<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/NCT02980029</url>
  </required_header>
  <id_info>
    <org_study_id>MCC-16-MULTI-22</org_study_id>
    <secondary_id>MCC-16-GI-98</secondary_id>
    <secondary_id>R01CA208343</secondary_id>
    <nct_id>NCT02980029</nct_id>
  </id_info>
  <brief_title>TVB 2640 for Resectable Colon Cancer Other Resectable Cancers; a Window Trial.</brief_title>
  <official_title>Pharmacodynamic Effects of Fatty Acid Synthase (FASN) Inhibition With TVB-2640 in Resectable Colon Cancer and Other Resectable Cancers; a Window Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mark Evers</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Kentucky</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary Objective&#xD;
&#xD;
      • To evaluate the pharmacodynamic effects on metabolic endpoints (malonyl carnitine and&#xD;
      tripalmitin levels) following short-term treatment with TVB-2640 in patients with resectable&#xD;
      cancers&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        -  To determine if short-term treatment with TVB-2640 decreases cancer cell proliferation.&#xD;
&#xD;
        -  To examine other biological endpoints and determine if TVB-2640 inhibits cell survival&#xD;
           signaling and lipid biogenesis.&#xD;
&#xD;
        -  To perform comprehensive metabolomic analysis in tumor tissues to identify metabolic&#xD;
           alterations induced by TVB-2640 treatment.&#xD;
&#xD;
        -  To correlate FASN levels in tumor with metabolic and biological endpoints to determine&#xD;
           if FASN inhibition has more pronounced effects in patients with increased expression.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will test the hypothesis that inhibition of FASN activity blocks tumor lipid&#xD;
      biosynthesis and alters the cellular metabolism in colon and other resectable cancers.&#xD;
&#xD;
        -  The study is a randomized, double-blind, placebo-controlled pharmacodynamic study.&#xD;
&#xD;
        -  Potentially eligible patients will be screened in the University of Kentucky Markey&#xD;
           Cancer Center clinics. Eligible patients with histologically or cytologically confirmed&#xD;
           resectable cancers without any distant metastases will be identified. Upon obtaining&#xD;
           informed consent, patients will be enrolled into the study and randomized to TVB-2640 or&#xD;
           placebo in a 2:1 fashion. Subjects and clinical investigators will be blinded to&#xD;
           treatment group assignment.&#xD;
&#xD;
        -  Baseline blood samples will be collected on Day 0 for all patients.&#xD;
&#xD;
        -  All enrolled patients will receive the study drug (TVB-2640 or placebo) at a BSA-derived&#xD;
           flat dose, orally once daily, starting Day 1. They will receive the study drug for 10-21&#xD;
           days (minimum of 10 days and a maximum of 21 days), i.e. from Day 1 to Day 10-21. The&#xD;
           last dose of the study drug will be on the day before the surgical resection.&#xD;
&#xD;
        -  For patients in both randomization groups, surgery will be performed anytime during the&#xD;
           window of Day 11- Day 22. On the day of surgery, surgical resection specimen and blood&#xD;
           samples will be collected.&#xD;
&#xD;
        -  All patients will be evaluated and graded for adverse events according to the NCI Common&#xD;
           Terminology for Adverse Events (CTCAE), version 4.03.&#xD;
&#xD;
        -  Patients will be followed for 4 weeks after the last dose of the study drug to monitor&#xD;
           for any drug-related adverse events.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 6, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Malonyl carnitine and tripalmitin levels will be measured in the preand post-treatment blood samples using mass spectrometry blood samples using mass spectrometry.</measure>
    <time_frame>Up to 56 Days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Expression of markers of tumor growth and cell proliferation (Ki67, β-catenin, c-Myc, survivin, p-AKT, etc) in the pre- treatment (where available) and post-treatment tumor samples will be evaluated using IHC</measure>
    <time_frame>Up to 56 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FASN levels in the pre-treatment and post-treatment tumor samples will be evaluated using IHCsamples will be evaluated using IHC.</measure>
    <time_frame>Up to 56 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TIP47 levels in pre-treatment (where available) and post-treatment tumor samples will be evaluated using IHC.</measure>
    <time_frame>Up to 56 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comprehensive profile of cellular metabolites involved in various pathways (glycolysis, PPP, Krebs cycle, glutaminolysis) will be assessed in the post-treatment tumor samples using mass spectrometry analyses.</measure>
    <time_frame>Up to 56 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mutation status of tumors will be evaluated by the Clearseq comprehensive cancer panel, which targets over 145 cancerassociated genes, including APC, CTNNB1, TP53, PIK3CA, BRAF and KRAS.</measure>
    <time_frame>Up to 56 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of TVB-2640 will be measured in the post-treatment blood samples using mass spectrometry analysis.</measure>
    <time_frame>Up to 56 Days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicities will be graded as per NCI-CTCAE v4.03, based on recorded adverse events, physical examinations, and clinical laboratory assessments.</measure>
    <time_frame>Up to 56 Days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">48</enrollment>
  <condition>Colon Cancer</condition>
  <arm_group>
    <arm_group_label>TVB-2640</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TVB-2640 is a potent and reversible inhibitor of the FASN enzyme.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TVB-2640</intervention_name>
