<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/NCT03778593</url>
  </required_header>
  <id_info>
    <org_study_id>GF BTC-2018</org_study_id>
    <nct_id>NCT03778593</nct_id>
  </id_info>
  <brief_title>FOLFIRINOX for 2nd-line Treatment of BTC</brief_title>
  <official_title>Phase II Trial of Modified FOLFIRINOX in Patients With Metastatic Biliary Tract Cancer After Failure of Gemcitabine/Cisplatin Chemotherapy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dong-A University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Dong-A University Hospital</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>
      Biliary tract cancer (BTC) is rare in the West, but it is relatively high in Asia, including&#xD;
      Korea. Currently used as the standard primary treatment in metastatic or locally advanced BTC&#xD;
      is gemcitabine/platinum combination chemotherapy.There is no standard secondary chemotherapy&#xD;
      recognized after the failure of the gemcitabine/platinum first line treatment. The&#xD;
      investigators try to evaluate role of 5-FU, leucovorin, irinotecan, and oxaliplatin&#xD;
      combination chemotherapy (FOLFIRINOX) for the patients who progressed after&#xD;
      gemcitabine/cisplatin first line chemotherapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      &lt;Biliary tract cancer&gt; Biliary tract cancer (BTC) is a common term for malignant tumors that&#xD;
      occur in gallbladder and bile duct, the path in which bile is released. According to the&#xD;
      anatomical location, biliary tract cancer is divided into intrahepatic cholangiocarcinoma and&#xD;
      extrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma is classified as&#xD;
      perihilar cholangiocarcinoma and distal cholangiocarcinoma. Biliary tract cancer is rare in&#xD;
      the West, but it is relatively high in Asia, including Korea. Biliary tract cancer occurs&#xD;
      annually in Korea, accounting for about 5,600 cases, 2.4 percent of the total cancer, and&#xD;
      ranks sixth in deaths from cancer. Biliary tract cancer is a type of cancer that is difficult&#xD;
      to treat because most patients are diagnosed with progressive diseases that cannot be&#xD;
      operated. Only about a quarter of patients are diagnosed with surgical-ready conditions as a&#xD;
      treatment where full surgical operation can be expected to complete, but the five-year&#xD;
      survival rate for operation is poor at 8-44% due to a high recurrence after surgery.&#xD;
&#xD;
      &lt;Metastatic or relapsed biliary tract cancer treatment&gt; Chemotherapy is the main treatment in&#xD;
      BTC, which is relapsed or metastatic status. 5- Fluorouracil (5-FU)-based treatment has been&#xD;
      shown to improve the survival period for pancreatic and bile cancer patients compared to the&#xD;
      optimal supportive care (5-FU/leucovorin ± etoposide 6.0 vs. 2.5 months, p &lt;0.01). Also,&#xD;
      chemotherapy helped maintain the quality of life. The improvement in quality of life over a&#xD;
      period of at least four months showed a significant difference compared to 10% in the group&#xD;
      that received only optimal supportive care for 36% of the chemotherapy group. (p &lt; 0.01).&#xD;
      Currently used as the standard primary treatment in metastatic or locally advanced BTC is&#xD;
      gemcitabine/platinum combination chemotherapy. In a large phase III study,&#xD;
      Gemcitabine/cisplatin significantly improved the median value of the progressive free&#xD;
      survival (PFS) period from 5.0 months to 8.0 months, and the overall survival (OS) period&#xD;
      from 8.1 months to 11.7 months, compared to the gemcitabine alone. If Cisplatin is not&#xD;
      available, oxaliplatin can be considered as a merger with gemcitabine. The&#xD;
      Gemcitabine/oxaliplatin regimen reported in the phase II and phase III studies PFS was&#xD;
      4.2-5.5 months, median for the OS period was 9.5-12.4 months.&#xD;
&#xD;
      &lt;Salvage treatment of biliary tract cancer&gt; To date, there is no standard secondary&#xD;
      chemotherapy recognized after the failure of the gemcitabine/platinum primary treatment.&#xD;
      Since BTC usually occurs at an advanced age and shows a low frequency of occurrence in the&#xD;
      West, there are practical limitations to conducting large-scale clinical research. So far,&#xD;
      there is no large three-phase study proving the benefits of secondary chemotherapy after the&#xD;
      failure of gemcitabine/platinum chemotherapy. Implementation of secondary chemotherapy in&#xD;
