<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/NCT02246049</url>
  </required_header>
  <id_info>
    <org_study_id>QUATTRO</org_study_id>
    <nct_id>NCT02246049</nct_id>
  </id_info>
  <brief_title>A Multicenter, Clinical Study of FOLFOXIRI With Bevacizumab As First-line Therapy in Patients With mCRC</brief_title>
  <acronym>QUATTRO</acronym>
  <official_title>A Multicenter, Clinical Phase II Study of FOLFOXIRI With Bevacizumab As First-line Therapy in Patients With Metastatic Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>EPS Corporation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>EPS Corporation</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study to assess efficacy and tolerability of combination therapy&#xD;
      FOLFOXIRI with Bevacizumab (BV) as a first-line therapy in patients with metastatic&#xD;
      colorectal cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a single-arm, multicentre phase II study evaluating the efficacy and safety of&#xD;
      Bevacizumab (BV) in combination with oxaliplatin, irinotecan hydrochloride, fluorouracil, and&#xD;
      leucovorin calcium regimen ( FOLFOXIRI +BV ; Falcone et al. ASCO2013) as first-line treatment&#xD;
      for Japanese metastatic colorectal cancer patients.&#xD;
&#xD;
      This study is composed two steps because of collecting safety issue in Japanese patient.&#xD;
&#xD;
      As First step (Step 1), It assess on the initial safety information in ten Japanese patients&#xD;
      of the end of 2nd cycle. it is evaluated by DMC.&#xD;
&#xD;
      In parallel with the confirmation of the initial safety issue, register up to 65 cases in&#xD;
      total and Step 1 patient, to evaluate the efficacy and safety (Step2).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2014</start_date>
  <completion_date type="Actual">February 2017</completion_date>
  <primary_completion_date type="Actual">February 2017</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>Progression-free survival (PFS) at 10 months</measure>
    <time_frame>PFS rate at 10 months from study entry</time_frame>
    <description>PFS by investigator-reported measurements according to CT image. PFS was calculated from the day of treatment start to the first observation of progression disease (PD) or death from any cause.&#xD;
PD was defined as Overall Response by RECIST criteria v1.1 according to CT image.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response rate (RR) by central review.</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>Response evaluation was performed according to RECIST criteria v1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rate (RR) by investigator-reported measurements.</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>Response evaluation was performed according to RECIST criteria v1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PFS by central review according to CT image.</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>PFS was calculated from the day of treatment start to the first observation of progression disease (PD) or death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>OS was calculated from the day of registration in this study to death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy by RAS status ; RR,PFS,OS</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>RR,PFS,OS according to tumor RAS status.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Up to 30 months</time_frame>
    <description>Adverse events were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All adverse events was collected in duration from starting treatment to whichever shorter &quot;after 30 days from withdrawal treatment&quot; or &quot;later treatment was started&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to treatment-failure</measure>
    <time_frame>Up to 30 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Completion rate in Induction treatment</measure>
    <time_frame>Up to 30 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relative Dose Intensity</measure>
    <time_frame>Up to 30 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment duration</measure>
    <time_frame>Up to 30 months</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">69</enrollment>
  <condition>Colorectal Neoplasms</condition>
  <arm_group>
    <arm_group_label>FOLFOXIRI plus bevacizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Induction therapy is followed by the maintenance therapy.&#xD;
[Induction treatment:FOLFOXIRI plus bevacizumab] Administered for a maximum of 12 cycles. BV: 5mg/kg (d.i.v.) L-OHP: 85 mg/sq.m (d.i.v.) CPT-11:165mg/sq.m (d.i.v.) l-LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks.&#xD;
[Maintenance treatment:5-FU / I-LV plus bevacizumab] BV:5mg/kg (d.i.v.) l-LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>FOLFOXIRI plus bevacizumab</arm_group_label>
    <other_name>BV</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-fluorouracil</intervention_name>
    <description>Given IV</description>
    <arm_group_label>FOLFOXIRI plus bevacizumab</arm_group_label>
    <other_name>5-FU</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan hydrochloride</intervention_name>
    <description>Given IV</description>
    <arm_group_label>FOLFOXIRI plus bevacizumab</arm_group_label>
    <other_name>CPT-11</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin calcium</intervention_name>
    <description>Given IV</description>
    <arm_group_label>FOLFOXIRI plus bevacizumab</arm_group_label>
    <other_name>I-LV</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>FOLFOXIRI plus bevacizumab</arm_group_label>
    <other_name>L-OHP</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written Informed consent.&#xD;
&#xD;
