<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/NCT03293784</url>
  </required_header>
  <id_info>
    <org_study_id>16CUTA07</org_study_id>
    <nct_id>NCT03293784</nct_id>
  </id_info>
  <brief_title>TNF-Inhibitor as Immune Checkpoint Inhibitor for Advanced MELanoma</brief_title>
  <acronym>TICIMEL</acronym>
  <official_title>TNF-Inhibitor as Immune Checkpoint Inhibitor for Advanced MELanoma - A Phase Ib Clinical Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Claudius Regaud</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut Claudius Regaud</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 1b, open-label study of immune checkpoints inhibitors Nivolumab+Ipilimumab&#xD;
      administered in combination with the anti-TNF-α either Infliximab or Certolizumab, in&#xD;
      patients with advanced melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be conducted in 2 consecutive parts:&#xD;
&#xD;
        -  Part 1 with 2 parallel cohorts (Nivolumab+Ipilimumab administered in combination with&#xD;
           anti-TNF-α Certolizumab (Cohort 1) and Nivolumab+Ipilimumab administered in combination&#xD;
           with anti-TNF-α Infliximab (Cohort 2)). 6 patients will be included in each cohort.&#xD;
&#xD;
        -  Part 2 (expansion phase) will then be scheduled after the most promising combination has&#xD;
           been confirmed; the choice of the combination will be based on safety, efficacy, and PD&#xD;
           data observed in both cohorts during the Part 1 of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 16, 2017</start_date>
  <completion_date type="Actual">August 10, 2023</completion_date>
  <primary_completion_date type="Actual">December 6, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Dose Limiting Toxicities (DLT) incidence, in part 1 of the study.</measure>
    <time_frame>12 weeks per patient (part 1)</time_frame>
    <description>For each patient, DLT incidence will be evaluated during the Part 1 of the study: 12 weeks after the initial dose of study drug.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability according to the classification of the National Cancer Institute Common Toxicity Criteria for Adverse Effects (NCI-CTCAE) Version 4.03.</measure>
    <time_frame>15 months per patient</time_frame>
    <description>The assessment of safety and tolerability will be based on the incidence of Adverse Events (AEs), Serious Adverse Events, AEs leading to discontinuation, and death. In addition, clinical laboratory test abnormalities will be examined. Tolerability will be evaluated by collecting dose interruptions and dose delays.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>24 months per patient</time_frame>
    <description>Progression Free Survival (PFS) is defined as the time from inclusion until progression or deaths; patients alive at last follow-up news are censored at this date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>24 months per patient</time_frame>
    <description>Objective Response Rate (ORR) is defined as the number of patients with Best Overall Response divided by the number of included patients in each cohort.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>COHORT 1</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Nivolumab+Ipilimumab in combination with Anti TNF-α Certolizumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>COHORT 2</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Nivolumab+Ipilimumab in combination with Anti TNF-α Infliximab</description>
  </arm_group>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Nivolumab+Ipilimumab in combination with Anti TNF-α Certolizumab</intervention_name>
    <description>Induction phase: Nivolumab (1mg/kg) and Ipilimumab (3 mg/kg) injected at Week 0, 3, 6, and 9 with Certolizumab injected at the dose of 400mg at weeks 0, 3, and 6, and at the dose of 200mg at week 9.&#xD;
Maintenance phase: Nivolumab (3 mg/kg) alone injected from week 12 and then every 2 weeks with Certolizumab (200 mg) injected from week 12 and then every 2 weeks.</description>
    <arm_group_label>COHORT 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Nivolumab+Ipilimumab in combination with Anti TNF-α Infliximab</intervention_name>
    <description>Induction phase: Nivolumab (1mg/kg) and Ipilimumab 3 mg/kg injected at Week 0, 3, 6, and 9 with Infliximab (5mg/kg) injected at weeks 0, 3 and 6.&#xD;
Maintenance phase: Nivolumab (3 mg/kg) alone injected from week 12 and then every 2 weeks with Infliximab (5mg/kg) injected from week 14 and then every 8 weeks.</description>
    <arm_group_label>COHORT 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient with histologically-proven metastatic and/or unresectable melanoma (stage&#xD;
             IIIc-IV, M1a-c as per AJCC 2009), including mucosal melanoma, without evidence of&#xD;