    <description>TVB-2640 is a potent and reversible inhibitor of the FASN enzyme. TVB-2640 inhibits the β-ketoacyl reductase (KR) enzymatic activity of the FASN enzyme. TVB-2640 is uncompetitive towards both NADPH and acetoacetyl-CoA in inhibiting KR activity.</description>
    <arm_group_label>TVB-2640</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed, resectable colon cancer without distant&#xD;
             metastases, who are candidates for surgical resection of the tumor.&#xD;
&#xD;
          -  Willing and able to provide written informed consent prior to initiation of any study&#xD;
             procedures.&#xD;
&#xD;
          -  Male or female who is ≥ 18 years of age on day of signing informed consent&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able&#xD;
             to carry out all pre-disease activities without restriction) or 1 (unable to perform&#xD;
             physically strenuous activity but ambulatory and able to carry out work of a light or&#xD;
             sedentary nature).&#xD;
&#xD;
          -  Adequate bone marrow function as evidenced by:&#xD;
&#xD;
               1. Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
               2. ANC count ≥ 1.5 X 109/L&#xD;
&#xD;
               3. Platelets ≥ 100 X 109/L&#xD;
&#xD;
          -  No significant ischemic heart disease or myocardial infarction (MI) within 6 months&#xD;
             before the first dose of study drug and currently has adequate cardiac function, as&#xD;
             evidenced by a left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by&#xD;
             multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and corrected QT&#xD;
             interval (QTc) &lt; 470 msec&#xD;
&#xD;
          -  Female subject of childbearing potential should have a negative urine or serum&#xD;
             pregnancy within 72 hours prior to receiving the first dose of study medication. If&#xD;
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test&#xD;
             will be required.&#xD;
&#xD;
          -  Female patients of childbearing potential should be willing to use 2 methods of birth&#xD;
             control, be surgically sterile, or abstain from heterosexual activity for the course&#xD;
             of the study through 90 days after the last dose of study medication. Subjects of&#xD;
             childbearing potential are those who have not been surgically sterilized or have not&#xD;
             been free from menses for &gt; 1 year.&#xD;
&#xD;
          -  Male patients should agree to use an adequate method of contraception starting with&#xD;
             the first dose of study therapy through 90 days after the last dose of study therapy,&#xD;
             or documented to be surgically sterile&#xD;
&#xD;
          -  Willing to participate in the study and comply with all study requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to swallow oral medications or impairment of GI function or GI disease that&#xD;
             may significantly alter drug absorption (including, but not limited to active&#xD;
             inflammatory bowel disease, malabsorption syndrome). Concomitant therapy with antacids&#xD;
             and anti-emetics is permissible&#xD;
&#xD;
          -  History of risk factors for torsades de pointes (e.g., heart failure, hypokalemia,&#xD;
             family history of long QT syndrome). Concomitant use of medications with a low risk of&#xD;
             QT/QTc prolongation (including, but not limited to diphenhydramine, famotidine,&#xD;
             ondansetron) is permissible.&#xD;
&#xD;
          -  Known psychiatric or substance abuse disorders that would interfere with cooperation&#xD;
             with the requirements of the trial.&#xD;
&#xD;
          -  Having received cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy,&#xD;
             biologic or immunotherapy, etc) or an investigational drug within 4 weeks (6 weeks for&#xD;
             mitomycin C and nitrosoureas) or 5 half-lives of that agent (whichever is shorter)&#xD;
             before the first dose of study drug.&#xD;
&#xD;
          -  Pregnant, breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the prescreening or screening visit&#xD;
             through 90 days after the last dose of trial treatment&#xD;
&#xD;
          -  Inoperable on the basis of co-existent medical problems&#xD;
&#xD;
          -  History of clinically significant dry eye (xerophthalmia) or other corneal abnormality&#xD;
             or, if a contact lens wearer, does not agree to abstain from contact lens use from Day&#xD;
             1 through the last dose of study drug.&#xD;
&#xD;
          -  Other concurrent disease (cardiovascular, renal, hepatic, etc.) or laboratory&#xD;
             abnormality that, in the investigator's opinion would increase the risk of&#xD;
             participating in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark B Evers, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lucille P. Markey Cancer Center at University of Kentucky</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mark B Evers, MD</last_name>
    <phone>859-257-4500</phone>
    <email>mark.evers@uky.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Kentucky</name>
      <address>
        <city>Lexington</city>
        <state>Kentucky</state>
        <zip>40536</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>October 12, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 2, 2016</study_first_posted>
  <last_update_submitted>January 18, 2023</last_update_submitted>
  <last_update_submitted_qc>January 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 20, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Kentucky</investigator_affiliation>
    <investigator_full_name>Mark Evers</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Resectable Tumors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colonic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02980029
org study id: MCC-16-MULTI-22
secondary id: MCC-16-GI-98
secondary id: R01CA208343
nct id: NCT02980029
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Primary Objective

