Temozolomide and VNP40101M in Treating Patients With Relapsed or Refractory Leukemias

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as temozolomide and VNP40101M, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Temozolomide may also help VNP40101M kill more cancer cells by making cancer cells more sensitive to the drug. Giving temozolomide together with VNP40101M may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of temozolomide and VNP40101M in treating patients with relapsed or refractory leukemias.

Detailed Description
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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.

Official Title
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A Phase I Study Of Cloretazine™ (VNP40101M) And Temozolomide In Patients With Hematologic Malignancies

Conditions
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Leukemia

Intervention / Treatment
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* Drug: laromustine
* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: laromustine|nan|
|Drug: temozolomide|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent adult acute myeloid leukemia, recurrent adult acute lymphoblastic leukemia, blastic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, secondary acute myeloid leukemia, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22)