<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/NCT01666730</url>
  </required_header>
  <id_info>
    <org_study_id>CASE1212</org_study_id>
    <nct_id>NCT01666730</nct_id>
  </id_info>
  <brief_title>Metformin Plus Modified FOLFOX 6 in Metastatic Pancreatic Cancer</brief_title>
  <official_title>A Phase II Study of Metformin Plus Modified FOLFOX 6 in Patients With Metastatic Pancreatic Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Case Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Case Comprehensive Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well metformin hydrochloride, leucovorin calcium,&#xD;
      fluorouracil, and oxaliplatin work in treating patients with metastatic pancreatic cancer.&#xD;
      Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes&#xD;
      needed for cell growth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil,&#xD;
      and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing&#xD;
      the cells or by stopping them from dividing. Giving metformin hydrochloride together with&#xD;
      combination chemotherapy may kill more tumor cells&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine if metformin (metformin hydrochloride) when added to FOLFOX ( leucovorin&#xD;
      calcium, fluorouracil, oxaliplatin) improves overall survival in patients with metastatic&#xD;
      pancreatic cancer.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess response rate (RR). II. To assess progression free survival (PFS). III. To&#xD;
      assess toxicity in patients with metastatic pancreatic cancer receiving FOLFOX and metformin.&#xD;
      IV. To identify tumor/serum correlative markers.&#xD;
&#xD;
      OUTLINE: Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-7&#xD;
      for an introductory period before the addition of FOLFOX. After the introductory period,&#xD;
      patients will continue metformin twice daily and FOLFOX therapy comprising leucovorin calcium&#xD;
      intravenously (IV) over 120 minutes, fluorouracil IV continuously over 46 hours, and&#xD;
      oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of&#xD;
      disease progression or unacceptable toxicity. After completion of study treatment, patients&#xD;
      are followed up for periodically.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 21, 2013</start_date>
  <completion_date type="Actual">August 1, 2018</completion_date>
  <primary_completion_date type="Actual">August 1, 2018</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>Median Overall Survival (OS)</measure>
    <time_frame>Time from first day of treatment to death from any cause, assessed up to 1 year</time_frame>
    <description>Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response Rate (RR) Objective Tumor Response Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to Response Evaluation Criteria in Solid Tumors (RECIST)</measure>
    <time_frame>1 year</time_frame>
    <description>CBR is the number of participants of the total analysis population who experience confirmed complete (CR) or partial response (PR) per RECIST&#xD;
CR = all detectable tumor has disappeared PR = a &gt;=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum Stable Disease (SD) = small changes that do not meet previously given criteria. Progressive disease (PD) = a &gt;=20% increase in target lesions&#xD;
The true response rate of the combination therapy for this patient population will be estimated based on the number of response using a binomial distribution and its confidence intervals will be estimated using Wilson's method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR) Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to RECIST</measure>
    <time_frame>1 year</time_frame>
    <description>CBR is the number of participants of the total analysis population who experience a CR, PR, or SD per RECIST&#xD;
CR = all detectable tumor has disappeared PR = a &gt;=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum SD = small changes that do not meet previously given criteria. PD = a &gt;=20% increase in target lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival According to RECIST 1.1 Criteria</measure>
    <time_frame>Time from first day of treatment received to the earlier documented disease progression or death from any cause, assessed up to 1 year</time_frame>
    <description>Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Grade 3 and 4 Toxicities According to NCI CTCAE Version 4.0</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>The toxicity profile of the combination will be tabulated.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Acinar Cell Adenocarcinoma of the Pancreas</condition>
  <condition>Duct Cell Adenocarcinoma of the Pancreas</condition>
  <condition>Recurrent Pancreatic Cancer</condition>
  <condition>Stage IV Pancreatic Cancer</condition>
  <arm_group>
    <arm_group_label>Treatment (metformin hydrochloride, FOLFOX)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>metformin hydrochloride</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (metformin hydrochloride, FOLFOX)</arm_group_label>
    <other_name>Glucophage</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>oxaliplatin</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (metformin hydrochloride, FOLFOX)</arm_group_label>
    <other_name>1-OHP</other_name>
    <other_name>Dacotin</other_name>
    <other_name>Dacplat</other_name>
    <other_name>Eloxatin</other_name>
    <other_name>L-OHP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>leucovorin calcium</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (metformin hydrochloride, FOLFOX)</arm_group_label>
    <other_name>CF</other_name>
    <other_name>CFR</other_name>
    <other_name>LV</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>fluorouracil</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (metformin hydrochloride, FOLFOX)</arm_group_label>
    <other_name>5-fluorouracil</other_name>
    <other_name>5-Fluracil</other_name>
    <other_name>5-FU</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (metformin hydrochloride, FOLFOX)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed metastatic pancreatic&#xD;
             adenocarcinoma (or any mixed pathology if adenocarcinoma is predominant)&#xD;
&#xD;
          -  Patients must have measurable disease, defined as at least one lesion that can be&#xD;
             accurately measured in at least one dimension (longest diameter to be recorded) as &gt;&#xD;
             20 mm with conventional techniques or as &gt; 10 mm with spiral computed tomography (CT)&#xD;
             scan&#xD;
&#xD;
          -  Patient must have not received systemic chemotherapy for metastatic disease; prior&#xD;
             chemotherapy, radiation therapy, concurrent chemoradiation are allowed if used for&#xD;
             treatment of non-metastatic disease; prior palliative radiation for symptom management&#xD;
             is allowed; any chemotherapy must have been completed 4 weeks prior to enrollment; any&#xD;
             radiotherapy must have been completed 2 weeks prior to enrollment&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 1,500/L&#xD;
