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

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.

Primary objective:

-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.

Exploratory objectives:

- 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.

- 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.