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A Phase I Trial of 5-Fluoro-2-Deoxycytidine With Tetrahydrouridine in Advanced Malignancies

Protocol # 06-C-0221

Why is this trial important?

The purpose of this trial is to evaluate a combination of 5-fluoro-2-deoxycytidine (FdCyd) and tetrahydrouridine (THU). These drugs have been shown, in pre-clinical models, to affect gene expression. It is thought that FdCyd may be able to block DNA methylation, a cellular process believed to be central to cancer development. Abnormal cells are able to grow and multiply when there is too much methylation, also known as hypermethylation, resulting in the silencing of genes that suppress the development of tumors.

The problem is that FdCyd appears to break down rapidly in the body to the extent that it is no longer able to block DNA methylation. The second drug in this combination therapy, THU, may be able to help prevent or delay FdCyd breakdown when the two drugs are given together, thereby reducing hypermethylation and allowing the tumor suppressor genes to remain active. As investigators conduct this first clinical study to test an FdCyd/THU combination in human beings, the goal is to understand the way in which it affects the methylation of tumor suppressor genes, find the maximum tolerated dose (MTD) and toxicity levels, and examine the treatment's effects on protein levels that foster cancer progression.

Who is eligible for this trial? (PDQ)

  • Patients with advanced, histologically-confirmed malignancies refractory to standard therapy or for which no standard therapy exists
  • Patients should have adequate liver, renal, and bone marrow function
  • All patients of child-bearing age, both male and female, must be advised to practice adequate contraception
  • Premenopausal women must have a negative pregnancy test prior to entry on the study
  • The presence of measurable disease is not required
  • Patients must have adequate organ function, defined as a serum bilirubin ≤ 1.5 mg/dl, platelets ≥ 125, 000/μl, absolute neutrophil count ≥ 1500/μl and serum creatinine ≤ 2.0 mg/dl

What types of drugs or therapies are being used?

5-fluoro-2-deoxyctidine (FdCyd) is a fluoropyridimine nucleoside analogue. Tetrahydrouridine (THU) is a cytidine deaminase inhibitor. Both FdCyd and THU are administered intravenously.

What is the study outline? (PDQ)

  • Study drug is administered using a 28-day repeating cycle as follows:
    • 5-Fluoro-2-Deoxyctidine (FdCyd) and Tetrahydrouridine (THU) is administered by mouth on Day 1 of Cycle 1 only (for subsequent cycles, FdCyd will be administered as an intravenous infusion over 3 hours along with an infusion of THU)
    • FdCyd is administered as an intravenous infusion over 3 hours, along with a daily infusion of THU for the following 4 consecutive days of treatment, followed by a 2-day break
    • FdCyd is administered as an intravenous infusion over 3 hours along with a daily infusion of THU for the following 5 consecutive days of treatment
    • No treatment for 2 weeks
  • The dose of THU is fixed at 350 mg/m2/day; the dose of FdCyd will be escalated based on the tolerability of lower doses
  • Three to six patients will be enrolled at each dose level
  • Blood for pharmacodynamic studies will be obtained on Day 1, 2, 12, and 15 of Cycle 1, and on Day 1, 12, and 15 of all subsequent cycles
  • No tumor biopsies will be performed

What is the frequency and duration of the visits?

Study drugs are administered in 4-week cycles. During each cycle, patients will be required to be in the area to receive therapy at the Clinical Center for 5 days each week for 2 consecutive weeks followed by 2 weeks off. Patients will be required to be admitted to the hospital for the first 5 days of cycle 1.

What are the costs?

There is no charge for medical care received at the National Institutes of Health (NIH) Clinical Center. Patients will be responsible for travel costs for their initial screening visits. In most cases, once patients are enrolled in a trial, the National Cancer Institute (NCI) will pay the transportation costs for all subsequent trial-related visits for patients who do not live in the local area. In addition, these patients will receive a small per diem to help offset the costs of meals and lodging if they are being treated as outpatients.

It will be important to maintain your current insurance plan to cover all medical care that is provided away from the NIH Clinical Center.

No U.S. citizen or permanent U.S. resident residing in the U.S. who otherwise meets the eligibility requirements will be denied enrollment in clinical research protocols because of their inability to pay the costs of travel and subsistence.

Who is the Principal Investigator?

Dr. James H. Doroshow has been Director of the Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI), National Institutes of Health (NIH) since 2004. From 1983 to 2004, Dr. Doroshow was the Associate Director for Clinical Research at the City of Hope (COH) Comprehensive Cancer Center in Duarte, Calif.; the Chairman of the COH Department of Medical Oncology and Therapeutics Research; and the Leader of the COH Cancer Center's Clinical and Experimental Therapeutics Program. From the time he received his first research grant in 1980, Dr. Doroshow was continuously funded by NCI and NIH until moving to NCI in 2004. He is the author of over 300 full-length publications in the areas of the molecular and clinical pharmacology of the anthracycline antibiotics, the role of oxidant stress in signal transduction, and novel therapeutic approaches to breast, gastrointestinal, lung, and gynecologic cancer.

Where is this trial taking place?

NIH Clinical Center
National Institutes of Health
NCI, Laboratory of Molecular Pharmacology, Developmental Therapeutics Section
10 Center Drive
Bethesda, Maryland 20892

Who are the contacts for this trial?

James Doroshow, M.D.
Principal Investigator
Phone: 301-496-4291

Shivaani Kummar, M.D.
Protocol Chair
Phone: 301-435-5402
kummars@mail.nih.gov

Referrals:

Janelle Bingham, R.N.
Referral Coordinator
Phone: 301-435-2715
Fax: 301-451-5433
jbingham@mail.nih.gov

Deborah Allen, R.N., O.C.N.
Research Nurse
Phone: 301-402-5640
Fax: 301-480-7281
allendeb@mail.nih.gov

Where can additional information be found?

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