Temozolomide and VNP40101M in Treating Patients With Relapsed or Refractory Leukemias

OBJECTIVES:

• Determine the maximum tolerated dose of temozolomide and VNP40101M in patients with relapsed or refractory leukemias.
• Determine the toxic effects of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation, multicenter study.

Patients receive oral temozolomide twice daily on days 1-3 (for 5 doses) followed by VNP401010M IV over 15-60 minutes on day 3 (course 1). Patients achieving a complete or partial response or having ≥ 50% reduction in bone marrow blasts may receive a second course of therapy no earlier than day 43. Courses may be repeated approximately every 6 weeks at the discretion of the sponsor and in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of temozolomide until a dose that depletes leukemic blast AGT in at least 4 of 6 patients is determined. Once this dose is determined, cohorts of 3-6 patients receive escalating doses of VNP401010M 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. Up to 10 patients are treated at the MTD.

PROJECTED ACCRUAL: Approximately 25 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

• Acute myeloid leukemia
• Acute lymphoblastic leukemia
• Chronic myelogenous leukemia in blast crisis
• Relapsed or refractory disease
• No known standard therapy that is anticipated to result in a durable remission exists
• CNS leukemia allowed

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT or AST ≤ 3 times ULN
• Chronic hepatitis allowed

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• No active heart disease, including any of the following:

• Myocardial infarction within the past 3 months
• Symptomatic coronary artery disease
• Arrhythmias not controlled by medication
• Uncontrolled congestive heart failure

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• No uncontrolled active infection

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Concurrent hydroxyurea allowed within the first 10 days of study drug administration for control of elevated blast levels or platelet counts

• Maximum hydroxyurea dose 5 g daily
• No persistent chronic toxic effects from prior chemotherapy > grade 1

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• Recovered from all prior therapy
• At least 2 weeks since prior myelosuppressive cytotoxic agents (in the absence of rapidly progressive disease)
• No more than 2 leukapheresis procedures within the first 10 days of study drug administration for control of elevated blast levels or platelet counts
• No concurrent disulfiram
• No other concurrent anticancer drugs
• No other concurrent standard or investigational treatment for leukemia