      actual clinicians is known to vary from country to country, depending on the medical judgment&#xD;
      of the responsible clinician. In a large-scale retrospective study by the Association des&#xD;
      Gastro-Enterologies Oncology (AGEO) group in France, 32.5% of the patients were treated with&#xD;
      second line therapy, and 75% of the patients were reported in Japan. A retrospective study&#xD;
      and a two-phase study and systematic literature review suggest that there will be a benefit&#xD;
      from the treatment if second line treatment is selected for patients whose general health is&#xD;
      relatively well maintained. Results of single or combination therapy using drugs such as&#xD;
      Irinotecan, oxaliplatin, 5-FU, S-1, and capecitabine were reported in phase II and&#xD;
      retrospective studies, yielding an average of 3.2 months of PFS, 7.7% of mean response rate,&#xD;
      and 7.2 months of OS.&#xD;
&#xD;
      The 5-FU/leucovorin/irinotecan (FOLFIRI) therapy, along with the capecitabine/irinotecan&#xD;
      therapy, is reported as the most commonly used secondary chemotherapy in the AGEO group in&#xD;
      France. A treatment strategy for continuous use of FOLFIRI as a secondary treatment after the&#xD;
      failure of Gemcitabine/oxaliplatin showed the median value for OS period of 21.9 months, and&#xD;
      the median value for the PFS period. The PFS and OS due to the FOLFIRI was found to be 3.2&#xD;
      months and 8.4 months, respectively. On the other hand, the FOLFOX therapy, which combines&#xD;
      oxaliplatin with 5-FU, showed a response rate of 21.6 % when administered as a secondary&#xD;
      treatment after the failure of gemcitabine/cisplatin, and a median PFS of 3.1 months. A phase&#xD;
      III study is currently underway that compares the administration of FOLFOX as a secondary&#xD;
      treatment with the optimum support. In Korea, there is a problem with the standard&#xD;
      reimbursement for applying to drugs prescribed to cancer patients, and in particular, cancer&#xD;
      drugs that can be used as secondary therapy in metastatic BTC patients are limited. There is&#xD;
      a need to improve the prognosis of BTC patients by expanding the use of various drugs that&#xD;
      have been proven through external clinical research.&#xD;
&#xD;
      &lt;5-FU, leucovorin, irinotecan, and oxaliplatin combination chemotherapy (FOLFIRINOX) regimen&#xD;
      for other cancer of BTC&gt; In a pre-clinical experiment, oxaliplatin and irinotecan have&#xD;
      synergistic effects and are known to have relatively no overlap of toxic effects among, 5-FU,&#xD;
      leucovorin, irinotecan, and oxaliplatin. The combination treatment of&#xD;
      5-FU/leukovorin/irinotecan/oxaliplatin (FOLFIRINOX) had a high therapeutic effect on&#xD;
      progressive pancreatic cancer and colon cancer. In a phase III study comparing FOLFIRINOX and&#xD;
      gemcitabine as a first line treatment in metastatic pancreatic cancer, the objective response&#xD;
      rate (32 vs. 9%), PFS (6.4 vs. 3.3 months) and OS (11.1 vs. 6.8 months) were significantly&#xD;
      higher in FOLFIRINOX. On the other hand, treatment-related toxicities, with a grade 3/4 of&#xD;
      neutropenia (46 vs. 21%), febrile neutropenia (5.4 vs. 1.2%), thrombocytopenia (9.1 vs.&#xD;
      3.6%), sensory neuropathy (9 vs. 0%), vomiting (23 vs. 18%), and diarrhea (113 vs. 2%) were&#xD;
      more common in FOLFIRINOX. In a phase III study comparing the&#xD;
      5-FU/leukovorin/irinotecan/oxaliplatin(FORFOXRI) and the 5-FU/leukovorin/irinotecan(FORFIRI)&#xD;
      as a first line treatment in metastatic colorectal cancer, the FORFOXRI group was objective&#xD;
      response (66 vs. 41 %), the PFS (9.8 vs. 6.9 months) and the OS (2.6 vs. 16.7 months) showed&#xD;
      significant improvements. In pancreatic cancer, FOLFIRINOX was a treatment that was limited&#xD;
      in patients with good general condition due to its high level of toxicity, including&#xD;
      neutropenia, but the dose-reduction proved to be applied not only as a primary treatment but&#xD;
      also as a secondary treatment. In a phase II study of pancreatic cancer patients in China,&#xD;
      there was a 29% of grade 3/4 neutropenia were reported due to the treatment of modified&#xD;
      FOLFIRINOX using oxaliplatin 68 mg/m2, irinotecan 135 mg/m2, and 5-FU injection of 2,400&#xD;
      mg/m2 for 46 hours, and there was no increase in mortality and febrile neutropenia. Other&#xD;
      major grade 3 or higher toxicity levels showed improved safety profiles with thrombocytopenia&#xD;
      (4.8%), anemia (8.1%), infection (4.8%), and elevated liver enzyme (14.5%).&#xD;
