Cytarabine With or Without VNP40101M in Treating Patients With Relapsed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cytarabine and VNP40101M, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This randomized phase III trial is studying cytarabine and VNP40101M to see how well they work compared to cytarabine alone in treating patients with relapsed acute myeloid leukemia.

Detailed Description
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OBJECTIVES: Primary Compare the complete response (CR) and CR (with platelet count < 100,000/mm^3 but ≥ 20,000/mm^3 [transfusion independent for ≥ 7 consecutive days]) (CRp) rates in patients with acute myeloid leukemia in first relapse treated with cytarabine with vs without VNP40101M. Secondary Compare time to progression in patients treated with these regimens. Compare duration of response in patients treated with these regimens. Compare the survival of patients treated with these regimens. Compare the toxicity of these regimens in these patients. OUTLINE: This is a randomized, double-blind, placebo-controlled, parallel group, multicenter study. Patients are stratified according to age (< 60 years vs ≥ 60 years) and duration of first complete response (CR) or CR (with platelet count < 100,000/mm³ but ≥ 20,000/mm³ [transfusion independent for ≥ 7 consecutive days]) (CRp) (< 12 months vs ≥ 12 months). Induction therapy: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive cytarabine IV continuously on days 1-3 and VNP40101M IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine). Arm II: Patients receive cytarabine as in arm I and placebo IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine). In both arms, patients demonstrating at least 20% reduction of blasts in bone marrow (based on total cellularity and percent blasts) after course 1 may receive 1 additional course of induction therapy between days 35-60 in the absence of disease progression or unacceptable toxicity. Patients achieving CR or CRp after 1 or 2 courses of induction therapy proceed to consolidation therapy. Consolidation therapy: Beginning 6 weeks after initial documentation of CR or CRp, patients receive 1 course of consolidation therapy, as per induction therapy, according to their randomized treatment arm. These patients may then proceed to other consolidation, maintenance, and/or intensification therapy (including stem cell transplantation) off study at the discretion of the physician. After completion of study treatment, patients are followed monthly for 6 months, every 2 months for 6 months, and then every 3 months for 2 years. PROJECTED ACCRUAL: A total of 420 patients (280 in arm I and 140 in arm II) will be accrued for this study within 24-30 months.

Official Title
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A Phase III Randomized of Cloretazine™ (VNP40101M) and Cytosine Arabinoside (AraC) in Patients With Acute Myeloid Leukemia in First Relapse

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cytarabine
* Drug: laromustine
* Other: placebo


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed acute myeloid leukemia (AML) Any WHO classification, excluding acute promyelocytic leukemia At least 10% blasts by bone marrow aspirate and/or biopsy In first relapse after achieving a first complete response (CR) OR CR (with platelet count < 100,000/mm³ but ≥ 20,000/mm³ [transfusion independent for ≥ 7 consecutive days]) (CRp) that lasted ≥ 3 months but ≤ 24 months after completion of the initial induction regimen Relapse confirmed by recurrence of blasts in peripheral blood, bone marrow histopathology, and/or histologically confirmed CNS or extramedullary disease PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 Life expectancy Not specified Hematopoietic See Disease Characteristics Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST ≤ 3 times ULN Chronic hepatitis allowed Renal Creatinine ≤ 2.0 mg/dL Cardiovascular No myocardial infarction within the past 3 months No uncontrolled arrhythmias No uncontrolled congestive heart failure Pulmonary No severe chronic obstructive pulmonary disease No requirement for supplemental oxygen at rest Immunologic No uncontrolled active infection Infections that are controlled and under active treatment with antibiotics allowed No evidence of invasive fungal infection by blood or tissue cultures Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study treatment No clinical evidence of another active malignancy by tumor marker, pathology, or radiologic studies No other severe medical condition that would preclude study treatment PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy At least 12 hours since prior hydroxyurea Endocrine therapy Not specified Radiotherapy Not specified Surgery Not specified Other No prior treatment while in first relapse except hydroxyurea No other concurrent standard or investigational treatment for AML No concurrent disulfiram (Antabuse®)

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
Allocation: Randomized
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction therapy arm I<br>Patients receive cytarabine IV continuously on days 1-3 and VNP40101M IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine). | Drug: cytarabine<br>* Given IV<br>Drug: laromustine<br>* Given IV<br>|
| Active Comparator: Induction therapy arm II<br>Patients receive cytarabine as in arm I and placebo IV over 30-60 minutes on day 2 (at least 12 hours after the start of cytarabine). | Drug: cytarabine<br>* Given IV<br>Other: placebo<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to tumor progression |  |  | 
| Duration of response |  |  | 
| Overall response |  |  | 
| Toxicity |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), recurrent adult acute myeloid leukemia, adult acute basophilic leukemia, adult acute eosinophilic leukemia, adult erythroleukemia (M6a), adult pure erythroid leukemia (M6b), adult acute megakaryoblastic leukemia (M7), adult acute minimally differentiated myeloid leukemia (M0), adult acute monoblastic leukemia (M5a), adult acute monocytic leukemia (M5b), adult acute myeloblastic leukemia with maturation (M2), adult acute myeloblastic leukemia without maturation (M1), adult acute myelomonocytic leukemia (M4)