<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/NCT01713387</url>
  </required_header>
  <id_info>
    <org_study_id>KHBO1202</org_study_id>
    <secondary_id>UMIN000007454</secondary_id>
    <nct_id>NCT01713387</nct_id>
  </id_info>
  <brief_title>A Phase I Study of Adjuvant Chemotherapy With GS in Biliary Tract Cancer Undergoing Resection Without Major Hepatectomy</brief_title>
  <official_title>A Phase I Study of Adjuvant Chemotherapy With Gemcitabine Plus S-1 in Patients With Biliary Tract Cancer Undergoing Curative Resection Without Major Hepatectomy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kansai Hepatobiliary Oncology Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Kansai Hepatobiliary Oncology Group</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To decide maximum tolerated dose and recommended dose of treatment using gemcitabine plus S-1&#xD;
      combination therapy in patients with biliary tract cancer undergoing resection without major&#xD;
      hepatectomy&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Surgery currently remains the only potentially curative treatment for biliary tract cancer&#xD;
      (BTC), and most patients develop recurrence. Therefore, effective adjuvant chemotherapy is&#xD;
      required to increase the curability of surgery and to prolong the survival in these patients.&#xD;
      However, to date, no standard adjuvant chemotherapy has been established, and a guideline for&#xD;
      BTC treatment recommends that trials of adjuvant chemotherapy be carried out.&#xD;
&#xD;
      Recently, there are two reports about gemcitabine (GEM) + S-1 combination (GS)chemotherapy&#xD;
      after surgical resection for patients with BTC. At Iwate Medical University, Takahara, et&#xD;
      al., performed a phase I study using a regimen of repeating 28 days as 1 course. Patients&#xD;
      received GEM on day 1 and day 15, and S-1 from day 1 to day 14. The recommended dose is 1,000&#xD;
      mg/m² of GEM and S-1 80 mg/m² after a pancreatoduodenectomy. The 2-year survival rate of the&#xD;
      34 patients that received the GS therapy was 78.6% (Cancer Chemother Pharmacol. 2012&#xD;
      May;69(5):1127-33). At Hiroshima University, a cycle of chemotherapy consisted of intravenous&#xD;
      GEM of 700 mg/m² on day 1 and oral S-1 of 50 mg/m² for 7 consecutive days, followed by a&#xD;
      1-week break from chemotherapy (14days as 1 course). Fifty patients received GS therapy and&#xD;
      had a significantly better 3-year survival rate (57%) compared with 53 cases of surgery alone&#xD;
      (30%). The GS adjuvant chemotherapy was feasible and the adverse event was minimal (Ann Surg.&#xD;
      2009 Dec;250(6):950-6).&#xD;
&#xD;
      Thus, the regimens of these two studies were 14 or 28 days as 1 course. There was no regimen&#xD;
      that consisted of GEM on day 1, 8 and S-1 for 14 consecutive days, followed by a 1-week break&#xD;
      from chemotherapy (21days as 1 course), which is frequently used for unresectable BTC and&#xD;
      pancreatic cancer.&#xD;
&#xD;
      Though a hepatectomy is frequently performed during surgery for BTC, it is unclear if the&#xD;
      effect of the anticancer agent is affected by a hepatectomy. Because GEM is metabolized by&#xD;
      cytidine deaminase primarily in the liver, the ability to metabolize GEM after a hepatectomy&#xD;
      is thought to decrease. Some clinical studies demonstrated that patients who had undergone a&#xD;
      hepatectomy could not tolerate the standard dose and schedule of GEM. For adjuvant&#xD;
      chemotherapy with GEM, it is necessary to separately examine whether or not the patient has&#xD;
      undergone a hepatectomy.&#xD;
&#xD;
      Considering these present conditions, we aimed to assess the safety and efficacy of GEM + S-1&#xD;
      combination chemotherapy (21days as 1 course regimen, which is frequently used for&#xD;
      unresectable BTC) for BTC with the patients undergoing curative resection without a&#xD;
      hepatectomy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 2012</start_date>
  <completion_date type="Actual">March 2017</completion_date>
  <primary_completion_date type="Actual">April 2015</primary_completion_date>
  <phase>Phase 1</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>Maximum tolerated dose</measure>
    <time_frame>6 weeks</time_frame>
    <description>To establish the maximum tolerated dose of gemcitabine plus S-1 in patients with biliary tract cancer undergoing curative resection without major hepatectomy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with dose limiting toxicity</measure>
    <time_frame>At the end of adjuvant chemotherapy (6 months)</time_frame>
    <description>Dose limiting toxicity is defined as follows&#xD;
Grade 4 neutropenia, thrombocytopenia&#xD;
Grade 3 or 4 febrile neutropenia&#xD;
Grade 3 or 4 non-hematological adverse events unless unresponsive to treatment&#xD;
Any adverse events resulting in interruption of dosing on day 8 in both the two courses&#xD;
Any adverse events resulting in dose modification or delay of longer than 2 weeks</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">38</enrollment>
  <condition>Biliary Tract Cancer</condition>
  <arm_group>
    <arm_group_label>gemcitabine , S-1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Level-2 Gem 800mg/msq, S-1 50mg/msq Level-1 Gem 800mg/msq, S-1 65mg/msq Level 1 Gem 1000mg/msq, S-1 65mg/msq Level 2 Gem 800mg/msq, S-1 80mg/msq</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine, S-1</intervention_name>
    <description>Dose of gemcitabine and S-1 and treatment schedule</description>
    <arm_group_label>gemcitabine , S-1</arm_group_label>
    <other_name>Gemcitabine;gemzer , S-1;TS-1</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Biliary tract cancer (BTC) with more than stage IB&#xD;
&#xD;
          2. BTC undergoing R0 or R1 resection without major hepatectomy&#xD;
&#xD;
          3. Older than 20 years old&#xD;
&#xD;
          4. PS 0 or 1&#xD;
&#xD;
          5. No treatment other than surgery&#xD;
&#xD;
          6. No dysfunction of main organs&#xD;
&#xD;
          7. Possible oral intake&#xD;
&#xD;
          8. Treatment start; after 4 weeks and within 12 weeks after surgery&#xD;
&#xD;
          9. Obtained written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with resection of major hepatectomy&#xD;
&#xD;
          2. Patients with double cancers&#xD;
&#xD;
          3. Patients having severe allergy&#xD;
&#xD;
          4. Patients with severe organ dysfunction&#xD;
&#xD;
          5. Patients with active infectious disease&#xD;
&#xD;
          6. Pregnancy&#xD;
&#xD;
          7. Patients with severe psychological disease&#xD;
&#xD;
          8. Patients seem inadequate for this study by investigators&#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>Hideyoshi Toyokawa, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Kansai Medical University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kansai Medical University</name>
      <address>
        <city>Hirakata</city>
        <state>Osaka</state>
        <zip>573-1191</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>September 18, 2012</study_first_submitted>
  <study_first_submitted_qc>October 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>October 5, 2017</last_update_submitted>
  <last_update_submitted_qc>October 5, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 9, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>adjuvant chemotherapy</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>Gemcitabine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01713387
org study id: KHBO1202
secondary id: UMIN000007454
nct id: NCT01713387
lead sponsor: 
has dmc: Yes
To decide maximum tolerated dose and recommended dose of treatment using gemcitabine plus S-1
      combination therapy in patients with biliary tract cancer undergoing resection without major
      hepatectomy
Surgery currently remains the only potentially curative treatment for biliary tract cancer
      (BTC), and most patients develop recurrence. Therefore, effective adjuvant chemotherapy is
      required to increase the curability of surgery and to prolong the survival in these patients.
      However, to date, no standard adjuvant chemotherapy has been established, and a guideline for
      BTC treatment recommends that trials of adjuvant chemotherapy be carried out.

