<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/NCT04430985</url>
  </required_header>
  <id_info>
    <org_study_id>GI 1949</org_study_id>
    <secondary_id>2019-004397-26</secondary_id>
    <nct_id>NCT04430985</nct_id>
  </id_info>
  <brief_title>FOLFOX + Immunotherapy With Intrahepatic Oxaliplatin for Patients With Metastatic Colorectal Cancer</brief_title>
  <acronym>IMMUNOX</acronym>
  <official_title>FOLFOX + Immunotherapy With Intrahepatic Administration of Oxaliplatin for Patients With Multiple Non-resectable Liver Metastasis From Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dorte Nielsen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Danish Cancer Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Herlev Hospital</source>
  <oversight_info>
    <has_dmc>No</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>
      In this trial chemotherapy regimen FOLFOX with intrahepatic administration of oxaliplatin is&#xD;
      combined with immunotherapy (nivolumab and ipilimumab) for the group of patients with&#xD;
      multiple liver metastasis from colorectal cancer. Investigators hope to increase the&#xD;
      disease-free survival after 3 years from 10 % to 30%.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Problems identifying eligble patients&#xD;
  </why_stopped>
  <start_date type="Actual">September 30, 2020</start_date>
  <completion_date type="Actual">September 6, 2021</completion_date>
  <primary_completion_date type="Actual">September 6, 2021</primary_completion_date>
  <phase>Phase 2</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>Disease-free Survival at 3 years</measure>
    <time_frame>3 years from start of treatment within the trial</time_frame>
    <description>Proportion of patients without signs of disease 3 years after treatment start</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patients becoming eligible for resection of liver metastasis</measure>
    <time_frame>Evaluation of resectability after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)</time_frame>
    <description>Number of patients with reduction of tumor burden to an extent that they become eligible for resection/radio frequency ablation of liver metastasis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate</measure>
    <time_frame>Evaluation by CT-scan after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)</time_frame>
    <description>Proportion of patients with complete or partial response according to RECIST v1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Evaluation by CT-scan after 8 cycles of treatment each cycle is 14 days) and every 3 months thereafter until progression (max 3 years)</time_frame>
    <description>Time from start of treatment to progression of disease or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Survival follow-up is planned for at least 3 years from treatment start</time_frame>
    <description>Time from start of treatment to death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of the treatment</measure>
    <time_frame>During the 16 weeks of treatment and 100 days thereafter (up to 31 weeks)</time_frame>
    <description>Incidence of treatment related Adverse Events</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Exploratory analysis of immunological response in tumor tissue</measure>
    <time_frame>Tumor tissue samples taken at baseline and week 16</time_frame>
    <description>Composition of immune infiltrates in order to define the immune cell subsets present within FFPE tumor tissue before and after exposure to therapy.</description>
  </other_outcome>
  <other_outcome>
    <measure>Explorative analysis of biomarkers predictive of response to the combination of nivolumab, ipilimumab in combination with FOLFOX</measure>
    <time_frame>Blood samples are drawn at baseline through study completion (up to 3 years)</time_frame>
    <description>Biomarker analyses include, but are not limited to a range of molecules with different characteristics such as DNA, Single Nucleotide Polymorphism (SNPs), RNA, microRNA, proteins and metabolites</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>FOLFOX + Immunotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>8 cycles of FOLFOX every 2 weeks with intrahepatic administration of oxaliplatin in cycles 1-4, thereafter (cycles 5-8) oxaliplatin i given i.v.; starting from cycle 3 this is combined with i.v. administration of nivolumab (cycle 3-8) and ipilimumab (cycle 3 + 6)&#xD;
Immunotherapy:&#xD;
Starting from cycle 3: Nivolumab 3 mg/kg i.v. on day 3 (every 2nd week, total of 6 administrations), Ipilimumab 1 mg/kg i.v. on day 3 (every 6th week, total of 2 administrations)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Day 1 in cycle 1-4: 100 mg/m2 intrahepatic administration Day 1 in cycle 5-8: oxaliplatin 85 mg/m2 i.v.</description>
