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BRIEF TITLE: Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)

A Multi-Histology Phase II Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)


  • Org Study ID: 090214
  • Secondary ID: 09-C-0214
  • NCT ID: NCT00978250
  • NCT Alias:
  • Sponsor: National Cancer Institute (NCI) - NIH
  • Source: National Institutes of Health Clinical Center (CC)

Brief Summary

Background: - Two experimental drugs, FdCyd (also called 5-fluoro-2'-deoxcytidine), and THU (also called tetrahydrouridine), are undergoing trials to test their effectiveness in treating cancer that has not responded to standard therapies. FdCyd is thought to work by changing how genes work in cancer cells. THU does not have any anticancer effects on its own, but it helps keep the other drug, FdCyd, from being broken down by the body. - These drugs are being tested on several separate clinical trials. Objectives: - To determine if FdCyd and THU can work together to control tumor growth. - To evaluate the safety and tolerability of FdCyd and THU when given together. Eligibility: - Individuals 18 years of age and older who have advanced non-small cell lung cancer, breast cancer, bladder cancer, or head or neck cancer that has progressed after receiving standard treatment or for which no effective therapy exists. Design: - The drugs are given over 28-day periods called cycles. FdCyd and THU are given through a vein for about 3 hours each day on days 1 5 and 8 12 of each cycle. - Clinical Center visits: FdCyd and THU will be given through a vein each day on days 1 5 and 8 12 of each cycle. During the Clinical Center visits, researchers will perform study tests and procedures to see how the study drugs are affecting the body. - Patients will undergo a number of tests and procedures during the treatment cycle, including physical examinations, blood and urine samples for standard tests, imaging studies (ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scans) to evaluate tumor growth, and blood and urine samples to evaluate the amount of FdCyd and THU in the body and the body's response to the drugs. - Patients may continue to receive FdCyd and THU if their cancer does not grow, if they do not have too many side effects, and if they are willing to do so.

Detailed Description


Background:

5-Fluoro-2'-deoxycytidine (FdCyd), a fluoropyrimidine nucleoside analog, has a short
(10-minute) half-life and is rapidly degraded in vivo by cytidine deaminase. However,
coadministration with tetrahydrouridine (THU), an inhibitor of cytidine/deoxycytidine
deaminase, has been shown to increase the AUC of the parent compound more than 4-fold.
Increased FdCyd exposure allows it to be taken up intracellularly and converted to its
triphosphate, which is incorporated into DNA and inhibits the action of the enzyme DNA
methyltransferase (DNMT). Inhibition of DNMT, and in turn DNA methylation, can result in the
re-expression of tumor suppressor genes.

Objectives:

- Determine progression-free survival (PFS) and/or the response rate (CR + PR) of FdCyd
administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over
3 hours along with THU in patients with breast cancer, head and neck cancer, non-small
cell lung cancer, and urothelial transitional cell carcinoma.

- Evaluate whether treatment with FdCyd and THU alters DNA methylation patterns in tumor
biopsy samples before and during treatment by LINE-1 analysis.

- Evaluate the safety and tolerability of FdCyd (100 mg/m(2)) + THU (350 mg/m(2))
administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over
3 hours.

- Measure changes in the number of CTCs following treatment with FdCyd plus THU.

Eligibility:

-Patients with histologically documented non-small cell lung cancer, head and neck cancer,
urothelial transitional cell carcinoma, and breast carcinoma.

Design:

- This is a multicenter trial with NCI as the coordinating center and the California
Cancer Consortium and UPMC as participating sites.

- FdCyd will be administered as an IV infusion over 3 hours with 20% of the daily dose of
THU administered as an IV push and the remaining 80% co-administered with FdCyd by
3-hour infusion daily for 5 consecutive days of treatment per week for 2 consecutive
weeks, followed by 2 weeks of no treatment, in a 28-day cycle.

- Blood and optional tumor biopsies for pharmacodynamic and pharmacokinetic studies will
be obtained.

- The study will accrue a maximum of 165 patients including all centers.

