<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/NCT03785873</url>
  </required_header>
  <id_info>
    <org_study_id>UMCC 2018.101</org_study_id>
    <secondary_id>HUM00151852</secondary_id>
    <nct_id>NCT03785873</nct_id>
  </id_info>
  <brief_title>Phase Ib/II Trial of Nal-Irinotecan and Nivolumab as Second-Line Treatment in Patients With Advanced Biliary Tract Cancer</brief_title>
  <official_title>A Single Arm Phase Ib/II Multi-Center Study of Nivolumab in Combination With Nanoliposomal-Irinotecan, 5-Fluorouracil, and Leucovorin as Second Line Therapy for Patients With Advanced Biliary Tract Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan Rogel Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ipsen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Michigan Rogel Cancer Center</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test the effectiveness (how well the drug works), safety, and&#xD;
      tolerability of the investigational drug combination of nivolumab plus&#xD;
      nanoliposomal-irinotecan, 5-fluorouracil, and leucovorin for patients with advanced or&#xD;
      metastatic biliary tract cancer after progression on first-line systemic therapy.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 22, 2019</start_date>
  <completion_date type="Anticipated">May 2025</completion_date>
  <primary_completion_date type="Anticipated">May 2025</primary_completion_date>
  <phase>Phase 1/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>Phase Ib: Incidence of dose-limiting toxicities (DLTs) of drug combination nanoliposomal-Irinotecan, 5-fluorouracil, leucovorin and nivolumab</measure>
    <time_frame>At 4 weeks after initiation of study treatment</time_frame>
    <description>Adverse events will be graded according to NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II: Median Progression-Free Survival (PFS)</measure>
    <time_frame>Up to 2 years after last dose of study treatment or 3 years after first date of treatment initiation for those that remain on treatment</time_frame>
    <description>Based on Kaplan-Meier estimates.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Until discontinuation of study treatment, up to approximately 2 years after initiating study treatment or 3 years after first date of treatment initiation for those that remain on treatment</time_frame>
    <description>Reportable adverse events are defined by the study protocol and graded according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v5.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>Up to 2 years after last dose of study treatment</time_frame>
    <description>Determined per the combined Response Evaluation Criteria in Solid Tumours (RECISTv1.1) and immune-related RECIST (irRECIST) criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival (OS)</measure>
    <time_frame>Up to 2 years after last dose of study treatment</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Biliary Tract Cancer</condition>
  <arm_group>
    <arm_group_label>Nal-Irinotecan and Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Intravenous (IV) infusion</description>
    <arm_group_label>Nal-Irinotecan and Nivolumab</arm_group_label>
    <other_name>Opdivo®, BMS-936558, MDX-1106, ONO-4538</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nanoliposomal-Irinotecan</intervention_name>
    <description>Intravenous (IV) infusion</description>
    <arm_group_label>Nal-Irinotecan and Nivolumab</arm_group_label>
    <other_name>Onivyde®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-Fluorouracil</intervention_name>
    <description>Intravenous (IV) infusion</description>
    <arm_group_label>Nal-Irinotecan and Nivolumab</arm_group_label>
    <other_name>5-FU</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin</intervention_name>
    <description>Intravenous (IV) infusion</description>
    <arm_group_label>Nal-Irinotecan and Nivolumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion&#xD;
&#xD;
          -  Patients must have a pathologically confirmed carcinoma of the biliary tract&#xD;
             (intra-hepatic, extra-hepatic (hilar, distal) or gall bladder) that is not eligible&#xD;
             for curative resection, transplantation, or ablative therapies. Tumors with mixed&#xD;
             hepatocellular and cholangiocarcinoma histology are excluded.&#xD;
&#xD;
          -  Patients must have received one and only one prior systemic therapy for advanced&#xD;
             disease. Prior therapies must have not included irinotecan or PD- 1/PD-L1 antibody.&#xD;
             Patient should have either progressed on or within 6 months of first-line systemic&#xD;
             therapy or deemed intolerant of that therapy.&#xD;
&#xD;
          -  Prior surgical resection, radiation, chemoembolization, radioembolization or other&#xD;
             local ablative therapies are permitted if completed ≥ 4 weeks prior to registration&#xD;
             AND if patient has recovered to ≤ grade 1 toxicity.&#xD;
&#xD;
          -  Patients must have radiographically measurable disease (as per RECISTv1.1) in at least&#xD;
             one site not previously treated with radiation or liver directed therapy (including&#xD;
             bland, chemo- or radio-embolization, or ablation) either within the liver or in a&#xD;
             metastatic lesion.&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Child-Pugh score of less than 7&#xD;