      • To evaluate the pharmacodynamic effects on metabolic endpoints (malonyl carnitine and
      tripalmitin levels) following short-term treatment with TVB-2640 in patients with resectable
      cancers

      Secondary Objectives

        -  To determine if short-term treatment with TVB-2640 decreases cancer cell proliferation.

        -  To examine other biological endpoints and determine if TVB-2640 inhibits cell survival
           signaling and lipid biogenesis.

        -  To perform comprehensive metabolomic analysis in tumor tissues to identify metabolic
           alterations induced by TVB-2640 treatment.

        -  To correlate FASN levels in tumor with metabolic and biological endpoints to determine
           if FASN inhibition has more pronounced effects in patients with increased expression.
This study will test the hypothesis that inhibition of FASN activity blocks tumor lipid
      biosynthesis and alters the cellular metabolism in colon and other resectable cancers.

        -  The study is a randomized, double-blind, placebo-controlled pharmacodynamic study.

        -  Potentially eligible patients will be screened in the University of Kentucky Markey
           Cancer Center clinics. Eligible patients with histologically or cytologically confirmed
           resectable cancers without any distant metastases will be identified. Upon obtaining
           informed consent, patients will be enrolled into the study and randomized to TVB-2640 or
           placebo in a 2:1 fashion. Subjects and clinical investigators will be blinded to
           treatment group assignment.

        -  Baseline blood samples will be collected on Day 0 for all patients.

        -  All enrolled patients will receive the study drug (TVB-2640 or placebo) at a BSA-derived
           flat dose, orally once daily, starting Day 1. They will receive the study drug for 10-21
           days (minimum of 10 days and a maximum of 21 days), i.e. from Day 1 to Day 10-21. The
           last dose of the study drug will be on the day before the surgical resection.

        -  For patients in both randomization groups, surgery will be performed anytime during the
           window of Day 11- Day 22. On the day of surgery, surgical resection specimen and blood
           samples will be collected.

        -  All patients will be evaluated and graded for adverse events according to the NCI Common
           Terminology for Adverse Events (CTCAE), version 4.03.

        -  Patients will be followed for 4 weeks after the last dose of the study drug to monitor
           for any drug-related adverse events.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Malonyl carnitine and tripalmitin levels will be measured in the preand post-treatment blood samples using mass spectrometry blood samples using mass spectrometry.
time frame: Up to 56 Days
measure: Expression of markers of tumor growth and cell proliferation (Ki67, β-catenin, c-Myc, survivin, p-AKT, etc) in the pre- treatment (where available) and post-treatment tumor samples will be evaluated using IHC
time frame: Up to 56 Days
measure: FASN levels in the pre-treatment and post-treatment tumor samples will be evaluated using IHCsamples will be evaluated using IHC.
time frame: Up to 56 Days
measure: TIP47 levels in pre-treatment (where available) and post-treatment tumor samples will be evaluated using IHC.
time frame: Up to 56 Days
measure: Comprehensive profile of cellular metabolites involved in various pathways (glycolysis, PPP, Krebs cycle, glutaminolysis) will be assessed in the post-treatment tumor samples using mass spectrometry analyses.
time frame: Up to 56 Days
measure: Mutation status of tumors will be evaluated by the Clearseq comprehensive cancer panel, which targets over 145 cancerassociated genes, including APC, CTNNB1, TP53, PIK3CA, BRAF and KRAS.
time frame: Up to 56 Days
measure: Levels of TVB-2640 will be measured in the post-treatment blood samples using mass spectrometry analysis.
time frame: Up to 56 Days
measure: Toxicities will be graded as per NCI-CTCAE v4.03, based on recorded adverse events, physical examinations, and clinical laboratory assessments.
time frame: Up to 56 Days
arm group label: TVB-2640
arm group type: Experimental
description: TVB-2640 is a potent and reversible inhibitor of the FASN enzyme.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo
intervention type: Drug
intervention name: TVB-2640
description: TVB-2640 is a potent and reversible inhibitor of the FASN enzyme. TVB-2640 inhibits the β-ketoacyl reductase (KR) enzymatic activity of the FASN enzyme. TVB-2640 is uncompetitive towards both NADPH and acetoacetyl-CoA in inhibiting KR activity.
arm group label: TVB-2640
intervention type: Other
intervention name: Placebo
description: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mark B Evers, MD
role: Principal Investigator
affiliation: Lucille P. Markey Cancer Center at University of Kentucky
last name: Mark B Evers, MD
phone: 859-257-4500
email: mark.evers@uky.edu
facility: 
status: Recruiting
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Kentucky
investigator full name: Mark Evers
investigator title: Principal Investigator
mesh term: Colonic Neoplasms
sharing ipd: No