GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia

OBJECTIVES:

I. Determine the maximum tolerated dose of GTI-2040 in patients with relapsed, refractory,
or high-risk acute leukemia, high-grade myelodysplastic syndromes, or refractory or blastic
phase chronic myelogenous leukemia.

II. Assess the toxicity and efficacy of this drug in these patients. III. Assess plasma and
intracellular pharmacokinetics of this drug in these patients.

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive GTI-2040 IV continuously on days 1-4 and 15-18. Treatment repeats every 28
days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of GTI-2040 until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6
patients experience dose-limiting toxicity.

Blood samples are collected on days 1, 4, 15, and 19 of course 1 for pharmacokinetic
studies. Samples are analyzed by proteomic assay, dCTP pool measurement, and real-time
polymerase chain reaction for mRNA of RRM2, RRM1, and p53R2.

Inclusion Criteria:

- Diagnosis of 1 of the following:

- Acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to
primary standard induction therapy

- Relapsed or refractory acute leukemia

- Chronic myelogenous leukemia (CML) in blast crisis at diagnosis OR that failed
prior aggressive induction chemotherapy

- Diagnosis of 1 of the following:

- Acute leukemia secondary to preexisting hematologic condition or prior
chemotherapy at diagnosis OR that failed prior aggressive induction chemotherapy

- Advanced myelodysplastic syndromes (intermediate-1 or greater)

- De novo acute leukemia (myeloid or nonmyeloid)

- Not a candidate for aggressive standard induction chemotherapy

- De novo AML or ALL (patients > 60 years of age)

- No suspected or proven active CNS leukemia

- ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100%

- Life expectancy >= 8 weeks

- Bilirubin =< 1.5 mg/dL

- AST and ALT < 3 times upper limit of normal (ULN)

- Creatinine =< 1.5 times ULN

- No HIV positivity

- Fertile patients must use effective contraception

- No history of allergic reactions attributed to other phosphorothiolated
oligonucleotides

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing, active, or poorly controlled infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Cardiac arrhythmia

- Poorly controlled pulmonary disease

- Psychiatric illness or social situation that would preclude study compliance

- Recovered from all prior therapies

- Prior autologous or allogeneic stem cell transplantation allowed (No active
graft-vs-host disease > grade 2)

- At least 2 weeks since prior and no concurrent cytotoxic chemotherapy

- At least 2 weeks since prior and no concurrent biologic therapy

- At least 2 weeks since any other prior investigational agent

- No other concurrent anticancer therapy, including radiotherapy or hormonal therapy

- Concurrent imatinib mesylate for CML allowed

- Not pregnant or nursing

- Negative pregancy test