&#xD;
          -  Platelets ≥ 100,000/L&#xD;
&#xD;
          -  Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
          -  Total bilirubin ≤ 2 mg/dL&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT]/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) ≤&#xD;
             2.5 x institutional upper limit of normal&#xD;
&#xD;
          -  Creatinine ≤ 1.5&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception&#xD;
             (double barrier method of birth control or abstinence) prior to study entry and for&#xD;
             the duration of study participation; should a woman become pregnant or suspect that&#xD;
             she is pregnant while she or her partner is participating in this study, she should&#xD;
             inform the treating physician immediately&#xD;
&#xD;
          -  Subjects must have the ability to understand and the willingness to sign a written&#xD;
             informed consent document&#xD;
&#xD;
          -  Patients with diabetes are eligible for this trial; all diabetic patients who are&#xD;
             enrolled on this study should discuss the need to change their diabetes management&#xD;
             regimen with their primary care physician or endocrinologist prior to enrollment&#xD;
&#xD;
          -  Diabetic patients who are on metformin are eligible as long as they have been on&#xD;
             metformin for less than 6 months (estimated 6 months or less duration of metformin&#xD;
             therapy from start of metformin to enrollment on study)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Chemotherapy within 4 weeks prior to entering the study, radiotherapy within 2 weeks&#xD;
             prior to entering the study or failure to recover from adverse events due to agents&#xD;
             administered more than 4 weeks earlier&#xD;
&#xD;
          -  Prior treatment toxicities must be resolved to ≤ grade 1 according to National Cancer&#xD;
             Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0&#xD;
&#xD;
          -  Current use of metformin for more than 6 months prior to enrollment on study&#xD;
&#xD;
          -  Use of any other investigational agents&#xD;
&#xD;
          -  Patients with untreated brain metastases should be excluded from this clinical trial&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or&#xD;
             biological composition to metformin or oxaliplatin or fluorouracil (5-FU)&#xD;
&#xD;
          -  Active second primary malignancy or history of second primary malignancy within the&#xD;
             last 3 years, with the exception of basal cell skin cancers or carcinoma in situ that&#xD;
             have been adequately treated&#xD;
&#xD;
          -  Patients with uncontrolled intercurrent illness including, but not limited to ongoing&#xD;
             or active infection, symptomatic congestive heart failure, unstable angina pectoris,&#xD;
             cardiac arrhythmia, or psychiatric illness/social situations that would limit&#xD;
             compliance with study requirements&#xD;
&#xD;
          -  Pregnant or nursing women&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients&#xD;
&#xD;
          -  Chronic or planned acute alcohol use of three or more drinks per day&#xD;
&#xD;
          -  Metabolic acidosis, acute or chronic, including ketoacidosis&#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>David Bajor, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2021</verification_date>
  <study_first_submitted>August 14, 2012</study_first_submitted>
  <study_first_submitted_qc>August 14, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 16, 2012</study_first_posted>
  <results_first_submitted>June 21, 2021</results_first_submitted>
  <results_first_submitted_qc>August 9, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">August 10, 2021</results_first_posted>
  <last_update_submitted>August 9, 2021</last_update_submitted>
  <last_update_submitted_qc>August 9, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 10, 2021</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>Adenocarcinoma</mesh_term>
    <mesh_term>Pancreatic Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Acinar Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Calcium</mesh_term>
    <mesh_term>Levoleucovorin</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 23, 2015</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/30/NCT01666730/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 4, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/30/NCT01666730/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
          <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Disease progression/relapse</title>
              <participants_list>
                <participants group_id="P1" count="18"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Participants enrolled in study</population>
      <group_list>
        <group group_id="B1">
          <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
          <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="50"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Median Overall Survival (OS)</title>
        <description>Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.</description>
        <time_frame>Time from first day of treatment to death from any cause, assessed up to 1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
            <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Median Overall Survival (OS)</title>
          <description>Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.</description>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.1" lower_limit="5.0" upper_limit="9.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response Rate (RR) Objective Tumor Response Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to Response Evaluation Criteria in Solid Tumors (RECIST)</title>
        <description>CBR is the number of participants of the total analysis population who experience confirmed complete (CR) or partial response (PR) per RECIST&#xD;
CR = all detectable tumor has disappeared PR = a &gt;=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum Stable Disease (SD) = small changes that do not meet previously given criteria. Progressive disease (PD) = a &gt;=20% increase in target lesions&#xD;
The true response rate of the combination therapy for this patient population will be estimated based on the number of response using a binomial distribution and its confidence intervals will be estimated using Wilson's method.</description>
        <time_frame>1 year</time_frame>
        <population>Patients that were evaluable for clinical response</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
            <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Response Rate (RR) Objective Tumor Response Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to Response Evaluation Criteria in Solid Tumors (RECIST)</title>
          <description>CBR is the number of participants of the total analysis population who experience confirmed complete (CR) or partial response (PR) per RECIST&#xD;
