<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/NCT03043547</url>
  </required_header>
  <id_info>
    <org_study_id>AIO-HEP-0116</org_study_id>
    <secondary_id>2016-003709-33</secondary_id>
    <nct_id>NCT03043547</nct_id>
  </id_info>
  <brief_title>Nal-IRI and 5-FU Compared to 5-FU in Patients With Cholangio- and Gallbladder Carcinoma Previously Treated With Gemcitabine-based Therapies</brief_title>
  <acronym>NALIRICC</acronym>
  <official_title>A Randomized Phase II Trial of Nal-IRI and 5-Fluorouracil Compared to 5-Fluorouracil in Patients With Cholangio- and Gallbladder Carcinoma Previously Treated With Gemcitabine-based Therapies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AIO-Studien-gGmbH</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Servier</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>AIO-Studien-gGmbH</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>
      is an open label, randomized, multicenter phase II trial&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary objective is to assess the efficacy of nal-IRI in gemcitabine pre-treated&#xD;
      patients with advanced, unresectable and metastatic cholangio- and gallbladder carcinoma&#xD;
      eligible for treatments after failure to respond to a gemcitabine-based treatment&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 24, 2017</start_date>
  <completion_date type="Actual">March 8, 2022</completion_date>
  <primary_completion_date type="Actual">December 8, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>progression-free survival</measure>
    <time_frame>approx 42 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>approx 42 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective tumor response rate (ORR) according to RECIST 1.1</measure>
    <time_frame>approx 42 months</time_frame>
    <description>Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity/Safety</measure>
    <time_frame>approx 42 months</time_frame>
    <description>according to Common Terminology Criteria for Adverse Events</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health related Quality of Life</measure>
    <time_frame>approx 42 months</time_frame>
    <description>EORTC QLQ-C30</description>
  </secondary_outcome>
  <other_outcome>
    <measure>biomarkers</measure>
    <time_frame>approx 42 months</time_frame>
    <description>Ca-19-9, CEA, CRP serum levels</description>
  </other_outcome>
  <other_outcome>
    <measure>Immunohistochemistry of Carboxylesterase (CES)</measure>
    <time_frame>approx 42 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Analyse whole blood</measure>
    <time_frame>approx 42 months</time_frame>
    <description>will be collected to potentially identify factors that may correlate with tumour response, sensitivity or resistance to nal-IRI</description>
  </other_outcome>
  <other_outcome>
    <measure>Analyse plasma</measure>
    <time_frame>approx 42 months</time_frame>
    <description>will be collected to potentially identify factors that may correlate with tumour response, sensitivity or resistance to nal-IRI</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">100</enrollment>
  <condition>Cholangiocarcinoma Non-resectable</condition>
  <condition>Cholangiocarcinoma Metastatic</condition>
  <condition>Cholangiocarcinoma of the Gallbladder</condition>
  <condition>Cholangiocarcinoma Advanced</condition>
  <arm_group>
    <arm_group_label>Nal-IRI + 5-FU + leucovorin (Arm A)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>nal-IRI [Irinotecan liposome] (80 mg/m2 as a 1.5 hour infusion), 5-FU [5-Fluorouracil] (2400 mg/m2 as 46 hour infusion) and leucovorin (400 mg/m2 as 0.5 hour infusion) (q2w)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>5-FU + leucovorin (Arm B)</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Control intervention/standard arm: 5-FU (2400 mg/m2 as 46 hour infusion) and leucovorin (400 mg/m2 as 0.5 hour infusion) (q2w)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>nal-IRI</intervention_name>
    <description>nal-IRI [Irinotecan liposome] (80 mg/m2 as a 1.5 hour infusion)</description>
    <arm_group_label>Nal-IRI + 5-FU + leucovorin (Arm A)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-FU</intervention_name>
    <description>5-FU [5-Fluorouracil] (2400 mg/m2 as 46 hour infusion)</description>
    <arm_group_label>5-FU + leucovorin (Arm B)</arm_group_label>
    <arm_group_label>Nal-IRI + 5-FU + leucovorin (Arm A)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>leucovorin</intervention_name>
    <description>leucovorin (400 mg/m2 as 0.5 hour infusion)</description>
    <arm_group_label>5-FU + leucovorin (Arm B)</arm_group_label>
    <arm_group_label>Nal-IRI + 5-FU + leucovorin (Arm A)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent incl. participation in translational research and any&#xD;
             locally-required authorization (EU Data Privacy Directive in the EU) obtained from the&#xD;
             subject prior to performing any protocol-related procedures, including screening&#xD;
             evaluations&#xD;
&#xD;
          2. Age ≥ 18 years at time of study entry&#xD;
&#xD;
          3. Histologically or cytologically confirmed, non-resectable, locally advanced or&#xD;
             metastatic cholangiocarcinoma or gall bladder carcinoma&#xD;
&#xD;
          4. Measurable or assessable disease according to RECIST 1.1&#xD;
&#xD;
          5. Documented disease progression after prior gemcitabine or gemcitabine containing&#xD;