          2. Histopathologically proven diagnosis of colorectal cancer (adenocarcinoma) excluding&#xD;
             vermiform appendix cancer and proctos cancer.&#xD;
&#xD;
          3. Not resectable metastatic colorectal cancer&#xD;
&#xD;
          4. Age at enrollment is &gt;= 20 and &lt;= 75 years&#xD;
&#xD;
          5. ECOG PS &lt; 2 if age &lt; 70 years, ECOG PS = 0 if age = 71-75 years&#xD;
&#xD;
          6. One or more measurable lesion in RECIST ver.1.1 criteria according to contrast&#xD;
             enhanced CT chest / abdomen / pelvis diagnosis.&#xD;
&#xD;
          7. Not previously treated with chemotherapy. ( Previous adjuvant by fluoropyrimidine&#xD;
             monotherapy is allowed if more than 24 weeks have elapsed between the end of adjuvant&#xD;
             therapy and first relapse.)&#xD;
&#xD;
          8. Vital organ functions (listed below) are preserved within 2 weeks prior to entry. Data&#xD;
             recorded nearest to the entry should be referred. Blood transfusion or erythropoiesis&#xD;
             stimulating agents less than 2 weeks prior to the tests are not allowed.&#xD;
&#xD;
             Neu. &gt;= 1,500/cubicmillimeter Pt. &gt;= 100,000/cubicmillimeter Hb. &gt;= 9.0 g/dL T-bil. &lt;=&#xD;
             upper limit of normal (ULN)*1.5 AST and ALT,ALP &lt;= upper limit of normal (ULN)*2.5 (&lt;=&#xD;
             ULN*5 in case of liver metastasis) Serum creatinine &lt;= upper limit of normal (ULN)&#xD;
             *1.5 PT-INR &lt; 1.5 Proteinuria &lt;= 2+&#xD;
&#xD;
          9. UGT1A1 genotype tested. Categorized into Wild or single Hetero.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previously treated with irradiation to bone marrow constituting 20% or more of&#xD;
             irradiation field.&#xD;
&#xD;
          2. Untreated brain metastases or spinal cord compression or primary brain tumors.&#xD;
&#xD;
          3. History of CNS disease.[except for asymptomatic Lacunar stroke]&#xD;
&#xD;
          4. Requiring chronic systemic corticosteroid treatment.&#xD;
&#xD;
          5. Current or recent ongoing treatment with anticoagulants.&#xD;
&#xD;
          6. Clinically significant cardiovascular disease for example cerebrovascular accidents,&#xD;
             myocardial infarction, unstable angina, congestive heart failure, serious cardiac&#xD;
             arrhythmia requiring medication.&#xD;
&#xD;
          7. Treatment with any investigational drug within 4 weeks.&#xD;
&#xD;
          8. Patient with Uncontrolled hypertension, Uncontrolled diabetes, Uncontrolled diarrhea,&#xD;
             &gt;=grade 1 peripheral neuropathy, Active peptic ulcer, Non-healing wound, Clinically&#xD;
             important diseases.&#xD;
&#xD;
          9. Major surgical procedure within 28 days prior to study treatment start, open biopsy,&#xD;
             or significant traumatic injury, or anticipation of the need for major surgical&#xD;
             procedure.[except for implantation of central venous catheter and port system.]&#xD;
&#xD;
         10. Lack of physical integrity of the upper gastrointestinal tract.&#xD;
&#xD;
         11. Pregnant women, lactating woman , positive by pregnancy test , wishing to become&#xD;
             pregnant, and Sexually active males.&#xD;
&#xD;
         12. Hepatitis B or hepatitis C. Evidence of HIV infection.&#xD;
&#xD;
         13. Previous Chemotherapy for other organs.&#xD;
&#xD;
         14. Other active co-existing malignancies.&#xD;
&#xD;
         15. History / Presence of thrombosis within 1 year requiring medication.&#xD;
&#xD;
         16. History / Presence of paralytic ileus, obstruction or gastrointestinal perforation.&#xD;
&#xD;
         17. Malignant coelomic fluid required drainage.&#xD;
&#xD;
         18. History of allergy to Chinese hamster ovary cell proteins, or any of the components of&#xD;
             the study medications.&#xD;
&#xD;
         19. History of fluoropyrimidine severe side effects caused by DPD defect.&#xD;
&#xD;
         20. Interstitial pneumonitis or pulmonary fibrosis.&#xD;
&#xD;
         21. Evidence or requiring systemic treatment for Infectious disease.&#xD;
&#xD;
         22. Patient who is judged by the investigator to be inappropriate for study participation&#xD;
             for any reason.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Takeshi Kato, M.D., Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Surgery, National Hospital Organization Osaka National Hospital.</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Akiyoshi Kanazawa, M.D., Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Surgery, Shimane Prefectural Central Hospital.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>EPS Corporation</name>
      <address>
        <city>Shinjuku</city>
        <state>Tokyo</state>
        <zip>162-0814</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>June 2017</verification_date>
  <study_first_submitted>September 12, 2014</study_first_submitted>
  <study_first_submitted_qc>September 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 22, 2014</study_first_posted>
  <last_update_submitted>June 15, 2017</last_update_submitted>
  <last_update_submitted_qc>June 15, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Metastatic colorectal cancer, bevacizumab, FOLFOXIRI</keyword>
  <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>Bevacizumab</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
    <mesh_term>Calcium</mesh_term>
    <mesh_term>Levoleucovorin</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/NCT02246049
org study id: QUATTRO
nct id: NCT02246049
lead sponsor: 
has dmc: Yes
The purpose of this study to assess efficacy and tolerability of combination therapy
      FOLFOXIRI with Bevacizumab (BV) as a first-line therapy in patients with metastatic
      colorectal cancer.