             active intra-cranial disease.&#xD;
&#xD;
          2. Subjects are included regardless of BRAFV600 mutation status. BRAFV600 mutation status&#xD;
             must be documented.&#xD;
&#xD;
          3. Measurable disease per RECIST 1.1&#xD;
&#xD;
          4. Age ≥18 years and ≤70 years at the time of study entry.&#xD;
&#xD;
          5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.&#xD;
&#xD;
          6. Life expectancy of at least 3 months.&#xD;
&#xD;
          7. Patient able to participate and willing to give informed consent prior to performance&#xD;
             of any study-related procedures and to comply with the study protocol.&#xD;
&#xD;
          8. Screening laboratory values must meet the following criteria and should be obtained&#xD;
             prior to commencement of treatment:&#xD;
&#xD;
             White blood count (WBC) ≥ 2000/μL Neutrophils ≥ 1500/μL Platelets ≥ 100 x103/μL&#xD;
             Hemoglobin &gt; 9.0 g/dL&#xD;
&#xD;
             Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using the&#xD;
             Cockcroft-Gault formula below):&#xD;
&#xD;
             Female CrCl = (140 - age in years) x weight in kg x 0.85 / 72 x serum creatinine in&#xD;
             mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 / 72 x serum creatinine&#xD;
             in mg/dL AST/ALT ≤ 3 x ULN (except subjects with hepatic metastasis, who can have&#xD;
             AST/ALT ≤ 5 x ULN) Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome,&#xD;
             who can have total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
          9. Adequate cardiac and respiratory functions defined as New York Heart Association&#xD;
             (NYHA) class 1 and SaO2 &gt; 90%.&#xD;
&#xD;
         10. Patient must be naïve to systemic treatment for locally advanced and/or metastatic&#xD;
             disease (i.e., no prior systemic anticancer therapy for advanced disease; stage IIIc&#xD;
             and IV). Prior adjuvant therapies (including Interferon α and Ipilimumab) is permitted&#xD;
             if it was completed at least 12 weeks before start of treatment and all related AEs&#xD;
             have either returned to baseline or stabilized.&#xD;
&#xD;
         11. Prior radiotherapy or radiosurgery must have been completed at least 4 weeks prior to&#xD;
             the first dose of the study treatment.&#xD;
&#xD;
         12. Women of childbearing potential (WOCBP) must use two appropriate methods of&#xD;
             contraception to avoid pregnancy for 23 weeks (30 days plus the time required for&#xD;
             Nivolumab/Ipilimumab to undergo five half-lives) after the last dose of&#xD;
             investigational drug.&#xD;
&#xD;
         13. Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             (minimum sensitivity 25IU/L or equivalent units of HCG) within 24 hours prior to the&#xD;
             start of study treatment.&#xD;
&#xD;
         14. Men who are sexually active with WOCBP must use two contraceptive methods including at&#xD;
             least one method with a failure rate of less than 1% per year for a period of 31 weeks&#xD;
             after the last dose of investigational product. Women who are not of childbearing&#xD;
             potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic&#xD;
             men do not require contraception.&#xD;
&#xD;
         15. Absence of any psychological, familial, sociological or geographical condition that&#xD;
             potentially hampers compliance with the study protocol and follow-up after treatment&#xD;
             discontinuation schedule.&#xD;
&#xD;
         16. Patient affiliated to a Social Health Insurance in France.&#xD;
&#xD;
         17. Patient must provide written informed consent prior to any study specific procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient pregnant, or breast-feeding.&#xD;
&#xD;
          2. Uveal melanoma.&#xD;
&#xD;
          3. Active and/or symptomatic intra cranial metastasis (including melanomatous&#xD;
             meningitis). Patients with intra cranial metastasis may be eligible if all known&#xD;
             lesions have been treated with stereotactic radiotherapy or surgery or both AND there&#xD;
             has been no magnetic resonance imaging (MRI) evidence of disease progression in the&#xD;
             CNS for ≥ 4 weeks after treatment and within 28 days prior the first dose of study&#xD;
             drug administration.&#xD;
&#xD;
          4. Previous treatment with B-RAF or MEK inhibitors within 12 weeks prior start of&#xD;
             treatment.&#xD;
&#xD;
          5. Hypersensitivity to the drugs of the study.&#xD;
&#xD;
          6. Any condition requiring systemic treatment with either corticosteroids (&gt; 10 mg daily&#xD;