             therapy, in locally advanced or metastatic setting. Examples of permitted therapies&#xD;
             include, but are not limited to:&#xD;
&#xD;
               1. Single agent gemcitabine&#xD;
&#xD;
               2. Any one gemcitabine-based regimen, with or without maintenance gemcitabine&#xD;
&#xD;
          6. ECOG performance status 0-1&#xD;
&#xD;
          7. Adequate blood count, liver-enzymes, and renal function:&#xD;
&#xD;
               -  ANC &gt; 1,500 cells/μL without the use of hematopoietic growth factors; and&#xD;
&#xD;
               -  Platelet count ≥ 100 x 10^9/L (&gt;100,000 per mm³) and&#xD;
&#xD;
               -  Hemoglobin &gt; 9 g/dL (blood transfusions are permitted for patients with&#xD;
                  hemoglobin levels below 9 g/dL)&#xD;
&#xD;
               -  Serum total bilirubin ≤ 3x upper normal limit (ULN) (biliary drainage is allowed&#xD;
                  for biliary obstruction; elevated bilirubin should be caused by obstruction not&#xD;
                  impaired liver function as assessed by albumin and INR values):&#xD;
&#xD;
               -  Albumin levels ≥ 3.0 g/dL&#xD;
&#xD;
               -  Patients not receiving therapeutic anticoagulation must have an INR &lt; 1.5 ULN and&#xD;
                  PTT &lt; 1.5 ULN within 7 days prior to randomization. The use of full dose&#xD;
                  anticoagulants is allowed as long as the INR or PTT is within therapeutic limits&#xD;
                  (according to the medical standard in the institution) and the patient has been&#xD;
                  on a stable dose for anticoagulants for at least three weeks at the time of&#xD;
                  randomization&#xD;
&#xD;
               -  AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal&#xD;
&#xD;
               -  Serum Creatinine ≤ 1.5 x ULN and a calculated glomerular filtration rate ≥ 30 mL&#xD;
                  per minute&#xD;
&#xD;
          8. Female patients with reproductive potential must have a negative urine or serum&#xD;
             pregnancy test within 7 days prior to start of treatment.&#xD;
&#xD;
          9. Subject is willing and able to comply with the protocol (including contraceptive&#xD;
             measures) for the duration of the study including undergoing treatment and scheduled&#xD;
             visits and examinations including follow up.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Active CNS metastases (indicated by clinical symptoms, cerebral oedema, steroid&#xD;
             requirement, or progressive disease); patient should have been off steroids for at&#xD;
             least 28 days prior to starting study therapy&#xD;
&#xD;
          2. Clinically significant gastrointestinal disorder including bleeding, inflammation,&#xD;
             occlusion, or diarrhoea &gt; grade 1&#xD;
&#xD;
          3. History of any second malignancy in the last 5 years; subjects with prior history of&#xD;
             in-situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other&#xD;
             malignancies are eligible if they have been continuously disease free for at least 5&#xD;
             years.&#xD;
&#xD;
          4. Active uncontrolled infection, chronic infectious diseases, immune deficiency&#xD;
             syndromes or an unexplained fever &gt; 38.5°C during screening visits or on the first&#xD;
             scheduled day of dosing (at the discretion of the investigator, patients with tumour&#xD;
             fever may be enrolled), which in the investigator's opinion might compromise the&#xD;
             patient's participation in the trial or affect the study outcome.&#xD;
&#xD;
          5. Premalignant hematologic disorders, e.g. myelodysplastic syndrome&#xD;
&#xD;
          6. Pre-existing lung disease&#xD;
&#xD;
          7. Clinically significant cardiovascular disease in (incl. myocardial infarction,&#xD;
             unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac&#xD;
             arrhythmia) 6 months before enrollment&#xD;
&#xD;
          8. History of hypersensitivity to any of the study drugs or any excipient (nal-IRI, other&#xD;
             liposomal products, fluoropyrimidines or leucovorin)&#xD;
&#xD;
          9. Allogeneic transplantation requiring immunosuppressive therapy or other major&#xD;
             immunosuppressive therapy&#xD;
&#xD;
         10. Severe non-healing wounds, ulcers or bone fractions&#xD;
&#xD;
         11. Evidence of bleeding diathesis or coagulopathy&#xD;
&#xD;
         12. Major surgical procedures, except open biopsy, nor significant traumatic injury within&#xD;
             28 days prior to randomization, or anticipation of the need for major surgical&#xD;
             procedure during the course of the study except for surgery of central intravenous&#xD;
             line placement for chemotherapy administration.&#xD;
&#xD;
         13. Medication that is known to interfere with any of the agents applied in the trial.&#xD;
&#xD;
         14. Female subjects who are pregnant, breast-feeding or male or female patients of&#xD;
             reproductive potential who are not employing an effective method of birth control&#xD;
             (failure rate of less than 1% per year). [Acceptable methods of contraception&#xD;
             are:implants, injectable contraceptives, combined oral contraceptives, intrauterine&#xD;
             pessaries (only hormonal devices), sexual abstinence or vasectomy of the partner].&#xD;
&#xD;
         15. Known Gilbert-Meulengracht syndrome&#xD;
&#xD;
         16. Any condition or comorbidity that, in the opinion of the investigator, would interfere&#xD;
