5-aza-4'-Thio-2'-Deoxycytidine (Aza-TdC) in People With Advanced Solid Tumors

Background

- Methylation-mediated silencing of genes is an epigenetic mechanism implicated in
carcinogenesis; agents that inhibit this mechanism are of clinical interest because of
their potential to re-activate silenced tumor suppressor genes. Two DNA hypomethylating
nucleosides, 5-azacytidine (azacytidine) and 5-aza-2'-deoxycytidine (decitabine) have
been approved by the FDA for the treatment of patients with myelodysplastic syndromes
and certain leukemias.

- The nucleoside analog 5-aza-4 -thio-2 -deoxycytidine (Aza-TdC) is incorporated into DNA,
where it engages the active site of DNA methyltransferase I (DNMT1), a maintenance
methyltransferase that contributes to the hypermethylation and silencing of tumor
suppressor genes. DNMT1 can become trapped in a covalent complex with DNA, thus
depleting free enzyme and inhibiting the normal maintenance methylation of CpG sites,
resulting in re-activation of tumor suppressor genes.

- Data suggest a correlation between Aza-TdC activity in solid tumor xenograft models and
decreased levels of DNMT1.

- Aza-TdC offers an improvement over traditional DNA methyltransferase inhibitors by
virtue of a higher incorporation rate into DNA at lower levels of cytotoxicity; Aza-TdC
has greater antitumor activity than another recently developed DNMT1 inhibitor, TdCyd,
in some solid tumor xenograft models. Treatment with Aza-TdC is anticipated to result in
the inhibition of tumor growth due to DNMT1 depletion at oral doses that are well
tolerated in extended dosing schedules.

Primary Objective:

-To establish the safety, tolerability, and MTD of oral Aza-TdC administered daily for 5 days
a week for 2 weeks, with one week off, q 21-day cycles, to patients with refractory solid
tumors

Secondary Objectives:

- To determine the pharmacokinetics of oral Aza-TdC

- To document preliminary evidence of Aza-TdC activity

- To determine effect of study treatment on re-expression of select genes silenced by
methylation in circulating tumor cells

Eligibility:

-Patients greater than or equal to 18 years of age must have histologically documented solid
tumors whose disease has progressed on standard therapy or for which there is no available
standard therapy

Study Design:

- Aza-TdC will be administered orally once a day for 5 days of each week for 2 weeks, with
one week off, in 21-day cycles.

- The trial will follow an accelerated titration design, changing to a traditional 3+3
dose escalation design (3-6 patients per cohort) once specified toxicity criteria are
met. Intrapatient dose escalation will be allowed.

- Blood samples will be obtained for pharmacokinetic analysis and to isolate circulating
tumor cells to assess re-expression of genes silenced by methylation.

- INCLUSION CRITERIA:

- Patients must have histologically documented solid tumors whose disease has progressed
on standard therapy or for which there is no available standard therapy.

- Age greater than or equal to 18 years of age.

- ECOG performance status < 2

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

- absolute neutrophil count greater or equal to1,500/mcL

- platelets greater than or equal to100,000/mcL

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

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

OR

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

- creatinine less than or equal to 1.5X institutional upper limit of normal

OR

--creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels above 1.5X institutional normal

- Because nucleoside analogs are known to be teratogenic, women of child-bearing
potential and men must agree to use two forms of contraception (hormonal or barrier
method of birth control; abstinence; sterilization) prior to study entry, for the
duration of study participation, and for 3 months after completing study treatment.
Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use two forms of contraception
prior to the study, for the duration of study participation, and for 3 months after
completion of administration of Aza-TdC.

- Patients must have completed any chemotherapy, radiation therapy, or biologic therapy
greater than or equal to 4 weeks or 5 half-lives (whichever is shorter) (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study. Patients must be greater
than or equal to 2 weeks since any prior palliative radiation or cyberknife therapy.
Patients must have recovered to grade 1 from prior toxicity or adverse events.
Patients with bone metastases or hypercalcemia on intravenous bisphosphonate treatment
prior to study entry may continue this treatment.

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

- Willingness to provide blood and urine samples for research purposes.

- Ability to swallow pills/capsules.

- Left ventricular ejection fraction greater than 45% or the institutional lower limit
of normal by either ECHO or MUGA at entry.

EXCLUSION CRITERIA:

- Patients who are receiving any other investigational agents.

- Pregnant women and women who are breastfeeding are excluded from this study.

- 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, known
Hepatitis B, known 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 1 month after treatment of the
brain metastases.

Patients should not be on anti-seizure medications. These patients may be enrolled at the
discretion of the Principal Investigator.

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

INCLUSION OF WOMEN AND MINORITIES:

Both men and women of all races and ethnic groups are eligible for this trial.