      Recently, there are two reports about gemcitabine (GEM) + S-1 combination (GS)chemotherapy
      after surgical resection for patients with BTC. At Iwate Medical University, Takahara, et
      al., performed a phase I study using a regimen of repeating 28 days as 1 course. Patients
      received GEM on day 1 and day 15, and S-1 from day 1 to day 14. The recommended dose is 1,000
      mg/m² of GEM and S-1 80 mg/m² after a pancreatoduodenectomy. The 2-year survival rate of the
      34 patients that received the GS therapy was 78.6% (Cancer Chemother Pharmacol. 2012
      May;69(5):1127-33). At Hiroshima University, a cycle of chemotherapy consisted of intravenous
      GEM of 700 mg/m² on day 1 and oral S-1 of 50 mg/m² for 7 consecutive days, followed by a
      1-week break from chemotherapy (14days as 1 course). Fifty patients received GS therapy and
      had a significantly better 3-year survival rate (57%) compared with 53 cases of surgery alone
      (30%). The GS adjuvant chemotherapy was feasible and the adverse event was minimal (Ann Surg.
      2009 Dec;250(6):950-6).

      Thus, the regimens of these two studies were 14 or 28 days as 1 course. There was no regimen
      that consisted of GEM on day 1, 8 and S-1 for 14 consecutive days, followed by a 1-week break
      from chemotherapy (21days as 1 course), which is frequently used for unresectable BTC and
      pancreatic cancer.

      Though a hepatectomy is frequently performed during surgery for BTC, it is unclear if the
      effect of the anticancer agent is affected by a hepatectomy. Because GEM is metabolized by
      cytidine deaminase primarily in the liver, the ability to metabolize GEM after a hepatectomy
      is thought to decrease. Some clinical studies demonstrated that patients who had undergone a
      hepatectomy could not tolerate the standard dose and schedule of GEM. For adjuvant
      chemotherapy with GEM, it is necessary to separately examine whether or not the patient has
      undergone a hepatectomy.

      Considering these present conditions, we aimed to assess the safety and efficacy of GEM + S-1
      combination chemotherapy (21days as 1 course regimen, which is frequently used for
      unresectable BTC) for BTC with the patients undergoing curative resection without a
      hepatectomy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose
time frame: 6 weeks
description: To establish the maximum tolerated dose of gemcitabine plus S-1 in patients with biliary tract cancer undergoing curative resection without major hepatectomy
measure: Number of Participants with dose limiting toxicity
time frame: At the end of adjuvant chemotherapy (6 months)
description: Dose limiting toxicity is defined as follows
Grade 4 neutropenia, thrombocytopenia
Grade 3 or 4 febrile neutropenia
Grade 3 or 4 non-hematological adverse events unless unresponsive to treatment
Any adverse events resulting in interruption of dosing on day 8 in both the two courses
Any adverse events resulting in dose modification or delay of longer than 2 weeks
arm group label: gemcitabine , S-1
arm group type: Experimental
description: Level-2 Gem 800mg/msq, S-1 50mg/msq Level-1 Gem 800mg/msq, S-1 65mg/msq Level 1 Gem 1000mg/msq, S-1 65mg/msq Level 2 Gem 800mg/msq, S-1 80mg/msq
intervention type: Drug
intervention name: Gemcitabine, S-1
description: Dose of gemcitabine and S-1 and treatment schedule
arm group label: gemcitabine , S-1
other name: Gemcitabine;gemzer , S-1;TS-1
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Hideyoshi Toyokawa, MD, PhD
role: Study Director
affiliation: Kansai Medical University
facility: 
country: Japan
responsible party type: Sponsor
mesh term: Biliary Tract Neoplasms
mesh term: Gemcitabine