             with evaluation of study treatment or interpretation of patient safety or study&#xD;
             results&#xD;
&#xD;
         17. Participation in another clinical study with an investigational product during the&#xD;
             last 30 days before inclusion or 5 half-lifes of previously used trial medication,&#xD;
             whichever is of longer duration.&#xD;
&#xD;
         18. Previous enrollment or randomization in the present study (does not include screening&#xD;
             failure).&#xD;
&#xD;
         19. Previous enrollment in the NIFE trial [AIO-YMO/HEP-0315]&#xD;
&#xD;
         20. Involvement in the planning and/or conduct of the study (applies to both Baxalta staff&#xD;
             and/or staff of sponsor and study site)&#xD;
&#xD;
         21. Patient who might be dependent on the sponsor, site or the investigator&#xD;
&#xD;
         22. Patient who has been incarcerated or involuntarily institutionalized by court order or&#xD;
             by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG.&#xD;
&#xD;
         23. Patients who are unable to consent because they do not understand the nature,&#xD;
             significance and implications of the clinical trial and therefore cannot form a&#xD;
             rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].&#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>Arndt Vogel, Prof.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover</name>
      <address>
        <city>Hannover</city>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>http://www.aio-portal.de</url>
    <description>AIO - Working Group for Medical Oncology from the German Cancer Society</description>
  </link>
  <link>
    <url>http://www.aio-studien-ggmbh.de/projekte.html</url>
    <description>AIO-Studien-gGmbH</description>
  </link>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>January 26, 2017</study_first_submitted>
  <study_first_submitted_qc>February 2, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 6, 2017</study_first_posted>
  <last_update_submitted>May 17, 2022</last_update_submitted>
  <last_update_submitted_qc>May 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>nal-IRI</keyword>
  <keyword>5-Fluorouracil</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cholangiocarcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</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/NCT03043547
org study id: AIO-HEP-0116
secondary id: 2016-003709-33
nct id: NCT03043547
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is an open label, randomized, multicenter phase II trial
The primary objective is to assess the efficacy of nal-IRI in gemcitabine pre-treated
      patients with advanced, unresectable and metastatic cholangio- and gallbladder carcinoma
      eligible for treatments after failure to respond to a gemcitabine-based treatment
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: progression-free survival
time frame: approx 42 months
measure: Overall survival
time frame: approx 42 months
measure: Objective tumor response rate (ORR) according to RECIST 1.1
time frame: approx 42 months
description: Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)
measure: Toxicity/Safety
time frame: approx 42 months
description: according to Common Terminology Criteria for Adverse Events
measure: Health related Quality of Life
time frame: approx 42 months
description: EORTC QLQ-C30
measure: biomarkers
time frame: approx 42 months
description: Ca-19-9, CEA, CRP serum levels
measure: Immunohistochemistry of Carboxylesterase (CES)
time frame: approx 42 months
measure: Analyse whole blood
time frame: approx 42 months
description: will be collected to potentially identify factors that may correlate with tumour response, sensitivity or resistance to nal-IRI
measure: Analyse plasma
time frame: approx 42 months
description: will be collected to potentially identify factors that may correlate with tumour response, sensitivity or resistance to nal-IRI
arm group label: Nal-IRI + 5-FU + leucovorin (Arm A)
arm group type: Experimental
description: nal-IRI [Irinotecan liposome] (80 mg/m2 as a 1.5 hour infusion), 5-FU [5-Fluorouracil] (2400 mg/m2 as 46 hour infusion) and leucovorin (400 mg/m2 as 0.5 hour infusion) (q2w)
arm group label: 5-FU + leucovorin (Arm B)
arm group type: Other
description: Control intervention/standard arm: 5-FU (2400 mg/m2 as 46 hour infusion) and leucovorin (400 mg/m2 as 0.5 hour infusion) (q2w)
intervention type: Drug
intervention name: nal-IRI
description: nal-IRI [Irinotecan liposome] (80 mg/m2 as a 1.5 hour infusion)
arm group label: Nal-IRI + 5-FU + leucovorin (Arm A)
intervention type: Drug
intervention name: 5-FU
description: 5-FU [5-Fluorouracil] (2400 mg/m2 as 46 hour infusion)
arm group label: 5-FU + leucovorin (Arm B)
arm group label: Nal-IRI + 5-FU + leucovorin (Arm A)
intervention type: Drug
intervention name: leucovorin
description: leucovorin (400 mg/m2 as 0.5 hour infusion)
arm group label: 5-FU + leucovorin (Arm B)
arm group label: Nal-IRI + 5-FU + leucovorin (Arm A)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Arndt Vogel, Prof.
role: Principal Investigator
affiliation: Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
facility: 
country: Germany
url: http://www.aio-portal.de
description: AIO - Working Group for Medical Oncology from the German Cancer Society
url: http://www.aio-studien-ggmbh.de/projekte.html
description: AIO-Studien-gGmbH
responsible party type: Sponsor
mesh term: Cholangiocarcinoma
mesh term: Leucovorin
sharing ipd: No