partial response) as per the RECIST 1.1 criteria including immune-related response criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To Evaluate the effect(s) combination FMT and immunotherapy has on the gut microbiome</measure>
    <time_frame>At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy (2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit</time_frame>
    <description>Stool sample for microbiome analysis will be collected in the form of used (visibly soiled) toilet paper packed in a labeled biohazard bad and brought with the participant to clinic. The stool sample can be obtained by the patient from a bowel movement up to 3 days prior to the visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers</measure>
    <time_frame>At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit</time_frame>
    <description>blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing Complete Blood Counts (WBC, HGB, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers</measure>
    <time_frame>At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit</time_frame>
    <description>blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing circulating T cells</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers</measure>
    <time_frame>At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit</time_frame>
    <description>blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing checkpoint molecules including PD-1, PD-L1, TIM-3, LAG-3, TIGIT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers</measure>
    <time_frame>At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit</time_frame>
    <description>blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing immune markers such as HLA-DR CD38 and CD28</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate the effect(s) combination FMT and immunotherapy has on patient's metabolomics</measure>
    <time_frame>At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy (2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit</time_frame>
    <description>A urine sample will be collected for metabolomics analysis.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>Study Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fecal Microbial Transplantation - all patients registered on study will receive one dose (80-100mg) of FMT. This is a single arm, unblinded study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fecal Microbial Transplantation</intervention_name>
    <description>All patients in this trial will receive FMT at least one week prior to treatment with approved immunotherapy (either pembrolizumab or nivolumab). Samples for FMT are sourced at and by the microbiology group under the supervision of Dr. Silverman at St Joseph's Hospital. Donor screening procedures are described in appendix 4. Transplant will be from one single donor for all participants unless Dr. Silverman's lab considers the need for more than one donor based on availability of donors. There will be no &quot;mixture&quot; of donor samples.&#xD;
Donor samples are manufactured into capsules according to Kao et al, 2017.</description>
    <arm_group_label>Study Intervention</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must be 18-years old or older&#xD;
&#xD;
          -  Patients must have a confirmed diagnosis of unresectable or metastatic cutaneous&#xD;
             melanoma (BRAF wild type or mutant)&#xD;
&#xD;
          -  Patients with ECOG performance of 0-2&#xD;
&#xD;
          -  Patients must be able to provide written informed consent and understand the&#xD;
             infectious risks associated with FMT administration&#xD;
&#xD;
          -  Must understand non-infectious risks associated with FMT administration&#xD;
&#xD;
          -  Ability to ingest capsules&#xD;
&#xD;
          -  Understand that data regarding the long-term safety risk of FMT are lacking&#xD;
&#xD;
          -  Patients receiving systemic steroids at physiologic doses are permitted to enroll&#xD;
             assuming steroid dose is not above the acceptable threshold (&gt; 10 mg prednisone daily&#xD;
             or equivalent)&#xD;
&#xD;
          -  Have measurable disease as per RECIST version 1.1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 120 days after the last dose of trial treatment.&#xD;
&#xD;
          -  Current or recent [in the last 90 days] exposure to high dose oral or IV&#xD;
             corticosteroids&#xD;
&#xD;
             o Patients who require intermittent use of bronchodilators or local steroid injections&#xD;
             are not excluded from the study&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency (e.g. HIV, transplantation) or receiving systemic&#xD;
             steroid therapy (&gt;10mg prednisone daily or equivalent) or any other form of&#xD;
             immunosuppressive therapy prior to trial treatment&#xD;
&#xD;
          -  Ongoing use of antibiotics or previous use of antibiotics in the last two weeks prior&#xD;
             to the FMT procedure&#xD;
&#xD;
          -  Presence of a chronic intestinal disease (e.g. Celiac, malabsorption, colonic tumor)&#xD;
&#xD;
          -  Presence of absolute contra-indications to FMT administration&#xD;
&#xD;
               -  Toxic megacolon&#xD;
&#xD;
               -  Severe dietary allergies (e.g. shellfish, nuts, seafood)&#xD;
&#xD;
               -  Inflammatory bowel disease&#xD;
&#xD;
               -  Anatomic contra-indications to colonoscopy&#xD;
&#xD;
          -  Expected to require any other form of systemic or localized anti-neoplastic therapy&#xD;
             while on study&#xD;
&#xD;
          -  Has a known history of a hematologic malignancy, primary brain tumor or sarcoma, or of&#xD;
             another primary solid tumor, unless the patient has undergone potentially curative&#xD;
             therapy with no evidence of that disease for five years&#xD;
&#xD;
             o NOTE: This time requirement also does not apply to patients who underwent successful&#xD;
             definitive resection of basal or squamous cell carcinoma of the skin, superficial&#xD;
             bladder cancer, in situ cancers including cervical cancer, breast cancer, melanoma, or&#xD;
             other in situ cancers.&#xD;
&#xD;
          -  Active central nervous system (CNS) metastases and/or leptomeningeal involvement&#xD;
&#xD;
          -  Patients with leptomeningeal disease (leptomeningeal enhancement on MRI/CT imaging&#xD;
             and/or positive CSF cytology)&#xD;
&#xD;
          -  Has an active autoimmune disease or a documented history of autoimmune disease or&#xD;
             syndrome that requires systemic steroids or immunosuppressive agents.&#xD;
&#xD;
             o Patients with vitiligo, type I diabetes, resolved childhood asthma/atopy are&#xD;
             exceptions to this rule&#xD;
&#xD;
          -  A history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis&#xD;
&#xD;
          -  Has serious concomitant illnesses, such as: cardiovascular disease (uncontrolled&#xD;
             congestive heart failure, hypertension, cardiac ischemia, myocardial infarction, and&#xD;
             severe cardiac arrhythmia), bleeding disorders, autoimmune diseases, severe&#xD;
             obstructive or restrictive pulmonary diseases, active systemic infections, and&#xD;
             inflammatory bowel disorders&#xD;
&#xD;
             o This includes HIV or AIDS-related illness, or active HBV and HCV&#xD;
&#xD;
          -  Has an active infection requiring systemic therapy.&#xD;
&#xD;
          -  Patient has received a live vaccine within 4 weeks prior to the first dose of&#xD;
             treatment&#xD;
&#xD;
             o Note: Seasonal influenza vaccines for injection are generally inactivated flu&#xD;
             vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are&#xD;
             live attenuated vaccines, and are not allowed.&#xD;
&#xD;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Lenehan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>London Regional Cancer Program</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>London Regional Cancer Program</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5W9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHUM</name>
      <address>
        <city>Montréal</city>
        <state>Ontario</state>
        <zip>H2X 0C1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Jewish General Hospital</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3T 1E2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>November 16, 2018</study_first_submitted>
  <study_first_submitted_qc>December 10, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <last_update_submitted>June 22, 2023</last_update_submitted>
  <last_update_submitted_qc>June 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 26, 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>
  </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/NCT03772899
org study id: MIMic
nct id: NCT03772899
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Immunotherapy has helped many cancer patients in the last 5 years by enhancing a patient's
      immune system to fight cancer. Anti-Programmed Death (PD-1) immunotherapy drugs such as
      pembrolizumab and nivolumab remove the breaks from cancer-fighting immune cells and have been
      effective in treating some melanoma patients. Despite the major breakthrough of immunotherapy
      in oncology treatment, many patients do not respond to this new class of anti-cancer drugs.