Overal Status Start Date Phase Study Type
Recruiting Start Date: August 20, 2009 Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Determine progression-free survival (PFS) and/or the response rate(CR + PR) of FdCyd

Primary Outcome 1 - Time Frame: 4 or 6 months

Condition:

  • Head and Neck Neoplasms
  • Lung Neoplasms
  • Urinary Bladder Neoplasms
  • Breast Neoplasms

Eligibility

Criteria:
- INCLUSION CRITERIA:

- Patients must have histologically documented metastatic or unresectable non-small cell
lung cancer, head and neck cancer, urothelial transitional cell carcinoma, or breast
cancer whose disease has progressed after at least one line of standard therapy.

- Patients with solid tumors (non-small cell lung cancer, head and neck cancer,
urothelial transitional cell carcinoma, and breast cancer) must have measurable
disease, defined as at least one lesion that can be accurately measured in at least
one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with
conventional techniques or as greater than or equal 10 mm with spiral CT scan.
Patients with the above tumor types whose disease is limited to the skin are eligible
at the discretion of the PI and must have a physical exam with documentation of skin
lesion(s) by color photography, including a ruler to estimate the size of the
lesion(s).

- Diagnosis of malignancy must be confirmed by the department of pathology at the
institution where the patient is enrolled prior to patient enrollment.

- Any prior therapy must have been completed greater than or equal to 4 weeks prior to
enrollment on protocol and the participant must have recovered to eligibility levels
from prior toxicity. Patients should be at least six weeks out from nitrosoureas and
mitomycin C. Prior radiation should have been completed greater than or equal to 4
weeks prior to study enrollment and all associated toxicities resolved to eligibility
levels. Patients must be greater than or equal to 2 weeks since any investigational
agent administered as part of a Phase 0 study (also referred to as an early Phase I
study" or "pre-Phase I study" where a sub-therapeutic dose of drug is administered) at
the PI's discretion, and should have recovered to eligibility levels from any
toxicities.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of FdCyd and THU in patients less than 18 years of age,
children are excluded from this study, but may be eligible for future pediatric Phase
I combination trials.

- Karnofsky performance status greater than or equal to 60%.

- Life expectancy of greater than 3 months.

- Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin less than 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of
normal; less than or equal to 5 times ULN for patients with liver metastases

- creatinine less than 1.5 times institutional upper limit of normal

OR

--creatinine clearance greater than or equal to 60 mL/min for patients with creatinine
levels above 1.5 times institutional upper limit of normal.

- Because FdCyd has been shown to be teratogenic in animals, pregnant women will be
excluded from this trial. Nursing women are also excluded, as there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with FdCyd. Women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) for the
duration of study participation, and for 3 months after completion of study. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she or her partner should inform the treating physician
immediately.

- Ability to understand and the willingness to sign a written informed consent document.

- Patients should not be receiving any other investigational agents.

EXCLUSION CRITERIA:

-Patients with clinically significant illnesses which would compromise participation in the
study, including, but not limited to: active or uncontrolled infection, immune deficiencies
or confirmed diagnosis of HIV infection, active infection with Hepatitis B or Hepatitis C,

uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure,
unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled
cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance

with study requirements.

-History of allergic reactions attributed to fluoropyrimidines (e.g., capecitabine,
fluorouracil, fluorodeoxyuridine) or tetrahydrouridine.
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Gender: All

Minimum Age: 18 Years

Maximum Age: 120 Years

Healthy Volunteers: No

Official Information

Name: James H Doroshow, M.D.

Role: Principal Investigator

Affiliation: National Cancer Institute (NCI)

Overall Contact

Name: Jennifer H Zlott

Phone: (301) 435-5664

Email: zlottjh@mail.nih.gov

Link: NIH Clinical Center Detailed Web Page

Locations

Facility Status Contact
University of California, Davis
Davis, California 95616
United States
Recruiting
City of Hope National Medical Center
Duarte, California 91010
United States
Recruiting
City of Hope Medical Group
South Pasadena, California 91030
United States
Recruiting
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland 20892
United States
Recruiting For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
(888) NCI-1937