This is a single-arm, multicentre phase II study evaluating the efficacy and safety of
      Bevacizumab (BV) in combination with oxaliplatin, irinotecan hydrochloride, fluorouracil, and
      leucovorin calcium regimen ( FOLFOXIRI +BV ; Falcone et al. ASCO2013) as first-line treatment
      for Japanese metastatic colorectal cancer patients.

      This study is composed two steps because of collecting safety issue in Japanese patient.

      As First step (Step 1), It assess on the initial safety information in ten Japanese patients
      of the end of 2nd cycle. it is evaluated by DMC.

      In parallel with the confirmation of the initial safety issue, register up to 65 cases in
      total and Step 1 patient, to evaluate the efficacy and safety (Step2).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free survival (PFS) at 10 months
time frame: PFS rate at 10 months from study entry
description: PFS by investigator-reported measurements according to CT image. PFS was calculated from the day of treatment start to the first observation of progression disease (PD) or death from any cause.
PD was defined as Overall Response by RECIST criteria v1.1 according to CT image.
measure: Response rate (RR) by central review.
time frame: Up to 18 months
description: Response evaluation was performed according to RECIST criteria v1.1.
measure: Response rate (RR) by investigator-reported measurements.
time frame: Up to 30 months
description: Response evaluation was performed according to RECIST criteria v1.1.
measure: PFS by central review according to CT image.
time frame: Up to 18 months
description: PFS was calculated from the day of treatment start to the first observation of progression disease (PD) or death from any cause.
measure: Overall survival (OS)
time frame: Up to 30 months
description: OS was calculated from the day of registration in this study to death from any cause.
measure: Efficacy by RAS status ; RR,PFS,OS
time frame: Up to 30 months
description: RR,PFS,OS according to tumor RAS status.
measure: Incidence of adverse events
time frame: Up to 30 months
description: Adverse events were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All adverse events was collected in duration from starting treatment to whichever shorter "after 30 days from withdrawal treatment" or "later treatment was started".
measure: Time to treatment-failure
time frame: Up to 30 months
measure: Completion rate in Induction treatment
time frame: Up to 30 months
measure: Relative Dose Intensity
time frame: Up to 30 months
measure: Treatment duration
time frame: Up to 30 months
arm group label: FOLFOXIRI plus bevacizumab
arm group type: Experimental
description: Induction therapy is followed by the maintenance therapy.
[Induction treatment:FOLFOXIRI plus bevacizumab] Administered for a maximum of 12 cycles. BV: 5mg/kg (d.i.v.) L-OHP: 85 mg/sq.m (d.i.v.) CPT-11:165mg/sq.m (d.i.v.) l-LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks.
[Maintenance treatment:5-FU / I-LV plus bevacizumab] BV:5mg/kg (d.i.v.) l-LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks.
intervention type: Biological
intervention name: Bevacizumab
description: Given IV
arm group label: FOLFOXIRI plus bevacizumab
other name: BV
intervention type: Drug
intervention name: 5-fluorouracil
description: Given IV
arm group label: FOLFOXIRI plus bevacizumab
other name: 5-FU
intervention type: Drug
intervention name: Irinotecan hydrochloride
description: Given IV
arm group label: FOLFOXIRI plus bevacizumab
other name: CPT-11
intervention type: Drug
intervention name: Leucovorin calcium
description: Given IV
arm group label: FOLFOXIRI plus bevacizumab
other name: I-LV
intervention type: Drug
intervention name: Oxaliplatin
description: Given IV
arm group label: FOLFOXIRI plus bevacizumab
other name: L-OHP
criteria: 
gender: All
minimum age: 20 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Takeshi Kato, M.D., Ph.D
role: Principal Investigator
affiliation: Department of Surgery, National Hospital Organization Osaka National Hospital.
last name: Akiyoshi Kanazawa, M.D., Ph.D
role: Principal Investigator
affiliation: Department of Surgery, Shimane Prefectural Central Hospital.
facility: 
country: Japan
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Leucovorin
mesh term: Bevacizumab
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Irinotecan
mesh term: Calcium
mesh term: Levoleucovorin