      Recently, evidence suggests that the microorganisms living in a patient's intestines play a
      major role in modifying the response to anti-PD-1drugs. Patients who respond to these drugs
      have a unique and healthy group of microorganisms in their gut. Therefore, positive
      modification of a cancer patient's gut microorganisms to create a more diverse and healthy
      microbiome may improve the response to immunotherapy. One method of modifying the microbiome
      is Fecal Microbial Transplantation (FMT) that is already being successfully used in the
      clinic to treat non-cancer patients with persistent bacterial infections.

      In this study, the investigators will combine FMT with the approved immunotherapy drugs
      pembrolizumab or nivolumab that are the standard of care for the treatment of advanced
      melanoma. The purpose of this study is to examine the safety of combining these two therapies
      in melanoma patients. The investigator will use fecal material from a healthy donor selected
      via our stringent protocol that is Health Canada approved. In addition to assessing the
      safety of the combination, the investigator will also study the effect of FMT on the immune
      system and microbial ecosystem of the gut.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: To evaluate the safety of combining Fecal Microbial Transplantation (FMT) using intestinal bacteria existing in the stool of healthy donors with immunotherapy in melanoma patients.
time frame: 60 months
description: Toxicity assessments and concurrent medication review will occur at every visit throughout immunotherapy treatment. Any adverse events after FMT administration will be followed until resolution or until judged stable by the investigator.
measure: Assess Objective Response Rate
time frame: At baseline and every 12 weeks thereafter up to 60 months
description: To evaluate whether combination of FMT and immunotherapy can enhance antitumor effect in melanoma patients by assessing the objective response rate (ORR; the rate of complete response plus partial response) as per the RECIST 1.1 criteria including immune-related response criteria.
measure: To Evaluate the effect(s) combination FMT and immunotherapy has on the gut microbiome
time frame: At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy (2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit
description: Stool sample for microbiome analysis will be collected in the form of used (visibly soiled) toilet paper packed in a labeled biohazard bad and brought with the participant to clinic. The stool sample can be obtained by the patient from a bowel movement up to 3 days prior to the visit.
measure: Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers
time frame: At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit
description: blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing Complete Blood Counts (WBC, HGB, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils)
measure: Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers
time frame: At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit
description: blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing circulating T cells
measure: Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers
time frame: At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit
description: blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing checkpoint molecules including PD-1, PD-L1, TIM-3, LAG-3, TIGIT
measure: Evaluate the effect(s) combination FMT and immunotherapy has on changes in immune blood biomarkers
time frame: At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy(2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit
description: blood samples will be collected to assess changes in immune blood biomarkers before and after FMT administration by assessing immune markers such as HLA-DR CD38 and CD28
measure: Evaluate the effect(s) combination FMT and immunotherapy has on patient's metabolomics
time frame: At baseline, prior to 1st dose of immunotherapy (1 week post FMT) and 2nd dose of immunotherapy (2, 3, or 4 weeks post FMT depending on type of immunotherapy received), and at the 3 month follow-up visit
description: A urine sample will be collected for metabolomics analysis.
arm group label: Study Intervention
arm group type: Experimental
description: Fecal Microbial Transplantation - all patients registered on study will receive one dose (80-100mg) of FMT. This is a single arm, unblinded study.
intervention type: Drug
intervention name: Fecal Microbial Transplantation
description: All patients in this trial will receive FMT at least one week prior to treatment with approved immunotherapy (either pembrolizumab or nivolumab). Samples for FMT are sourced at and by the microbiology group under the supervision of Dr. Silverman at St Joseph's Hospital. Donor screening procedures are described in appendix 4. Transplant will be from one single donor for all participants unless Dr. Silverman's lab considers the need for more than one donor based on availability of donors. There will be no "mixture" of donor samples.
Donor samples are manufactured into capsules according to Kao et al, 2017.
arm group label: Study Intervention
criteria: 
gender: All
minimum age: 19 Years
maximum age: N/A
healthy volunteers: No
last name: John Lenehan, MD
role: Principal Investigator
affiliation: London Regional Cancer Program
facility: 
facility: 
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Melanoma