<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/NCT02232152</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00028139</org_study_id>
    <secondary_id>NCI-2014-01779</secondary_id>
    <secondary_id>CCCWFU #59314</secondary_id>
    <secondary_id>P30CA012197</secondary_id>
    <nct_id>NCT02232152</nct_id>
  </id_info>
  <brief_title>CPI-613 and Fluorouracil in Treating Patients With Metastatic Colorectal Cancer That Cannot Be Removed by Surgery</brief_title>
  <official_title>A Phase I Clinical Trial of Fluorouracil (5-FU) + CPI-613 Combination in Previously Treated Metastatic Colorectal Cancer Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot phase I trial studies the side effects and best dose of CPI-613 when given&#xD;
      together with fluorouracil in treating patients with colorectal cancer that has spread to&#xD;
      other parts of the body and cannot be removed by surgery. CPI-613 may kill tumor cells by&#xD;
      turning off their mitochondria. Mitochondria are used by tumor cells to produce energy and&#xD;
      are the building blocks needed to make more tumor cells. By shutting off these mitochondria,&#xD;
      CPI-613 deprives the tumor cells of energy and other supplies that they need to survive and&#xD;
      grow in the body. Drugs used in chemotherapy, such as fluorouracil, work in different ways to&#xD;
      stop the growth of tumor cells, either by killing the cells, by stopping them from dividing,&#xD;
      or by stopping them from spreading. Giving CPI-613 with fluorouracil may kill more tumor&#xD;
      cells.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the maximum tolerated dose (MTD) of CPI-613 (6,8-bis[benzylthio]octanoic&#xD;
      acid), when used in combination with 5-FU (fluorouracil), in patients with non-resectable&#xD;
      metastatic colorectal cancer who have failed FOLFOX (leucovorin calcium, fluorouracil and&#xD;
      oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) and,&#xD;
      if Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type, then a epidermal growth&#xD;
      factor receptor (EGFR) inhibitor-based regimen.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To assess the pharmacokinetic (PK), safety and efficacy of various doses of CPI-613, when&#xD;
      used in combination with 5-FU, in patients with non-resectable metastatic colorectal cancer.&#xD;
&#xD;
      OUTLINE: This is a dose-escalation study of 6,8-bis(benzylthio)octanoic acid.&#xD;
&#xD;
      Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-4&#xD;
      and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in&#xD;
      the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 2 months for 3 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 6, 2015</start_date>
  <completion_date type="Actual">January 11, 2023</completion_date>
  <primary_completion_date type="Actual">February 19, 2019</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>MTD of 6,8-bis(benzylthio)octanoic acid in combination with fluorouracil based on the incidence of dose-limiting toxicities graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</measure>
    <time_frame>Up to 2 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of toxicity of 6,8-bis(benzylthio)octanoic acid and fluorouracil combination graded according to NCI CTCAE version 4.0</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Examine toxicities by assessing each toxicity by grade.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK parameters (maximum observed concentration, area under the curve, half-life, elimination rate constant, drug clearance, and volume of distribution) of 6,8-bis(benzylthio)octanoic acid in plasma samples</measure>
    <time_frame>Week 1: days 1 and 4 before infusion of 6,8-bis(benzylthio)octanoic acid and at 30 minutes, 1, 1.5, 2, 4, 6 and 8 (optional) hours after the completion of infusion</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Time from the first dose of 6,8-bis(benzylthio)octanoic acid to disease progression, assessed up to 3 years</time_frame>
    <description>Plot a PFS curve using Kaplan-Meier methods, examine median PFS.</description>
  </other_outcome>
  <other_outcome>
    <measure>Overall response rate (ORR) (i.e., sum of complete response [CR] and partial response [PR])</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Assess ORR and its 95% confidence interval.</description>
  </other_outcome>
  <other_outcome>
    <measure>Disease control rate (DCR) (i.e., sum of CR, PR, and stable disease)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Assess DCR and its 95% confidence interval.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Mucinous Adenocarcinoma of the Colon</condition>
  <condition>Mucinous Adenocarcinoma of the Rectum</condition>
  <condition>Recurrent Colon Cancer</condition>
  <condition>Recurrent Rectal Cancer</condition>
  <condition>Signet Ring Adenocarcinoma of the Colon</condition>
  <condition>Signet Ring Adenocarcinoma of the Rectum</condition>
  <condition>Stage IIIA Colon Cancer</condition>
  <condition>Stage IIIA Rectal Cancer</condition>
  <condition>Stage IIIB Colon Cancer</condition>
  <condition>Stage IIIB Rectal Cancer</condition>
  <condition>Stage IIIC Colon Cancer</condition>
  <condition>Stage IIIC Rectal Cancer</condition>
  <condition>Stage IVA Colon Cancer</condition>
  <condition>Stage IVA Rectal Cancer</condition>
  <condition>Stage IVB Colon Cancer</condition>
  <condition>Stage IVB Rectal Cancer</condition>
  <arm_group>
    <arm_group_label>Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-4 and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>6,8-bis(benzylthio)octanoic acid</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)</arm_group_label>
    <other_name>alpha-lipoic acid analogue CPI-613</other_name>
    <other_name>CPI-613</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>fluorouracil</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)</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>pharmacological study</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)</arm_group_label>
    <other_name>pharmacological studies</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically and cytologically confirmed metastatic colorectal adenocarcinoma&#xD;
             (colon, rectal or colorectal cancer) that is not resectable&#xD;
&#xD;
          -  Have failed or have not tolerated FOLFOX, FOLFIRI and, if KRAS wild type, then a EGFR&#xD;
             inhibitor-based regimen&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status being 0-2&#xD;
&#xD;
          -  Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically&#xD;
             sterile) must use accepted contraceptive methods (abstinence, intrauterine device&#xD;
