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

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

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.

Study Overview

• Status: Terminated
• Conditions: Colon Cancer
• Intervention / Treatment: Other: Placebo; Drug: TVB-2640

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University Of Kentucky

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo
Experimental: TVB-2640; TVB-2640 is a potent and reversible inhibitor of the FASN enzyme.	Drug: TVB-2640; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Malonyl carnitine and tripalmitin levels will be measured in the preand post-treatment blood samples using mass spectrometry blood samples using mass spectrometry.	Up to 56 Days

Secondary Outcome Measures

Outcome Measure	Time Frame
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	Up to 56 Days
FASN levels in the pre-treatment and post-treatment tumor samples will be evaluated using IHCsamples will be evaluated using IHC.	Up to 56 Days
TIP47 levels in pre-treatment (where available) and post-treatment tumor samples will be evaluated using IHC.	Up to 56 Days
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.	Up to 56 Days
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.	Up to 56 Days
Levels of TVB-2640 will be measured in the post-treatment blood samples using mass spectrometry analysis.	Up to 56 Days
Toxicities will be graded as per NCI-CTCAE v4.03, based on recorded adverse events, physical examinations, and clinical laboratory assessments.	Up to 56 Days

Collaborators and Investigators

• Sponsor: Mark Evers
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Mark B Evers, MD, Lucille P. Markey Cancer Center at University of Kentucky

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2017
• Primary Completion (Actual): October 22, 2023
• Study Completion (Actual): October 22, 2023

Study Registration Dates

• First Submitted: October 12, 2016
• First Submitted That Met QC Criteria: November 29, 2016
• First Posted (Estimated): December 2, 2016

Study Record Updates

• Last Update Posted (Actual): October 22, 2024
• Last Update Submitted That Met QC Criteria: October 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Resectable Tumors
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Colonic Diseases; Colonic Neoplasms
• Other Study ID Numbers: MCC-16-MULTI-22; MCC-16-GI-98 (Other Identifier: UK Markey Cancer Center (former protocol number)); R01CA208343 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No