&#xD;
      &lt;Rationale of this trial&gt;&#xD;
&#xD;
      As a 2nd line treatment for metastatic BTC the assessment of modified FOLFIRINOX is supported&#xD;
      by:&#xD;
&#xD;
        -  The prognosis for metastatic BTC, which fails first line therapy, is poor and has no&#xD;
           standardized treatment. Therefore, better treatment modalities are required to improve&#xD;
           the survival of patients who no longer respond to first line treatment and to maintain&#xD;
           the quality of life.&#xD;
&#xD;
        -  Treatments that use irinotecan or oxaliplatin as secondary therapy for metastatic BTC&#xD;
           have been shown in retrospective and phase II studies and are actually used in clinical&#xD;
           practice of other countries.&#xD;
&#xD;
        -  Oxaliplatin and irinotecan have synergistic effects and the FOLFIRINOX therapy, which&#xD;
           uses both drugs together in 5-FU/leucovorin, has been shown to increase efficacy in&#xD;
           pancreatic and colon cancer.&#xD;
&#xD;
        -  The modified FOLFIRINOX, which was used with reduced dosage, indicates an acceptable&#xD;
           toxic profile while maintaining its efficacy&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 1, 2019</start_date>
  <completion_date type="Actual">January 14, 2021</completion_date>
  <primary_completion_date type="Actual">March 1, 2019</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>
    <intervention_model_description>mFOLFIRINOX (5-FU, Irinotecan, oxaliplatin, Leucovorin)</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Response rate of treated participants</measure>
    <time_frame>up to 6 months</time_frame>
    <description>Rate of response including complete response and partial response by treatment. Response will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS) duration of treated participants</measure>
    <time_frame>up to 12 months</time_frame>
    <description>duration measure from treatment day to progression + death events. Calculated by Kaplan-Meier survival analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS) duration of treated participants</measure>
    <time_frame>up to 12 months</time_frame>
    <description>duration measure from treatment day to death events. Calculated by Kaplan-Meier survival analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events of participants</measure>
    <time_frame>up to 12 months</time_frame>
    <description>all adverse events during treatment. Evaluated with National Cancer Institute(NCI)-] Common Terminology Criteria for Adverse Events (CTCAE) v4.03</description>
  </secondary_outcome>
  <other_outcome>
    <measure>EORTC -QoL-C30</measure>
    <time_frame>up to 12 months</time_frame>
    <description>Evaluate patients' life quality evaluation during treatment every 2 months with questionaires.&#xD;
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (EORTC QOL-C30) will be used.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Biliary Tract Cancer</condition>
  <arm_group>
    <arm_group_label>mFOLFIRINOX</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>D1 Oxaliplatin 65 mg/m2 + 5% dextrose water (5DW) 200 mL mix IV over 2 hours followed by, D1 Leucovorin 400 mg/m2 + 5DW 200 ml mix IV over 2 hours D1 Irinotecan 135 mg/m2 + 5DW 500 mL mix IV over 2 hours (concurrent with the leucovorin infusion) D1-2 5-Fluorouracil 1000 mg/m2 + 5DW 1 liter (1L) continuous IV over 23 hours repeat every 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-Fluorouracil</intervention_name>
    <description>D1-2 5-Fluorouracil 1000 mg/m2 + 5DW 1L continuous IV over 23 hours q 2 weeks</description>
    <arm_group_label>mFOLFIRINOX</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin</intervention_name>
    <description>D1 Leucovorin 400 mg/m2 + 5DW 200 ml mix IV over 2 hours q 2 weeks</description>
    <arm_group_label>mFOLFIRINOX</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <description>D1 Irinotecan 135 mg/m2 + 5DW 500 mL mix IV over 2 hours (concurrent with the leucovorin infusion) q 2weeks</description>
    <arm_group_label>mFOLFIRINOX</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>D1 Oxaliplatin 65 mg/m2 + 5DW 200 mL mix IV over 2 hours q 2 weeks</description>
    <arm_group_label>mFOLFIRINOX</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5% dextrose water</intervention_name>
    <description>mix fluid with 5-FU, leucovorin, irinotecan, and oxaliplatin</description>
    <arm_group_label>mFOLFIRINOX</arm_group_label>
    <other_name>5DW</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed BTC (cholangiocarcinoma or gall bladder (GB) cancer) , except&#xD;