             [IUD], oral contraceptive or double barrier device) during the study, and must have a&#xD;
             negative serum or urine pregnancy test within 1 week prior to treatment initiation&#xD;
&#xD;
          -  Fertile men must practice effective contraceptive methods during the study, unless&#xD;
             documentation of infertility exists&#xD;
&#xD;
          -  At least 2 weeks must have elapsed from any prior surgery&#xD;
&#xD;
          -  Granulocyte count &gt;= 1500/mm^3&#xD;
&#xD;
          -  White blood cell (WBC) &gt;= 3500 cells/mm^3 or &gt;= 3.5 bil/L&#xD;
&#xD;
          -  Platelet count &gt;= 100,000 cells/mm^3 or &gt;= 100 bil/L&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1500 cells/mm^3 or &gt;= 1.5 bil/L&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL or &gt;= 90 g/L&#xD;
&#xD;
          -  Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) =&lt; 3 x&#xD;
             upper normal limit (UNL), alanine aminotransferase (ALT/serum glutamate pyruvate&#xD;
             transaminase [SGPT]) =&lt; 3 x UNL (=&lt; 5 x UNL if liver metastases present)&#xD;
&#xD;
          -  Bilirubin =&lt; 1.5 x UNL&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 mg/dL or 13 umol/L&#xD;
&#xD;
          -  International normalized ratio or INR must be =&lt; 1.5 unless on therapeutic blood&#xD;
             thinners&#xD;
&#xD;
          -  No evidence of active infection and no serious infection within the past month&#xD;
&#xD;
          -  Mentally competent, ability to understand and willingness to sign the informed consent&#xD;
             form&#xD;
&#xD;
          -  At least one measurable lesion as assessed by computed tomography (CT) scan using&#xD;
             Response Evaluation Criteria in Solid Tumors (RECIST) criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Therapy with CPI-613 prior to participating in this trial&#xD;
&#xD;
          -  Known hypersensitivity to 5-FU injection, poor nutritional state, known dipyrimidine&#xD;
             dehydrogenase deficiency, or taking sorivudine (such as Usevir, brovavir, etc.)&#xD;
&#xD;
          -  History of hypersensitivity to active or inactive excipients of any component of&#xD;
             treatment&#xD;
&#xD;
          -  Previous radiotherapy for central nervous system metastases&#xD;
&#xD;
          -  Patients receiving any other standard or investigational treatment for their cancer,&#xD;
             or any other investigational agent for any indication, within the past 2 weeks prior&#xD;
             to initiation of treatment with study drugs&#xD;
&#xD;
          -  Serious medical illness that would potentially increase patients' risk for toxicity&#xD;
&#xD;
          -  Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g.,&#xD;
             active peptic ulcer disease)&#xD;
&#xD;
          -  History of abdominal fistula or gastrointestinal perforation =&lt; 6 months prior to&#xD;
             treatment with study drugs&#xD;
&#xD;
          -  Pregnant women, or women of child-bearing potential not using reliable means of&#xD;
             contraception&#xD;
&#xD;
          -  Lactating females&#xD;
&#xD;
          -  Fertile men unwilling to practice contraceptive methods during the study period&#xD;
&#xD;
          -  Any condition or abnormality which may, in the opinion of the investigator, compromise&#xD;
             the safety of patients&#xD;
&#xD;
          -  Unwilling or unable to follow protocol requirements&#xD;
&#xD;
          -  Symptomatic heart disease including but not limited to symptomatic congestive heart&#xD;
             failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic&#xD;
             myocardial infarction or symptomatic congestive heart failure&#xD;
&#xD;
          -  Patients with a history of myocardial infarction that is &lt; 3 months prior to&#xD;
             registration&#xD;
&#xD;
          -  Evidence of active infection, or serious infection within the past month&#xD;
&#xD;
          -  Patients with known human immunodeficiency virus (HIV) infection, hepatitis B, or&#xD;
             hepatitis C&#xD;
&#xD;
          -  Patients who have received cancer immunotherapy of any type within the past 2 weeks&#xD;
             prior to initiation of CPI-613 treatment; steroid use for management of refractory&#xD;
             pain or for contrast induced allergy is allowed&#xD;
&#xD;
          -  Requirement for immediate palliative treatment of any kind including surgery&#xD;
&#xD;
          -  Any condition or abnormality which may, in the opinion of the investigator, compromise&#xD;
             the safety of the patient&#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>Caio Rocha Lima, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Comprehensive Cancer Center of Wake Forest University</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>September 2, 2014</study_first_submitted>
  <study_first_submitted_qc>September 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2014</study_first_posted>
  <last_update_submitted>August 2, 2023</last_update_submitted>
  <last_update_submitted_qc>August 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 7, 2023</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>Rectal Neoplasms</mesh_term>
    <mesh_term>Colonic Neoplasms</mesh_term>
    <mesh_term>Adenocarcinoma, Mucinous</mesh_term>
    <mesh_term>Cystadenocarcinoma</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thioctic Acid</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <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>September 5, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/52/NCT02232152/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT02232152
org study id: IRB00028139
secondary id: NCI-2014-01779
secondary id: CCCWFU #59314
secondary id: P30CA012197
nct id: NCT02232152
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This pilot phase I trial studies the side effects and best dose of CPI-613 when given
      together with fluorouracil in treating patients with colorectal cancer that has spread to
      other parts of the body and cannot be removed by surgery. CPI-613 may kill tumor cells by
      turning off their mitochondria. Mitochondria are used by tumor cells to produce energy and
      are the building blocks needed to make more tumor cells. By shutting off these mitochondria,
      CPI-613 deprives the tumor cells of energy and other supplies that they need to survive and
      grow in the body. Drugs used in chemotherapy, such as fluorouracil, work in different ways to
      stop the growth of tumor cells, either by killing the cells, by stopping them from dividing,
      or by stopping them from spreading. Giving CPI-613 with fluorouracil may kill more tumor
      cells.
PRIMARY OBJECTIVES:

