Phase I Study of Continuous Infusion Schedule of FMdC in Hematologic Malignancies

Patients with leukemias that have relapsed from previous therapies have a low cure rate.
Hence the need to discover new antileukemic agents. Tezacitabine is a nucleoside analogue
with equivalent or even superior activity when compared with ara-C in leukemic cell lines. It
has shown significant antitumor activity in vitro and in vivo tumor models. Several phase I
studies with various dosing schedules have been conducted in solid tumors where the
dose-limiting toxicity (DLT) is mainly myelosuppression, usually a favorable feature for
development of leukemia. In a phase I study in hematological malignancies, we used
Tezacitabine as a bolus infusion daily x 5. The DLT consisted of grade 3 CNS toxicities and
mucositis in 3/6 patients. The study is ongoing and we are currently evaluating a dose level
of 7.5 mg/m2 as possible Maximum Tolerated Dose (MTD). However, in view of the fact that
tezacitabine is a cell cycle specific agent with a short terminal plasma half-life of 2 to 6
hours, a continuous infusion dosing schedule may enhance the activity and reduce the
incidence of adverse effects of tezacitabine.

- Patient with relapsed/refractory acute leukemias (AML, ALL, high-grade myelodysplastic
syndromes, CMML in transformation with >/= 10% peripheral blood/bone marrow blasts,
CML in blast crisis), or patients with relapsed/refractory CLL and an absolute
neutrophil count of >/= 1,000/ml and platelet count of >/= 75,000/ml.

- Signed informed consent indicating that patients are aware of the investigational
nature of this study, and in keeping with the policies of this hospital. The only
acceptable consent form is attached at the end of this protocol.

- Age >/= 15 years.

- ECOG performance status
- No severe, concurrent disease, infection, or co-morbidity that, in the judgment of the
Investigator, would make the patient inappropriate for study entry.

- Pregnant and/or lactating females are not eligible.

- Normal organ function (serum bilirubin £ 2 mg/dL, serum creatinine £ 2 mg/dL).
Patients with renal or liver dysfunction due to organ leukemic involvement may be
eligible after discussion with the principle investigator.

- Patients must be off of all previous chemotherapy, immunotherapy, or radiotherapy for
at least 2 weeks prior to entering this study, and must have recovered from all toxic
effects, unless life-threatening increases in tumor burden occur.