    <arm_group_label>FOLFOX + Immunotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-Fluorouracil</intervention_name>
    <description>Day 1 each cycle: 400 mg/m2 i.v. bolus, 2400 mg/m2 i.v.over 46 hrs</description>
    <arm_group_label>FOLFOX + Immunotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin</intervention_name>
    <description>Day 1 each cycle: 400 mg/m2 i.v.</description>
    <arm_group_label>FOLFOX + Immunotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Day 3 in cycle 3 to 8: 3 mg/kg i.v.</description>
    <arm_group_label>FOLFOX + Immunotherapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Day 3 in cycle 3 and 6: 1 mg/kg i.v.</description>
    <arm_group_label>FOLFOX + Immunotherapy</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Informed consent&#xD;
&#xD;
          -  Age: 18 - 79 years&#xD;
&#xD;
          -  Performance status 0-1.&#xD;
&#xD;
          -  Histologically documented colorectal cancer (In case primary tumor has not yet been&#xD;
             removed, it should be possible to be removed by surgery)&#xD;
&#xD;
          -  Tumor is immunohistochemically microsatellite stable (MSS)&#xD;
&#xD;
          -  More than 5 liver metastasis, not eligible for liver resection or radiofrequency&#xD;
             ablation (RFA)&#xD;
&#xD;
          -  Presence of liver metastasis documented on CT-scan with no documented extrahepatic&#xD;
             disease except from primary tumor in situ.&#xD;
&#xD;
          -  Measurable disease according to RECIST 1.1&#xD;
&#xD;
          -  Involved liver tissue under 70 %&#xD;
&#xD;
          -  Perfusion of liver metastasis possible via a. hepatica&#xD;
&#xD;
          -  ANC &gt;= 1,5 x 10¨9/ml og Platelets &gt;= 100 x 10¨9/ml ,&#xD;
&#xD;
          -  Estimated creatinine clearance &gt;= 60 ml/min&#xD;
&#xD;
          -  INR &lt; 1,4 and bilirubin &lt;= 1,5 x ULN&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current or prior second malignancy within 5 years, except from basal cell carcinoma or&#xD;
             carcinoma in situ cervix uteri.&#xD;
&#xD;
          -  Severe medical condition, such as severe cardiac disease or AMI within 1 year&#xD;
&#xD;
          -  Uncontrolled infection.&#xD;
&#xD;
          -  Patients positive for HIV, HBV-sAG or HCV antibody&#xD;
&#xD;
          -  Participants with active, known or suspected autoimmune disease. Participants with&#xD;
             vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune&#xD;
             condition only requiring hormone replacement, psoriasis not requiring systemic&#xD;
             treatment, or conditions not expected to recur in the absence of an external trigger&#xD;
             are permitted to enroll.&#xD;
&#xD;
          -  Current or prior use of immunosuppressive medication within 14 days before the first&#xD;
             dose of ipilimumab, nivolumab. The following are exceptions to this criterion:&#xD;
&#xD;
               -  Intranasal, inhaled, or topical steroids; or local steroid injections (e.g.&#xD;
                  intra-articular injection)&#xD;
&#xD;
               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of&#xD;
                  prednisone or equivalent&#xD;
&#xD;
               -  Steroids as premedication for hypersensitivity reactions (e.g. CT scan&#xD;
                  premedication)&#xD;
&#xD;
          -  Patients requiring treatment with oral prednisolon of dose &gt; 10 mg daily&#xD;
&#xD;
          -  Previous severe, unexpected reaction related to treatment with fluoropyrimidine.&#xD;
&#xD;
          -  Previous treatment with oxaliplatin or immunotherapy&#xD;
&#xD;
          -  Neuropathy that is contraindicated for treatment with oxaliplatin&#xD;
&#xD;
          -  Pregnant or breastfeeding women. Women with childbearing potential (WOCBP) should have&#xD;
             a negative pregnancy test and agree to use highly effective method(s) of contraception&#xD;
             during treatment and 6 months thereafter.&#xD;
&#xD;
          -  Men who are sexually active with WOCBP who do not agree to use highly effective&#xD;
             method(s) of contraception during treatment and 7 months after immunotherapy or 6&#xD;
             months after chemotherapy (which period is the longest)&#xD;
&#xD;
          -  Patients who, for linguistic, intellectual or cultural reasons, will not be able to&#xD;
             fully understand the concept of treatment and respond to any. complications.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>79 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ole Larsen, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Herlev Hospital, Department of Oncology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Herlev University Hospital, Department of Oncology</name>
      <address>
