A Phase II Study of Cloretazine® (VNP40101M) for Elderly Patients With De Novo Poor Risk Acute Myelogenous Leukemia

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed de novo acute myeloid leukemia (AML)

- No acute promyelocytic leukemia [t(15;17)]

- No favorable cytogenetics, including t(15;17), t(8;21), or inv 16

- No secondary AML, defined as having a history of an antecedent hematologic
disorder (myelodysplastic syndromes [MDS] or myeloproliferative disease), or
history of prior chemotherapy or radiation for a disease other than AML

- Must have ≥ 1 of the following poor-risk features:

- Any of the following unfavorable cytogenetics:

- Del (5q)/-5q

- -7/del(7q)

- Abnormal 3q, 9q, 11q, 20q, 21q, or 17p

- t(6;9)

- t(9;22)

- Trisomy 8

- Complex karyotypes (≥ 3 unrelated abnormalities)

- At least 70 years of age

- ECOG performance status (PS) of 2

- Cardiac dysfunction* that would limit the use of anthracycline therapy, as
defined by any of the following:

- Ejection fraction ≤ 50%

- History of significant coronary artery disease, defined as ≥ 1 vessel
stenosis requiring medical treatment, stent placement, or surgical bypass
graft

- History of congestive heart failure or myocardial infarction

- Significant arrhythmia, including any of the following:

- Atrial flutter (excluding atrial fibrillation)

- Sick sinus syndrome

- Ventricular arrhythmia

- Heart valve disease

- Mitral valve prolapse allowed

- Other heart disease, at the discretion of the principal investigator

- Pulmonary dysfunction not related to AML, defined by 1 of the following:

- DLCO and/or FEV_1 < 80% and ≥ 50% normal range

- Dyspnea on slight activity or at rest

- Requires oxygen

- Hepatic dysfunction related to chronic hepatitis or liver cirrhosis

- Other organ dysfunction or comorbidity that precludes standard cytotoxic
induction treatment (e.g., "3+7"), at the discretion of the principal
investigator NOTE: *Patients with a history of heart disease as defined above
must be on appropriate medication and have their disease under control

- No known CNS disease

PATIENT CHARACTERISTICS:

- ECOG PS 0-2

- AST and ALT ≤ 5 times upper limit of normal

- Bilirubin ≤ 2.0 mg/dL

- Creatinine ≤ 2.0 mg/dL

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after
completion of study treatment

- No active, uncontrolled infection

- Patients with an infection who are under active treatment with antibiotics and
whose infections are controlled are eligible

- Chronic hepatitis allowed

- No clinical evidence of ongoing second malignancy unrelated to AML or MDS

- No evidence of left bundle branch block on screening ECG

- No obligate use of cardiac pacemaker or atrial fibrillation

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 24 hours since prior metronidazole

- No prior low-dose, single-agent, cytotoxic chemotherapy (e.g., cytarabine,
decitabine, or azacitidine)

- No concurrent disulfiram

- No other concurrent standard or investigational therapy for AML except for the
following:

- Concurrent hydroxyurea to control rising white blood cell counts

- Dosage must be 4-6 grams daily for up to 4 days

- Concurrent leukapheresis to control blast cell counts

- Must be completed within the first 5 days of study therapy

- No more than 2 procedures per day or 4 procedures total

- Investigational supportive care agents (e.g., antimicrobials or antifungal
agents), at the discretion of the protocol sponsor