      I. To determine the maximum tolerated dose (MTD) of CPI-613 (6,8-bis[benzylthio]octanoic
      acid), when used in combination with 5-FU (fluorouracil), in patients with non-resectable
      metastatic colorectal cancer who have failed FOLFOX (leucovorin calcium, fluorouracil and
      oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) and,
      if Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type, then a epidermal growth
      factor receptor (EGFR) inhibitor-based regimen.

      SECONDARY OBJECTIVES:

      I. To assess the pharmacokinetic (PK), safety and efficacy of various doses of CPI-613, when
      used in combination with 5-FU, in patients with non-resectable metastatic colorectal cancer.

      OUTLINE: This is a dose-escalation study of 6,8-bis(benzylthio)octanoic acid.

      Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-4
      and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 2 months for 3 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: MTD of 6,8-bis(benzylthio)octanoic acid in combination with fluorouracil based on the incidence of dose-limiting toxicities graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
time frame: Up to 2 weeks
measure: Incidence of toxicity of 6,8-bis(benzylthio)octanoic acid and fluorouracil combination graded according to NCI CTCAE version 4.0
time frame: Up to 3 years
description: Examine toxicities by assessing each toxicity by grade.
measure: PK parameters (maximum observed concentration, area under the curve, half-life, elimination rate constant, drug clearance, and volume of distribution) of 6,8-bis(benzylthio)octanoic acid in plasma samples
time frame: Week 1: days 1 and 4 before infusion of 6,8-bis(benzylthio)octanoic acid and at 30 minutes, 1, 1.5, 2, 4, 6 and 8 (optional) hours after the completion of infusion
measure: Progression-free survival (PFS)
time frame: Time from the first dose of 6,8-bis(benzylthio)octanoic acid to disease progression, assessed up to 3 years
description: Plot a PFS curve using Kaplan-Meier methods, examine median PFS.
measure: Overall response rate (ORR) (i.e., sum of complete response [CR] and partial response [PR])
time frame: Up to 3 years
description: Assess ORR and its 95% confidence interval.
measure: Disease control rate (DCR) (i.e., sum of CR, PR, and stable disease)
time frame: Up to 3 years
description: Assess DCR and its 95% confidence interval.
arm group label: Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)
arm group type: Experimental
description: Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-4 and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: 6,8-bis(benzylthio)octanoic acid
description: Given IV
arm group label: Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)
other name: alpha-lipoic acid analogue CPI-613
other name: CPI-613
intervention type: Drug
intervention name: fluorouracil
description: Given IV
arm group label: Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)
other name: 5-fluorouracil
other name: 5-Fluracil
other name: 5-FU
intervention type: Other
intervention name: pharmacological study
description: Correlative studies
arm group label: Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)
other name: pharmacological studies
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Caio Rocha Lima, MD
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
facility: 
country: United States
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Rectal Neoplasms
mesh term: Colonic Neoplasms
mesh term: Adenocarcinoma, Mucinous
mesh term: Cystadenocarcinoma
mesh term: Recurrence
mesh term: Thioctic Acid
mesh term: Fluorouracil
provided document: 