             ampulla of Vater cancer&#xD;
&#xD;
          2. In the event that the progression of the gemcitabine/cisplatin is experienced during&#xD;
             or after discontinuation of the first line treatment for metastatic, locally advanced&#xD;
             or relapsed (it may be considered as a first line treatment that recurrence within six&#xD;
             months of completion of the adjuvant or neo-adjuvant chemotherapy using&#xD;
             gemcitabine/cisplatin)&#xD;
&#xD;
          3. Patient (or legal representative) has completed an approved consent documents that he&#xD;
             or she will participate in the test after receiving sufficient information about the&#xD;
             clinical trial&#xD;
&#xD;
          4. East clinical oncology group (ECOG) performance status 0-1&#xD;
&#xD;
          5. One or more measurable lesions by RECIST v1.1.&#xD;
&#xD;
          6. Appropriate organ functions; A. Liver: bilirubin ≤ 3 mg/dL, aspartate aminotransferase&#xD;
             (AST) or alanine aminotransferase (ALT) ≤ 2.5 x ULN (in cases of liver metastasis, AST&#xD;
             or ALT ≤ 5 x ULN) B. Kidney: An estimate of creatine clearance rate according to the&#xD;
             Cockcroft-Gault formula (or local institution's standard method) &gt; 30 mili-liter&#xD;
             (mL)/min C. Hemoglobin ≥ 9 g/dL (transfusion allowed), absolute neutrophil count (ANC)&#xD;
             ≥ 1500/μL, platelet count ≥ 75,000/μL.&#xD;
&#xD;
          7. Expected life time over 3 months.&#xD;
&#xD;
          8. Over 19 years old.&#xD;
&#xD;
          9. In case of proper bile excretion function&#xD;
&#xD;
         10. Have the will and ability to comply with the clinical trial plan during the study&#xD;
             period, including treatment and scheduled visits and examination.&#xD;
&#xD;
         11. For pre-menopausal women and for women less than one year after the onset of&#xD;
             menopause, serum or urine pregnancy tests shall be confirmed negative during&#xD;
             screening.&#xD;
&#xD;
         12. For men and fertile women, the use of effective contraceptive methods should be agreed&#xD;
             (effective contraception should be used for at least 30 days prior to the initial&#xD;
             administration of a investigational drug, the trial period, and at least 90 days after&#xD;
             the discontinuation of the test participation).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. ≥ 2 of prior chemotherapy for progressive BTC (except for adjuvant/neo-adjuvant&#xD;
             chemotherapy with resting of more than six months)&#xD;
&#xD;
          2. Symptomatic or untreated brain metastasis or spinal cord compression metastasis.&#xD;
&#xD;
          3. Previous treatment using Irinotecan or oxaliplatin&#xD;
&#xD;
          4. In case of major surgery within four weeks just before registration, excluding biopsy&#xD;
             for diagnosis&#xD;
&#xD;
          5. In case of chemotherapy or radiation therapy was received within three weeks prior to&#xD;
             the administration of a test medication&#xD;
&#xD;
          6. Grade 2 or higher peripheral neuropathy&#xD;
&#xD;
          7. Grade 2 or higher toxicities caused by a previous cancer treatment based on NCI-CTCAE&#xD;
             v 4.03 other than hair loss&#xD;
&#xD;
          8. A person diagnosed with another malignant tumor within the last five years. Exceptions&#xD;
             include basal or squamous cell carcinoma of the skin or intraepithelial neoplasia&#xD;
             (bladder, uterine cervical, colorectal, breast)&#xD;
&#xD;
          9. Pregnant or nursing woman&#xD;
&#xD;
         10. If there is a severe or uncontrolled systemic disease, active infection, active&#xD;
             bleeding tendency or organ transplantation history (including allo-hematopoietic stem&#xD;
             cell transplantation)&#xD;
&#xD;
         11. The following virus infection A. Known positive history for human immunodeficiency&#xD;
             virus (Human Immunodeficiency virus, HIV) test or known acquired immunodeficiency&#xD;
             syndrome (AIDS) B. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection&#xD;
             (positive Hepatitis B surface -Ag (+) or HCV RNA (+) if anti-HCV Ab screening test is&#xD;
             positive)&#xD;
&#xD;
         12. If there is a known alcohol or drug abuse&#xD;
&#xD;
         13. In cases of clinically significant (i.e., active) cardiovascular disease: cerebral&#xD;
             hemorrhage/brain infarction, myocardial infarction (pre-registration &lt; 6 months),&#xD;