             prednisone equivalents) or other immunosuppressive medications within 14 days of study&#xD;
             drug administration. Inhaled or topical steroids and adrenal replacement doses &gt; 10 mg&#xD;
             daily prednisone equivalents are permitted in the absence of active autoimmune&#xD;
             disease.&#xD;
&#xD;
          7. Clinically significant cardiac dysfunction including congenital, familial, and genetic&#xD;
             cardiac disorders, current instable angina, current symptomatic congestive heart&#xD;
             failure of NYHA class 2 and higher, current uncontrolled hypertension ≥ grade 3; Left&#xD;
             Ventricular Ejection Fraction (LVEF) below institutional lower limit of normal (LLN)&#xD;
             or below 50%, whichever is lower.&#xD;
&#xD;
          8. Patient with active malignancy other than melanoma or a history of previous within the&#xD;
             past 3 years; except for patients with resected Basal cell carcinoma or resected&#xD;
             Spindle cell carcinoma, resected carcinoma in situ of the cervix and resected&#xD;
             carcinoma in situ of the breast.&#xD;
&#xD;
          9. History of untreated tuberculosis and/or positive quantiferon test without previous&#xD;
             prophylaxis tuberculosis treatment, or untreated active infection with mycobacterium&#xD;
             tuberculosis. For patients with asymptomatic (including radiologic symptoms) infection&#xD;
             with mycobacterium tuberculosis, inclusion may be possible after 4 weeks of adequate&#xD;
             antibiotics treatment.&#xD;
&#xD;
         10. Active, known or suspected autoimmune disease including but not restricted to multiple&#xD;
             sclerosis, optical nevritis and demyelinating neuropathy. Subjects are permitted to&#xD;
             enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to&#xD;
             autoimmune condition only requiring hormone replacement, psoriasis not requiring&#xD;
             systemic treatment, or conditions not expected to recur in the absence of an external&#xD;
             trigger.&#xD;
&#xD;
         11. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus&#xD;
             (HCV ribonucleic acid or HCV antibody) indicating acute or chronic infection.&#xD;
&#xD;
         12. Known history of testing positive for human immunodeficiency virus (HIV) or known&#xD;
             acquired immunodeficiency syndrome (AIDS).&#xD;
&#xD;
         13. Vaccination with any live attenuated conventional vaccine within the 3 months&#xD;
             preceding the start of study treatment.&#xD;
&#xD;
         14. Any current severe or uncontrolled disease, including, but not limited to ongoing or&#xD;
             active infection.&#xD;
&#xD;
         15. Patient included in another study with an experimental molecule and/or procedure.&#xD;
&#xD;
         16. Unwillingness or inability to provide written informed consent.&#xD;
&#xD;
         17. Any psychological, familial, geographic or social situation, according to the judgment&#xD;
             of investigator, potentially preventing the compliance of treatment and the study&#xD;
             protocol.&#xD;
&#xD;
         18. Patient who has forfeited his/her freedom by administrative or legal award or who is&#xD;
             under guardianship.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Nicolas MEYER</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Claudius Regaud</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut Claudius Regaud IUCT-ONCOPOLE</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>September 20, 2017</study_first_submitted>
  <study_first_submitted_qc>September 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 26, 2017</study_first_posted>
  <last_update_submitted>August 11, 2023</last_update_submitted>
  <last_update_submitted_qc>August 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Melanoma</keyword>
  <keyword>Immune checkpoint</keyword>
  <keyword>Nivolumab</keyword>
  <keyword>Ipilimumab</keyword>
  <keyword>Infliximab</keyword>
  <keyword>Certolizumab</keyword>
  <keyword>PD-1</keyword>
  <keyword>TNFa</keyword>
  <keyword>CTLA-4</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>Infliximab</mesh_term>
    <mesh_term>Certolizumab Pegol</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</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/NCT03293784
org study id: 16CUTA07
nct id: NCT03293784
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is a Phase 1b, open-label study of immune checkpoints inhibitors Nivolumab+Ipilimumab
      administered in combination with the anti-TNF-α either Infliximab or Certolizumab, in
      patients with advanced melanoma.
