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.
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.
