Phase I Trial of 4'-Thio-2'-Deoxycytidine (TdCyd) in Patients 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 4'-thio-2'-deoxycytidine (TdCyd) 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 reactivation of tumor suppressor genes.

- Data generated at Southern Research Institute and the NCI suggest a correlation between
TdCyd activity in solid tumor xenograft models and decreased levels of DNMT1.

- TdCyd offers an improvement over current DNA methyltransferase inhibitors by virtue of a
higher incorporation rate into DNA at lower levels of cytotoxicity; treatment with TdCyd
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.

- Two patients on dose levels 6 and 7 developed Pneumocystis jiroveci pneumonia (PJP) so
all patients will be administered PJP prophylaxis.

Primary Objective:

-To establish the safety, tolerability, and MTD of oral TdCyd 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 TdCyd

- To document preliminary evidence of TdCyd activity

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

Eligibility:

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

Study Design:

- TdCyd 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.

- Patients must have measurable or evaluable disease.

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

- ECOG performance status less than or equal to 2.

- Life expectancy > 3 months.

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

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

2. platelets greater than or equal to 100,000/mcL

3. total bilirubin less than or equal to 1.5 times institutional upper limit of
normal

4. AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of
normal

5. creatinine less than or equal to 1.5 times institutional upper limit of normal

OR

e. creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above 1.5 times 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 TdCyd.

- 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 administration of a study drug in a phase 0
or equivalent study and 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.

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, 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 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.