3-AP and High-Dose Cytarabine in Treating Patients With Advanced Hematologic Malignancies

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of 3-AP (Triapine) administered with high-dose cytarabine in patients with advanced hematologic malignancies.

SECONDARY OBJECTIVES:

I. Determine the clinical activity of this regimen in these patients. II. Determine the effect of treatment with 3-AP (Triapine) on intracellular levels of cytarabine in these patients.

OUTLINE: This is a dose-escalation study of 3-AP (Triapine).

Patients receive high-dose cytarabine IV over 2 hours on days 1-5 and 3-AP (Triapine) IV over 2 hours on days 2-5. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients in each stratum receive escalating doses of 3-AP (Triapine) 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.

Patients are followed for up to 2 years.

PROJECTED ACCRUAL: A total of 6-48 patients (3-24 per stratum) will be accrued for this study within 15-24 months.

Inclusion criteria

• Histologically confirmed diagnosis of 1 of the following hematologic malignancies:

• Relapsed or refractory acute myeloid leukemia (AML)
• Relapsed or refractory acute lymphoblastic leukemia
• Secondary AML, including AML arising from antecedent hematologic diseases, such as myelodysplastic syndromes or myeloproliferative disorders OR therapy-related AML
• Chronic myeloid leukemia in accelerated or blast phase
• Refractory to standard therapy or no standard therapy exists
• No known brain metastases
• Performance status - CALGB 0-2
• Performance status - Karnofsky 60-100%
• No G6PD deficiency
• Bilirubin < 2.0 mg/dL (unless due to Gilbert's syndrome)
• AST and ALT < 2.5 times upper limit of normal (ULN)
• Creatinine < 1.5 times ULN
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No pulmonary disease requiring oxygen
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior allergic reactions attributed to compounds of similar chemical or biological composition to study drugs
• No neuropathy
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other concurrent uncontrolled illness
• No concurrent biologic agents
• At least 72 hours since prior hydroxyurea
• At least 2 weeks since other prior chemotherapy (6 weeks for mitomycin or nitrosoureas)
• No other concurrent chemotherapy
• At least 2 weeks since prior radiotherapy
• No concurrent radiotherapy
• Recovered from all prior therapy
• At least 4 weeks since prior investigational agents
• No other concurrent investigational therapy
• No other concurrent anticancer therapy
• No concurrent combination antiretroviral therapy for HIV-positive patients