             unstable angina, congestive heart failure (NYHA classification ≥2) or arrhythmia&#xD;
             needed drug therapy.&#xD;
&#xD;
         14. In case of a mental state in which it is impossible to understand and provide the&#xD;
             consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sung Yong Oh, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dong-A University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dong-A University Hospital</name>
      <address>
        <city>Busan</city>
        <zip>49201</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 14, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>February 2, 2021</last_update_submitted>
  <last_update_submitted_qc>February 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dong-A University Hospital</investigator_affiliation>
    <investigator_full_name>Sung Yong Oh</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>biliary tract carcinoma</keyword>
  <keyword>5-FU</keyword>
  <keyword>Irinotecan</keyword>
  <keyword>oxaliplatin</keyword>
  <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>Oxaliplatin</mesh_term>
    <mesh_term>Irinotecan</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/NCT03778593
org study id: GF BTC-2018
nct id: NCT03778593
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Biliary tract cancer (BTC) is rare in the West, but it is relatively high in Asia, including
      Korea. Currently used as the standard primary treatment in metastatic or locally advanced BTC
      is gemcitabine/platinum combination chemotherapy.There is no standard secondary chemotherapy
      recognized after the failure of the gemcitabine/platinum first line treatment. The
      investigators try to evaluate role of 5-FU, leucovorin, irinotecan, and oxaliplatin
      combination chemotherapy (FOLFIRINOX) for the patients who progressed after
      gemcitabine/cisplatin first line chemotherapy.
<Biliary tract cancer> Biliary tract cancer (BTC) is a common term for malignant tumors that
      occur in gallbladder and bile duct, the path in which bile is released. According to the
      anatomical location, biliary tract cancer is divided into intrahepatic cholangiocarcinoma and
      extrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma is classified as
      perihilar cholangiocarcinoma and distal cholangiocarcinoma. Biliary tract cancer is rare in
      the West, but it is relatively high in Asia, including Korea. Biliary tract cancer occurs
      annually in Korea, accounting for about 5,600 cases, 2.4 percent of the total cancer, and
      ranks sixth in deaths from cancer. Biliary tract cancer is a type of cancer that is difficult
      to treat because most patients are diagnosed with progressive diseases that cannot be
      operated. Only about a quarter of patients are diagnosed with surgical-ready conditions as a
      treatment where full surgical operation can be expected to complete, but the five-year
      survival rate for operation is poor at 8-44% due to a high recurrence after surgery.

      <Metastatic or relapsed biliary tract cancer treatment> Chemotherapy is the main treatment in
      BTC, which is relapsed or metastatic status. 5- Fluorouracil (5-FU)-based treatment has been
      shown to improve the survival period for pancreatic and bile cancer patients compared to the
      optimal supportive care (5-FU/leucovorin ± etoposide 6.0 vs. 2.5 months, p <0.01). Also,
      chemotherapy helped maintain the quality of life. The improvement in quality of life over a
      period of at least four months showed a significant difference compared to 10% in the group
      that received only optimal supportive care for 36% of the chemotherapy group. (p < 0.01).
      Currently used as the standard primary treatment in metastatic or locally advanced BTC is
      gemcitabine/platinum combination chemotherapy. In a large phase III study,
      Gemcitabine/cisplatin significantly improved the median value of the progressive free
      survival (PFS) period from 5.0 months to 8.0 months, and the overall survival (OS) period
      from 8.1 months to 11.7 months, compared to the gemcitabine alone. If Cisplatin is not
      available, oxaliplatin can be considered as a merger with gemcitabine. The
      Gemcitabine/oxaliplatin regimen reported in the phase II and phase III studies PFS was
      4.2-5.5 months, median for the OS period was 9.5-12.4 months.

      <Salvage treatment of biliary tract cancer> To date, there is no standard secondary
      chemotherapy recognized after the failure of the gemcitabine/platinum primary treatment.
