FdCyd and THU for Advanced Solid Tumors

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.

- Intravenous FdCyd with THU has been evaluated in a Phase I clinical trial with some
preliminary evidence of activity. This trial will investigate oral administration of the
drugs, which was shown to be feasible in an expansion cohort of the previous trial.

Primary objectives:

-Establish the safety and tolerability of oral FdCyd in combination with oral THU
administered on an intermittent schedule in 21-day cycles to patients with refractory solid
tumors

Exploratory objectives:

- Determine the pharmacokinetics of oral FdCyd and oral THU

- Document preliminary evidence of activity of oral FdCyd and oral THU

- Determine effect of study treatment on re-expression of p16 and other select genes
silenced by methylation in circulating tumor cells and tumor biopsies

- Evaluate the effect of study treatment on DNA (cytosine-5)-methyltransferase 1 and 3
(DNMT1 and DNMT3) expression in tumor biopsies

Eligibility:

-Adults with histologically documented solid tumors whose disease has progressed after at
least one line of standard therapy.

Design:

- This is a multicenter trial with NCI as the coordinating center.

- FdCyd and THU will be administered on an intermittent schedule in 21-day cycles. THU
will be administered orally at a fixed dose of 3000 mg 30 minutes prior to FdCyd.

- The trial will follow a standard Phase I dose escalation design (3-6 patients per
cohort).

- Consideration will be given to increasing the days of administration of FdCyd with THU
after a target maximum plasma concentration of FdCyd is reached.

- Blood and urine for pharmacokinetic studies will be obtained from all patients. Blood
for pharmacodynamic studies will be obtained after we achieve a target Cmax of 1microM.

- Up to 25 patients will be enrolled in the expansion cohort, from which mandatory pre-
and post-dose tumor biopsies will be collected for the assessment of pharmacodynamic
endpoints, at dose level 8 (160 mg FdCyd+3000 mg THU 1x daily days 1-6 days week 1, days
8-13 week 2, in 21-day cycles)

- INCLUSION CRITERIA:

- Patients must have histologically documented solid tumors whose disease has progressed
on standard therapy that is known to be associated with a survival advantage or have
disease for which there is no known standard therapy.

- Patients must have measurable or evaluable disease.

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

- Patients must have completed any chemotherapy, radiation therapy, biologic therapy, or
major surgery greater than or equal to 4 weeks prior to enrollment (6 weeks for
nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since
any prior administration of a study drug in a Phase 0 or equivalent study, at the
discretion of the Principal Investigator. Patients must have recovered to eligibility
levels from prior toxicity or adverse events. Patients with bone metastases or
hypercalcemia on IV bisphosphonate treatment prior to study entry may continue this
treatment.

- Age greater than or equal to18 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 countgreater than or equal to 1,500/mcL

- plateletsgreater than or equal to 100,000/mcL

- total bilirubinless than or equal to 1.5 X institutional upper limit of
normal

- AST(SGOT)/ALT(SGPT)greater than or equal to 3 X institutional upper limit of
normal

- creatinineless than 1.5 X institutional upper limit of normal

OR

--creatinine clearancegreater than or equal to 60 ML/min for patients with
creatinine levels

Above 1.5 X institutional upper limit of normal

- Because FdCyd has been shown to be teratogenic in animals, pregnant women are 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 childbearing potential must agree to either abstain from sexual
intercourse or use two forms of acceptable birth control, including one barrier
method, for 4 weeks prior to study entry, for the duration of study participation, and
for 3 months after completion of study. Men must use a latex condom every time they
have sexual intercourse during therapy and for 3 months after study completion, even
if they have had a successful vasectomy. 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.

- Ability to swallow liquids.

- Willingness to provide blood and urine samples, and biopsy samples if on the expansion
phase of the study, for research purposes. For the expansion cohort, patients must
have tumor amenable to biospy (excisional or incision biopsies of skin or H & N
lesions under visualization) and willingness to undergo a tumor biopsy or patient will
be undergoing a procedure due to medical necessity during which the tissue may be
collected, or tumor biopsy tissue from a previous research study or medical care is
available for submission at registration. Criteria for the submission of tissue are:

- Tissue must have been collected within 3 months prior to registration

- Patient has not received any intervening therapy for their cancer since the
collection of the tumor sample

- Tumor tissue must meet the minimum requirements

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, known HIV infection requiring protease inhibitor therapy, Hepatitis B,
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.

- Patients with known brain metastases or carcinomatous meningitis are excluded from
this clinical trial, with the exception of patients whose brain metastatic disease
status has remained stable for greater than or equal to 2 months after treatment of
the brain metastases. Patients should be on stable doses of anti-seizure medications.
These patients may be enrolled at the discretion of the Principal Investigator.

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

- Malabsorption syndrome or other conditions that would interfere with intestinal
absorption.