&#xD;
          -  ECOG performance status of 0-1&#xD;
&#xD;
          -  Ability to understand and willingness to sign IRB-approved informed consent&#xD;
&#xD;
          -  Available archived tissue (FFPE block or 20 unstained slides from prior core biopsy or&#xD;
             surgery)&#xD;
&#xD;
          -  Must be able to tolerate CT and/or MRI with contrast&#xD;
&#xD;
          -  Adequate organ function (per protocol) assessed ≤2 weeks prior to registration&#xD;
&#xD;
        Exclusion&#xD;
&#xD;
          -  Must not have received systemic steroid therapy, or any other form of&#xD;
             immunosuppressive therapy within 14 days prior to registration. Short bursts of&#xD;
             steroids of 5-7 days (for COPD exacerbation or other similar indication) are allowed.&#xD;
&#xD;
          -  No prior history of solid organ transplantation or brain metastasis (unless treated,&#xD;
             asymptomatic and stable).&#xD;
&#xD;
          -  Must not have undergone a major surgical procedure &lt; 4 weeks prior to registration.&#xD;
&#xD;
          -  Must not have an active second malignancy other than non-melanoma skin cancer or&#xD;
             cervical carcinoma in situ. Patients with history of malignancy are eligible provided&#xD;
             primary treatment of that cancer was completed &gt; 1 year prior to registration and the&#xD;
             patient is free of clinical or radiologic evidence of recurrent or progressive&#xD;
             malignancy.&#xD;
&#xD;
          -  Must have no ongoing active, uncontrolled infections (afebrile for &gt; 48 hours off&#xD;
             antibiotics).&#xD;
&#xD;
          -  Must not have received a live vaccine within 30 days of registration&#xD;
&#xD;
          -  Must not have a psychiatric illness, other significant medical illness, or social&#xD;
             situation which, in the investigator's opinion, would limit compliance or ability to&#xD;
             comply with study requirements.&#xD;
&#xD;
          -  Women must not be pregnant or breastfeeding since 5-fluorouracil, nal- irinotecan&#xD;
             and/or nivolumab may harm the fetus or child. All females of childbearing potential&#xD;
             (not surgically sterilized and between menarche and 1- year post menopause) must have&#xD;
             a blood test to rule out pregnancy within 2 weeks prior to registration.&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use 2 methods of adequate&#xD;
             contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study&#xD;
             entry, for the duration of study participation, and for 5 months (for women) and 7&#xD;
             months (for men) following completion of study therapy.&#xD;
&#xD;
          -  Participants with an active, known or suspected autoimmune disease which may affect&#xD;
             vital organ function, or has/may require systemic immunosuppressive therapy for&#xD;
             management are excluded. Participants with type I diabetes mellitus, hypothyroidism&#xD;
             only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or&#xD;
             alopecia) not requiring systemic treatment, or conditions not expected to recur in the&#xD;
             absence of an external trigger are permitted to enroll.&#xD;
&#xD;
          -  Participants with a condition requiring systemic treatment with either corticosteroids&#xD;
             (&gt;10 mg daily prednisone equivalent) or other immunosuppressive medications within 14&#xD;
             days of registration are excluded. Inhaled, ocular, intra-articular, intra-nasal or&#xD;
             topical steroids, and adrenal replacement steroid doses &gt;10 mg daily prednisone&#xD;
             equivalent, are permitted in the absence of active autoimmune disease.&#xD;
&#xD;
          -  No known UGT1A1* variants or Gilbert's syndrome&#xD;
&#xD;
          -  Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for&#xD;
             treatment of either a psychiatric or physical (e.g. infectious disease) illness would&#xD;
             be excluded.&#xD;
&#xD;
          -  No known hypersensitivity to 5-fluorouracil, leucovorin, irinotecan, and/or nivolumab.&#xD;
&#xD;
          -  Must not have ongoing bowel obstruction.&#xD;
&#xD;
          -  No known HIV, Hepatitis B or Hepatitis C infection that is untreated and/or with a&#xD;
             detectable viral load.&#xD;
&#xD;
          -  Patients must not have uncontrolled intercurrent illness including, but not limited&#xD;
             to, interstitial lung disease, symptomatic congestive heart failure, unstable angina&#xD;
             pectoris, uncontrolled cardiac arrhythmia.&#xD;
&#xD;
          -  No known medical condition (e.g. a condition associated with uncontrolled diarrhea&#xD;
             such as ulcerative colitis or acute diverticulitis) that, in the investigator's&#xD;
             opinion, would increase the risk associated with study participation or interfere with&#xD;
             the interpretation of safety results.&#xD;
&#xD;
          -  Patients must not be on warfarin, strong CYP3A4 inducers (such as phenytoin,&#xD;
             phenobarbital, primidone, carbamazepine, rifampin, rifabutin, rifapentine or St.&#xD;
             John's wort), strong CYP3A4 inhibitors (such as ketoconazole, clarithromycin,&#xD;
             indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir,&#xD;
             telaprevir, voriconazole), and strong UGT1A1 inhibitors (such as atazanavir,&#xD;
             gemfibrozil, indinavir and ketoconazole).&#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>Vaibhav Sahai, MBBS, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Michigan Rogel Cancer Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cancer and Hematology Centers of Western Michigan</name>
      <address>
        <city>Grand Rapids</city>
        <state>Michigan</state>
        <zip>49503</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virginia Mason</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98101</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Wisconsin</name>
      <address>
        <city>Madison</city>
        <state>Wisconsin</state>
        <zip>53705</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 20, 2018</study_first_submitted>
  <study_first_submitted_qc>December 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 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 23, 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>Biliary Tract 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>Nivolumab</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>IPD that underlie the results published in peer reviewed research articles, after deidentification.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_time_frame>Beginning 9 months and ending 36 months following article publication.</ipd_time_frame>
    <ipd_access_criteria>Investigators whose proposed use of the data is for meta-analysis, and has been approved by an independent review committee identified for this purpose. Proposals should be directed to vsahai@umich.edu. To gain access, data requestors will need to sign a data access agreement.</ipd_access_criteria>
  </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/NCT03785873
org study id: UMCC 2018.101
secondary id: HUM00151852
nct id: NCT03785873
lead sponsor: 
collaborator: 
collaborator: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The purpose of this study is to test the effectiveness (how well the drug works), safety, and
      tolerability of the investigational drug combination of nivolumab plus
      nanoliposomal-irinotecan, 5-fluorouracil, and leucovorin for patients with advanced or
      metastatic biliary tract cancer after progression on first-line systemic therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase Ib: Incidence of dose-limiting toxicities (DLTs) of drug combination nanoliposomal-Irinotecan, 5-fluorouracil, leucovorin and nivolumab
time frame: At 4 weeks after initiation of study treatment
description: Adverse events will be graded according to NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0
measure: Phase II: Median Progression-Free Survival (PFS)
time frame: Up to 2 years after last dose of study treatment or 3 years after first date of treatment initiation for those that remain on treatment
description: Based on Kaplan-Meier estimates.
measure: Incidence of adverse events
time frame: Until discontinuation of study treatment, up to approximately 2 years after initiating study treatment or 3 years after first date of treatment initiation for those that remain on treatment
description: Reportable adverse events are defined by the study protocol and graded according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v5.0.
measure: Overall Response Rate (ORR)
time frame: Up to 2 years after last dose of study treatment
description: Determined per the combined Response Evaluation Criteria in Solid Tumours (RECISTv1.1) and immune-related RECIST (irRECIST) criteria
measure: Median Overall Survival (OS)
time frame: Up to 2 years after last dose of study treatment
arm group label: Nal-Irinotecan and Nivolumab
arm group type: Experimental
intervention type: Drug
intervention name: Nivolumab
description: Intravenous (IV) infusion
arm group label: Nal-Irinotecan and Nivolumab
other name: Opdivo®, BMS-936558, MDX-1106, ONO-4538
intervention type: Drug
intervention name: Nanoliposomal-Irinotecan
description: Intravenous (IV) infusion
arm group label: Nal-Irinotecan and Nivolumab
other name: Onivyde®
intervention type: Drug
intervention name: 5-Fluorouracil
description: Intravenous (IV) infusion
arm group label: Nal-Irinotecan and Nivolumab
other name: 5-FU
intervention type: Drug
intervention name: Leucovorin
description: Intravenous (IV) infusion
arm group label: Nal-Irinotecan and Nivolumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Vaibhav Sahai, MBBS, MS
role: Principal Investigator
affiliation: University of Michigan
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Biliary Tract Neoplasms
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Nivolumab
mesh term: Irinotecan
sharing ipd: Yes
ipd description: IPD that underlie the results published in peer reviewed research articles, after deidentification.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd time frame: Beginning 9 months and ending 36 months following article publication.
ipd access criteria: Investigators whose proposed use of the data is for meta-analysis, and has been approved by an independent review committee identified for this purpose. Proposals should be directed to vsahai@umich.edu. To gain access, data requestors will need to sign a data access agreement.