      Since BTC usually occurs at an advanced age and shows a low frequency of occurrence in the
      West, there are practical limitations to conducting large-scale clinical research. So far,
      there is no large three-phase study proving the benefits of secondary chemotherapy after the
      failure of gemcitabine/platinum chemotherapy. Implementation of secondary chemotherapy in
      actual clinicians is known to vary from country to country, depending on the medical judgment
      of the responsible clinician. In a large-scale retrospective study by the Association des
      Gastro-Enterologies Oncology (AGEO) group in France, 32.5% of the patients were treated with
      second line therapy, and 75% of the patients were reported in Japan. A retrospective study
      and a two-phase study and systematic literature review suggest that there will be a benefit
      from the treatment if second line treatment is selected for patients whose general health is
      relatively well maintained. Results of single or combination therapy using drugs such as
      Irinotecan, oxaliplatin, 5-FU, S-1, and capecitabine were reported in phase II and
      retrospective studies, yielding an average of 3.2 months of PFS, 7.7% of mean response rate,
      and 7.2 months of OS.

      The 5-FU/leucovorin/irinotecan (FOLFIRI) therapy, along with the capecitabine/irinotecan
      therapy, is reported as the most commonly used secondary chemotherapy in the AGEO group in
      France. A treatment strategy for continuous use of FOLFIRI as a secondary treatment after the
      failure of Gemcitabine/oxaliplatin showed the median value for OS period of 21.9 months, and
      the median value for the PFS period. The PFS and OS due to the FOLFIRI was found to be 3.2
      months and 8.4 months, respectively. On the other hand, the FOLFOX therapy, which combines
      oxaliplatin with 5-FU, showed a response rate of 21.6 % when administered as a secondary
      treatment after the failure of gemcitabine/cisplatin, and a median PFS of 3.1 months. A phase
      III study is currently underway that compares the administration of FOLFOX as a secondary
      treatment with the optimum support. In Korea, there is a problem with the standard
      reimbursement for applying to drugs prescribed to cancer patients, and in particular, cancer
      drugs that can be used as secondary therapy in metastatic BTC patients are limited. There is
      a need to improve the prognosis of BTC patients by expanding the use of various drugs that
      have been proven through external clinical research.

      <5-FU, leucovorin, irinotecan, and oxaliplatin combination chemotherapy (FOLFIRINOX) regimen
      for other cancer of BTC> In a pre-clinical experiment, oxaliplatin and irinotecan have
      synergistic effects and are known to have relatively no overlap of toxic effects among, 5-FU,
      leucovorin, irinotecan, and oxaliplatin. The combination treatment of
      5-FU/leukovorin/irinotecan/oxaliplatin (FOLFIRINOX) had a high therapeutic effect on
      progressive pancreatic cancer and colon cancer. In a phase III study comparing FOLFIRINOX and
      gemcitabine as a first line treatment in metastatic pancreatic cancer, the objective response
      rate (32 vs. 9%), PFS (6.4 vs. 3.3 months) and OS (11.1 vs. 6.8 months) were significantly
      higher in FOLFIRINOX. On the other hand, treatment-related toxicities, with a grade 3/4 of
      neutropenia (46 vs. 21%), febrile neutropenia (5.4 vs. 1.2%), thrombocytopenia (9.1 vs.
      3.6%), sensory neuropathy (9 vs. 0%), vomiting (23 vs. 18%), and diarrhea (113 vs. 2%) were
      more common in FOLFIRINOX. In a phase III study comparing the
      5-FU/leukovorin/irinotecan/oxaliplatin(FORFOXRI) and the 5-FU/leukovorin/irinotecan(FORFIRI)
      as a first line treatment in metastatic colorectal cancer, the FORFOXRI group was objective
      response (66 vs. 41 %), the PFS (9.8 vs. 6.9 months) and the OS (2.6 vs. 16.7 months) showed
      significant improvements. In pancreatic cancer, FOLFIRINOX was a treatment that was limited
      in patients with good general condition due to its high level of toxicity, including
      neutropenia, but the dose-reduction proved to be applied not only as a primary treatment but
      also as a secondary treatment. In a phase II study of pancreatic cancer patients in China,
      there was a 29% of grade 3/4 neutropenia were reported due to the treatment of modified
      FOLFIRINOX using oxaliplatin 68 mg/m2, irinotecan 135 mg/m2, and 5-FU injection of 2,400
      mg/m2 for 46 hours, and there was no increase in mortality and febrile neutropenia. Other
      major grade 3 or higher toxicity levels showed improved safety profiles with thrombocytopenia
      (4.8%), anemia (8.1%), infection (4.8%), and elevated liver enzyme (14.5%).

