Clinical Trials /

TVB 2640 for Resectable Colon Cancer Other Resectable Cancers; a Window Trial.

NCT02980029

Description:

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.

Related Conditions:
  • Colon Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: TVB 2640 for Resectable Colon Cancer Other Resectable Cancers; a Window Trial.
  • Official Title: Pharmacodynamic Effects of Fatty Acid Synthase (FASN) Inhibition With TVB-2640 in Resectable Colon Cancer and Other Resectable Cancers; a Window Trial.

Clinical Trial IDs

  • ORG STUDY ID: MCC-16-MULTI-22
  • SECONDARY ID: MCC-16-GI-98
  • NCT ID: NCT02980029

Conditions

  • Colon Cancer

Interventions

DrugSynonymsArms
TVB-2640TVB-2640

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
TVB-2640ExperimentalTVB-2640 is a potent and reversible inhibitor of the FASN enzyme.
  • TVB-2640
PlaceboPlacebo ComparatorPlacebo

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Histologically or cytologically confirmed, resectable colon cancer without distant
                 metastases, who are candidates for surgical resection of the tumor.
    
              -  Willing and able to provide written informed consent prior to initiation of any study
                 procedures.
    
              -  Male or female who is ≥ 18 years of age on day of signing informed consent
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 (fully active, able
                 to carry out all pre-disease activities without restriction) or 1 (unable to perform
                 physically strenuous activity but ambulatory and able to carry out work of a light or
                 sedentary nature).
    
              -  Adequate bone marrow function as evidenced by:
    
                   1. Hemoglobin ≥ 9 g/dL
    
                   2. ANC count ≥ 1.5 X 109/L
    
                   3. Platelets ≥ 100 X 109/L
    
              -  No significant ischemic heart disease or myocardial infarction (MI) within 6 months
                 before the first dose of study drug and currently has adequate cardiac function, as
                 evidenced by a left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by
                 multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and corrected QT
                 interval (QTc) < 470 msec
    
              -  Female subject of childbearing potential should have a negative urine or serum
                 pregnancy within 72 hours prior to receiving the first dose of study medication. If
                 the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
                 will be required.
    
              -  Female patients of childbearing potential should be willing to use 2 methods of birth
                 control, be surgically sterile, or abstain from heterosexual activity for the course
                 of the study through 90 days after the last dose of study medication. Subjects of
                 childbearing potential are those who have not been surgically sterilized or have not
                 been free from menses for > 1 year.
    
              -  Male patients should agree to use an adequate method of contraception starting with
                 the first dose of study therapy through 90 days after the last dose of study therapy,
                 or documented to be surgically sterile
    
              -  Willing to participate in the study and comply with all study requirements.
    
            Exclusion Criteria:
    
              -  Inability to swallow oral medications or impairment of GI function or GI disease that
                 may significantly alter drug absorption (including, but not limited to active
                 inflammatory bowel disease, malabsorption syndrome). Concomitant therapy with antacids
                 and anti-emetics is permissible
    
              -  History of risk factors for torsades de pointes (e.g., heart failure, hypokalemia,
                 family history of long QT syndrome). Concomitant use of medications with a low risk of
                 QT/QTc prolongation (including, but not limited to diphenhydramine, famotidine,
                 ondansetron) is permissible.
    
              -  Known psychiatric or substance abuse disorders that would interfere with cooperation
                 with the requirements of the trial.
    
              -  Having received cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy,
                 biologic or immunotherapy, etc) or an investigational drug within 4 weeks (6 weeks for
                 mitomycin C and nitrosoureas) or 5 half-lives of that agent (whichever is shorter)
                 before the first dose of study drug.
    
              -  Pregnant, breastfeeding, or expecting to conceive or father children within the
                 projected duration of the trial, starting with the prescreening or screening visit
                 through 90 days after the last dose of trial treatment
    
              -  Inoperable on the basis of co-existent medical problems
    
              -  History of clinically significant dry eye (xerophthalmia) or other corneal abnormality
                 or, if a contact lens wearer, does not agree to abstain from contact lens use from Day
                 1 through the last dose of study drug.
    
              -  Other concurrent disease (cardiovascular, renal, hepatic, etc.) or laboratory
                 abnormality that, in the investigator's opinion would increase the risk of
                 participating in the study.
          
    Maximum Eligible Age:99 Years
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:Accepts Healthy Volunteers

    Primary Outcome Measures

    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
    Safety Issue:
    Description:

    Secondary Outcome Measures

    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
    Safety Issue:
    Description:
    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
    Safety Issue:
    Description:
    Measure:TIP47 levels in pre-treatment (where available) and post-treatment tumor samples will be evaluated using IHC.
    Time Frame:Up to 56 Days
    Safety Issue:
    Description:
    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
    Safety Issue:
    Description:
    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
    Safety Issue:
    Description:
    Measure:Levels of TVB-2640 will be measured in the post-treatment blood samples using mass spectrometry analysis.
    Time Frame:Up to 56 Days
    Safety Issue:
    Description:
    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
    Safety Issue:
    Description:

    Details

    Phase:Phase 1
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Mark Evers

    Trial Keywords

    • Resectable Tumors

    Last Updated

    September 26, 2018