CR = all detectable tumor has disappeared PR = a &gt;=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum Stable Disease (SD) = small changes that do not meet previously given criteria. Progressive disease (PD) = a &gt;=20% increase in target lesions&#xD;
The true response rate of the combination therapy for this patient population will be estimated based on the number of response using a binomial distribution and its confidence intervals will be estimated using Wilson's method.</description>
          <population>Patients that were evaluable for clinical response</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate (CBR) Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to RECIST</title>
        <description>CBR is the number of participants of the total analysis population who experience a CR, PR, or SD per RECIST&#xD;
CR = all detectable tumor has disappeared PR = a &gt;=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum SD = small changes that do not meet previously given criteria. PD = a &gt;=20% increase in target lesions</description>
        <time_frame>1 year</time_frame>
        <population>Patients that were evaluable for clinical response</population>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
            <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Benefit Rate (CBR) Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to RECIST</title>
          <description>CBR is the number of participants of the total analysis population who experience a CR, PR, or SD per RECIST&#xD;
CR = all detectable tumor has disappeared PR = a &gt;=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum SD = small changes that do not meet previously given criteria. PD = a &gt;=20% increase in target lesions</description>
          <population>Patients that were evaluable for clinical response</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival According to RECIST 1.1 Criteria</title>
        <description>Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.</description>
        <time_frame>Time from first day of treatment received to the earlier documented disease progression or death from any cause, assessed up to 1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
            <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival According to RECIST 1.1 Criteria</title>
          <description>Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.</description>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.1" lower_limit="1.8" upper_limit="6.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Grade 3 and 4 Toxicities According to NCI CTCAE Version 4.0</title>
        <description>The toxicity profile of the combination will be tabulated.</description>
        <time_frame>Up to 1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
            <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Grade 3 and 4 Toxicities According to NCI CTCAE Version 4.0</title>
          <description>The toxicity profile of the combination will be tabulated.</description>
          <units>Events</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Grade 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AEs will be collect up to 1 year</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Treatment (Metformin Hydrochloride, FOLFOX)</title>
          <description>Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.&#xD;
metformin hydrochloride: Given PO&#xD;
oxaliplatin: Given IV&#xD;
leucovorin calcium: Given IV&#xD;
fluorouracil: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v4.0</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="45" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Bile duct stenosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hepatobiliary disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Infection- Klebsiella Bacteremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Head Injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Death related to disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pulmonary embolism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE v4.0</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="33" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="46" subjects_affected="24" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="21" subjects_affected="10" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="18" subjects_affected="13" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="32" subjects_affected="17" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="9" subjects_affected="6" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="35" subjects_affected="20" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="18" subjects_affected="13" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="10" subjects_affected="7" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="59" subjects_affected="28" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="9" subjects_affected="4" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="12" subjects_affected="10" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="32" subjects_affected="17" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="19" subjects_affected="11" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="29" subjects_affected="16" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="23" subjects_affected="12" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="38" subjects_affected="17" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="32" subjects_affected="20" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="24" subjects_affected="16" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="30" subjects_affected="16" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="48" subjects_affected="18" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="28" subjects_affected="9" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="26" subjects_affected="13" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="16" subjects_affected="10" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="10" subjects_affected="9" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="8" subjects_affected="7" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="8" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="21" subjects_affected="10" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="6" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="11" subjects_affected="11" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="18" subjects_affected="14" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. David Bajor</name_or_title>
      <organization>University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center</organization>
      <phone>1-800-641-2422</phone>
      <email>CTUReferral@UHhospitals.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01666730
org study id: CASE1212
nct id: NCT01666730
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This phase II trial studies how well metformin hydrochloride, leucovorin calcium,
      fluorouracil, and oxaliplatin work in treating patients with metastatic pancreatic cancer.