The study will be conducted in 2 consecutive parts:

        -  Part 1 with 2 parallel cohorts (Nivolumab+Ipilimumab administered in combination with
           anti-TNF-α Certolizumab (Cohort 1) and Nivolumab+Ipilimumab administered in combination
           with anti-TNF-α Infliximab (Cohort 2)). 6 patients will be included in each cohort.

        -  Part 2 (expansion phase) will then be scheduled after the most promising combination has
           been confirmed; the choice of the combination will be based on safety, efficacy, and PD
           data observed in both cohorts during the Part 1 of the study.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Dose Limiting Toxicities (DLT) incidence, in part 1 of the study.
time frame: 12 weeks per patient (part 1)
description: For each patient, DLT incidence will be evaluated during the Part 1 of the study: 12 weeks after the initial dose of study drug.
measure: Safety and tolerability according to the classification of the National Cancer Institute Common Toxicity Criteria for Adverse Effects (NCI-CTCAE) Version 4.03.
time frame: 15 months per patient
description: The assessment of safety and tolerability will be based on the incidence of Adverse Events (AEs), Serious Adverse Events, AEs leading to discontinuation, and death. In addition, clinical laboratory test abnormalities will be examined. Tolerability will be evaluated by collecting dose interruptions and dose delays.
measure: Progression Free Survival
time frame: 24 months per patient
description: Progression Free Survival (PFS) is defined as the time from inclusion until progression or deaths; patients alive at last follow-up news are censored at this date.
measure: Objective Response Rate
time frame: 24 months per patient
description: Objective Response Rate (ORR) is defined as the number of patients with Best Overall Response divided by the number of included patients in each cohort.
arm group label: COHORT 1
arm group type: Other
description: Nivolumab+Ipilimumab in combination with Anti TNF-α Certolizumab
arm group label: COHORT 2
arm group type: Other
description: Nivolumab+Ipilimumab in combination with Anti TNF-α Infliximab
intervention type: Combination Product
intervention name: Nivolumab+Ipilimumab in combination with Anti TNF-α Certolizumab
description: Induction phase: Nivolumab (1mg/kg) and Ipilimumab (3 mg/kg) injected at Week 0, 3, 6, and 9 with Certolizumab injected at the dose of 400mg at weeks 0, 3, and 6, and at the dose of 200mg at week 9.
Maintenance phase: Nivolumab (3 mg/kg) alone injected from week 12 and then every 2 weeks with Certolizumab (200 mg) injected from week 12 and then every 2 weeks.
arm group label: COHORT 1
intervention type: Combination Product
intervention name: Nivolumab+Ipilimumab in combination with Anti TNF-α Infliximab
description: Induction phase: Nivolumab (1mg/kg) and Ipilimumab 3 mg/kg injected at Week 0, 3, 6, and 9 with Infliximab (5mg/kg) injected at weeks 0, 3 and 6.
Maintenance phase: Nivolumab (3 mg/kg) alone injected from week 12 and then every 2 weeks with Infliximab (5mg/kg) injected from week 14 and then every 8 weeks.
arm group label: COHORT 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Nicolas MEYER
role: Principal Investigator
affiliation: Institut Claudius Regaud
facility: 
country: France
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Infliximab
mesh term: Certolizumab Pegol
mesh term: Nivolumab
mesh term: Ipilimumab