      <Rationale of this trial>

      As a 2nd line treatment for metastatic BTC the assessment of modified FOLFIRINOX is supported
      by:

        -  The prognosis for metastatic BTC, which fails first line therapy, is poor and has no
           standardized treatment. Therefore, better treatment modalities are required to improve
           the survival of patients who no longer respond to first line treatment and to maintain
           the quality of life.

        -  Treatments that use irinotecan or oxaliplatin as secondary therapy for metastatic BTC
           have been shown in retrospective and phase II studies and are actually used in clinical
           practice of other countries.

        -  Oxaliplatin and irinotecan have synergistic effects and the FOLFIRINOX therapy, which
           uses both drugs together in 5-FU/leucovorin, has been shown to increase efficacy in
           pancreatic and colon cancer.

        -  The modified FOLFIRINOX, which was used with reduced dosage, indicates an acceptable
           toxic profile while maintaining its efficacy
allocation: N/A
intervention model: Single Group Assignment
intervention model description: mFOLFIRINOX (5-FU, Irinotecan, oxaliplatin, Leucovorin)
primary purpose: Treatment
masking: None (Open Label)
measure: Response rate of treated participants
time frame: up to 6 months
description: Rate of response including complete response and partial response by treatment. Response will be evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
measure: Progression free survival (PFS) duration of treated participants
time frame: up to 12 months
description: duration measure from treatment day to progression + death events. Calculated by Kaplan-Meier survival analysis.
measure: Overall survival (OS) duration of treated participants
time frame: up to 12 months
description: duration measure from treatment day to death events. Calculated by Kaplan-Meier survival analysis.
measure: Incidence of Treatment-Emergent Adverse Events of participants
time frame: up to 12 months
description: all adverse events during treatment. Evaluated with National Cancer Institute(NCI)-] Common Terminology Criteria for Adverse Events (CTCAE) v4.03
measure: EORTC -QoL-C30
time frame: up to 12 months
description: Evaluate patients' life quality evaluation during treatment every 2 months with questionaires.
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (EORTC QOL-C30) will be used.
arm group label: mFOLFIRINOX
arm group type: Experimental
description: D1 Oxaliplatin 65 mg/m2 + 5% dextrose water (5DW) 200 mL mix IV over 2 hours followed by, D1 Leucovorin 400 mg/m2 + 5DW 200 ml mix IV over 2 hours D1 Irinotecan 135 mg/m2 + 5DW 500 mL mix IV over 2 hours (concurrent with the leucovorin infusion) D1-2 5-Fluorouracil 1000 mg/m2 + 5DW 1 liter (1L) continuous IV over 23 hours repeat every 2 weeks
intervention type: Drug
intervention name: 5-Fluorouracil
description: D1-2 5-Fluorouracil 1000 mg/m2 + 5DW 1L continuous IV over 23 hours q 2 weeks
arm group label: mFOLFIRINOX
intervention type: Drug
intervention name: Leucovorin
description: D1 Leucovorin 400 mg/m2 + 5DW 200 ml mix IV over 2 hours q 2 weeks
arm group label: mFOLFIRINOX
intervention type: Drug
intervention name: Irinotecan
description: D1 Irinotecan 135 mg/m2 + 5DW 500 mL mix IV over 2 hours (concurrent with the leucovorin infusion) q 2weeks
arm group label: mFOLFIRINOX
intervention type: Drug
intervention name: Oxaliplatin
description: D1 Oxaliplatin 65 mg/m2 + 5DW 200 mL mix IV over 2 hours q 2 weeks
arm group label: mFOLFIRINOX
intervention type: Drug
intervention name: 5% dextrose water
description: mix fluid with 5-FU, leucovorin, irinotecan, and oxaliplatin
arm group label: mFOLFIRINOX
other name: 5DW
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Sung Yong Oh, M.D.
role: Principal Investigator
affiliation: Dong-A University Hospital
facility: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Dong-A University Hospital
investigator full name: Sung Yong Oh
investigator title: Associate Professor
mesh term: Biliary Tract Neoplasms
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Irinotecan
sharing ipd: No