      Metformin hydrochloride may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil,
      and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing
      the cells or by stopping them from dividing. Giving metformin hydrochloride together with
      combination chemotherapy may kill more tumor cells
PRIMARY OBJECTIVES:

      I. To determine if metformin (metformin hydrochloride) when added to FOLFOX ( leucovorin
      calcium, fluorouracil, oxaliplatin) improves overall survival in patients with metastatic
      pancreatic cancer.

      SECONDARY OBJECTIVES:

      I. To assess response rate (RR). II. To assess progression free survival (PFS). III. To
      assess toxicity in patients with metastatic pancreatic cancer receiving FOLFOX and metformin.
      IV. To identify tumor/serum correlative markers.

      OUTLINE: Patients receive metformin hydrochloride orally (PO) twice daily (BID) on days 1-7
      for an introductory period before the addition of FOLFOX. After the introductory period,
      patients will continue metformin twice daily and FOLFOX therapy comprising leucovorin calcium
      intravenously (IV) over 120 minutes, fluorouracil IV continuously over 46 hours, and
      oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of
      disease progression or unacceptable toxicity. After completion of study treatment, patients
      are followed up for periodically.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Median Overall Survival (OS)
time frame: Time from first day of treatment to death from any cause, assessed up to 1 year
description: Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.
measure: Response Rate (RR) Objective Tumor Response Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to Response Evaluation Criteria in Solid Tumors (RECIST)
time frame: 1 year
description: CBR is the number of participants of the total analysis population who experience confirmed complete (CR) or partial response (PR) per RECIST
CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum Stable Disease (SD) = small changes that do not meet previously given criteria. Progressive disease (PD) = a >=20% increase in target lesions
The true response rate of the combination therapy for this patient population will be estimated based on the number of response using a binomial distribution and its confidence intervals will be estimated using Wilson's method.
measure: Clinical Benefit Rate (CBR) Based on Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans According to RECIST
time frame: 1 year
description: CBR is the number of participants of the total analysis population who experience a CR, PR, or SD per RECIST
CR = all detectable tumor has disappeared PR = a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum SD = small changes that do not meet previously given criteria. PD = a >=20% increase in target lesions
measure: Progression Free Survival According to RECIST 1.1 Criteria
time frame: Time from first day of treatment received to the earlier documented disease progression or death from any cause, assessed up to 1 year
description: Calculated using Kaplan Meier methods and the median will be estimated assuming an exponential distribution.
measure: Number of Grade 3 and 4 Toxicities According to NCI CTCAE Version 4.0
time frame: Up to 1 year
description: The toxicity profile of the combination will be tabulated.
arm group label: Treatment (metformin hydrochloride, FOLFOX)
arm group type: Experimental
description: Patients receive metformin hydrochloride PO BID on days 1-14 and FOLFOX therapy comprising leucovorin calcium IV over 120 minutes, fluorouracil IV continuously over 46 hours, and oxaliplatin IV over 120 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: metformin hydrochloride
description: Given PO
arm group label: Treatment (metformin hydrochloride, FOLFOX)
other name: Glucophage
intervention type: Drug
intervention name: oxaliplatin
description: Given IV
arm group label: Treatment (metformin hydrochloride, FOLFOX)
other name: 1-OHP
other name: Dacotin
other name: Dacplat
other name: Eloxatin
other name: L-OHP
intervention type: Drug
intervention name: leucovorin calcium
description: Given IV
arm group label: Treatment (metformin hydrochloride, FOLFOX)
other name: CF
other name: CFR
other name: LV
intervention type: Drug
intervention name: fluorouracil
description: Given IV
arm group label: Treatment (metformin hydrochloride, FOLFOX)
other name: 5-fluorouracil
other name: 5-Fluracil
other name: 5-FU
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Treatment (metformin hydrochloride, FOLFOX)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: David Bajor, MD
role: Principal Investigator
affiliation: University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Pancreatic Neoplasms
mesh term: Carcinoma, Acinar Cell
mesh term: Leucovorin
mesh term: Metformin
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Calcium
mesh term: Levoleucovorin
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 