        <city>Herlev</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>October 19, 2021</last_update_submitted>
  <last_update_submitted_qc>October 19, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Herlev Hospital</investigator_affiliation>
    <investigator_full_name>Dorte Nielsen</investigator_full_name>
    <investigator_title>Professor Dorte Nielsen, MD, PhD, DMSc</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT04430985
org study id: GI 1949
secondary id: 2019-004397-26
nct id: NCT04430985
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In this trial chemotherapy regimen FOLFOX with intrahepatic administration of oxaliplatin is
      combined with immunotherapy (nivolumab and ipilimumab) for the group of patients with
      multiple liver metastasis from colorectal cancer. Investigators hope to increase the
      disease-free survival after 3 years from 10 % to 30%.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease-free Survival at 3 years
time frame: 3 years from start of treatment within the trial
description: Proportion of patients without signs of disease 3 years after treatment start
measure: Patients becoming eligible for resection of liver metastasis
time frame: Evaluation of resectability after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)
description: Number of patients with reduction of tumor burden to an extent that they become eligible for resection/radio frequency ablation of liver metastasis
measure: Objective response rate
time frame: Evaluation by CT-scan after 8 cycles (each cycle is 14 days) of treatment (i.e after 16 weeks)
description: Proportion of patients with complete or partial response according to RECIST v1.1
measure: Progression free survival
time frame: Evaluation by CT-scan after 8 cycles of treatment each cycle is 14 days) and every 3 months thereafter until progression (max 3 years)
description: Time from start of treatment to progression of disease or death
measure: Overall survival
time frame: Survival follow-up is planned for at least 3 years from treatment start
description: Time from start of treatment to death
measure: Safety and tolerability of the treatment
time frame: During the 16 weeks of treatment and 100 days thereafter (up to 31 weeks)
description: Incidence of treatment related Adverse Events
measure: Exploratory analysis of immunological response in tumor tissue
time frame: Tumor tissue samples taken at baseline and week 16
description: Composition of immune infiltrates in order to define the immune cell subsets present within FFPE tumor tissue before and after exposure to therapy.
measure: Explorative analysis of biomarkers predictive of response to the combination of nivolumab, ipilimumab in combination with FOLFOX
time frame: Blood samples are drawn at baseline through study completion (up to 3 years)
description: Biomarker analyses include, but are not limited to a range of molecules with different characteristics such as DNA, Single Nucleotide Polymorphism (SNPs), RNA, microRNA, proteins and metabolites
arm group label: FOLFOX + Immunotherapy
arm group type: Experimental
description: 8 cycles of FOLFOX every 2 weeks with intrahepatic administration of oxaliplatin in cycles 1-4, thereafter (cycles 5-8) oxaliplatin i given i.v.; starting from cycle 3 this is combined with i.v. administration of nivolumab (cycle 3-8) and ipilimumab (cycle 3 + 6)
Immunotherapy:
Starting from cycle 3: Nivolumab 3 mg/kg i.v. on day 3 (every 2nd week, total of 6 administrations), Ipilimumab 1 mg/kg i.v. on day 3 (every 6th week, total of 2 administrations)
intervention type: Drug
intervention name: Oxaliplatin
description: Day 1 in cycle 1-4: 100 mg/m2 intrahepatic administration Day 1 in cycle 5-8: oxaliplatin 85 mg/m2 i.v.
arm group label: FOLFOX + Immunotherapy
intervention type: Drug
intervention name: 5-Fluorouracil
description: Day 1 each cycle: 400 mg/m2 i.v. bolus, 2400 mg/m2 i.v.over 46 hrs
arm group label: FOLFOX + Immunotherapy
intervention type: Drug
intervention name: Leucovorin
description: Day 1 each cycle: 400 mg/m2 i.v.
arm group label: FOLFOX + Immunotherapy
intervention type: Drug
intervention name: Nivolumab
description: Day 3 in cycle 3 to 8: 3 mg/kg i.v.
arm group label: FOLFOX + Immunotherapy
intervention type: Device
intervention name: Ipilimumab
description: Day 3 in cycle 3 and 6: 1 mg/kg i.v.
arm group label: FOLFOX + Immunotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 79 Years
healthy volunteers: No
last name: Ole Larsen, MD, PhD
role: Principal Investigator
affiliation: Herlev Hospital, Department of Oncology
facility: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Herlev Hospital
investigator full name: Dorte Nielsen
investigator title: Professor Dorte Nielsen, MD, PhD, DMSc
mesh term: Colorectal Neoplasms
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: No