GTI-2040 and High-Dose Cytarabine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and recommended phase II dose of GTI-2040 and high-dose cytarabine in patients with relapsed or refractory acute myeloid leukemia.

SECONDARY OBJECTIVES:

I. Determine the therapeutic response in patients treated with this regimen. II. Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a dose-escalation study. Patients are stratified according to age (under age 60 vs age 60 and over). Patients are assigned to 1 of 2 strata.

Stratum I (under age 60): Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 2 hours twice daily on days 2, 4, and 6.

Stratum II (age 60 and over): Patients receive GTI-2040 IV continuously on days 1-6 and high-dose cytarabine IV over 4 hours once daily on days 2-6.

In both strata, treatment continues in the absence of unacceptable toxicity.

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

PROJECTED ACCRUAL: A total of 6-51patients will be accrued for this study within 2-16 months.

Inclusion criteria

• Histologically confirmed acute myeloid leukemia according to the WHO classification
• Relapsed or refractory disease, meeting 1 of the following criteria:

• Unresponsive to initial treatment
• Recurrent disease after treatment with prior conventional or high-dose chemotherapy with or without stem cell support
• CNS involvement allowed provided there are no residual leukemic cells detected in the cerebrospinal fluid after intrathecal or radiation chemotherapy
• Performance status - ECOG 0-2
• At least 4 weeks
• Bilirubin no greater than 2 times upper limit of normal* (ULN) (unless due to Gilbert's syndrome)
• AST and ALT no greater than 3 times ULN*
• Creatinine no greater than 1.5 mg/dL*
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• Resting ejection fraction at least 50%*
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergy to study medications
• No ongoing or active infection requiring IV antibiotics
• No other concurrent uncontrolled illness
• No serious medical or psychiatric illness that would preclude giving informed consent
• More than 4 weeks since prior chemotherapy (except hydroxyurea) (6 weeks for nitrosoureas or mitomycin)
• No other concurrent chemotherapy
• No concurrent hormonal therapy except steroids for adrenal failure and hormones for non-disease-related conditions (e.g., insulin for diabetes)
• More than 4 weeks since prior radiotherapy
• No concurrent palliative radiotherapy
• Prior therapy with antisense oligonucleotides allowed provided no toxic effects were experienced that were directly attributable to the antisense agents
• No other concurrent investigational agents
• No other concurrent anticancer therapy
• No concurrent chronic systemic anticoagulant therapy for medical conditions (e.g., prior deep vein thrombosis or atrial fibrillation)

• Concurrent heparin to maintain central line patency (i.e., catheter flush) is allowed
• No concurrent combination antiretroviral therapy for HIV-positive patients