MS-275 and Azacitidine in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia

OBJECTIVES:

I. Determine the safety and toxicity of MS-275 and azacitidine in patients with
myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.

II. Determine the maximum tolerated dose and optimal phase II dose of MS-275 when combined
with azacitidine in these patients.

III. Determine, preliminarily, the potential therapeutic activity of this regimen in these
patients.

IV. Correlate MS-275 pharmacokinetics with clinical response and laboratory correlative
endpoints in patients treated with this regimen.

OUTLINE: This is a multicenter, dose-escalation study of MS-275. Patients receive azacitidine
subcutaneously on days 1-10 and oral MS-275 on days 3 and 10.

Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of MS-275 until the maximum tolerated dose
(MTD) is determined. Patients receive adjusted doses of azacitidine based on clinical
response. 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 9 additional patients are treated at the MTD.

[Note: Patients who do not achieve hematologic improvement or partial or complete response
but who have stable disease after 4 courses of therapy may receive an additional 4 courses of
therapy at a higher dose than what was originally assigned]

Inclusion Criteria:

- Diagnosis of 1 of the following:

- Histologically confirmed myelodysplastic syndromes (MDS) by bone marrow
aspiration and/or biopsy

- International Prognostic Scoring System (IPSS) score of intermediate-1,
intermediate-2, or high

- International Prognostic Scoring System (IPSS) score of intermediate-1,
intermediate-2, or high

- Low IPSS score allowed provided patient has a clinically significant cytopenia
(i.e., absolute neutrophil count < 1,000/mm^3, untransfused hemoglobin < 8 g/dL,
platelet count < 20,000/mm^3, or anemia requiring transfusion)

- Chronic myelomonocytic leukemia

- Acute myeloid leukemia (AML)

- Relapsed or refractory disease

- Untreated AML allowed provided patient meets >= 1 of the following criteria:

- Age 60 and over

- AML arising in the setting of an antecedent hematologic disorder

- High-risk cytogenetic abnormalities

- Medical conditions that may compromise the ability to give cytotoxic chemotherapy
as the primary modality

- Refused cytotoxic chemotherapy

- WBC < 30,000/mm3 for >= 2 weeks before study entry

- Acute promyelocytic leukemia allowed provided patient is in at least second relapse
and has already received treatment regimens containing arsenic trioxide and
isotretinoin

- No clinical evidence of CNS or pulmonary leukostasis or CNS leukemia

- Peformance status:

- Zubrod 0-2

- Life expectancy:

- At least 6 months

- Hematopoietic:

- See Disease Characteristics

- Hemoglobin ≥ 8 g/dL (transfusion allowed)

- No disseminated intravascular coagulation

- Renal:

- Creatinine normal OR

- Creatinine clearance >= 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after study
treatment

- No untreated, active infection

- No other serious or uncontrolled medical condition

- More than 3 weeks since prior hematopoietic growth factors for this malignancy

- At least 3 weeks since prior hydroxyurea (2 weeks for AML patients)

- No concurrent hydroxyurea

- Recovered from all prior therapy

- At least 2 weeks since prior cytotoxic therapy (AML patients)

- More than 3 weeks since other prior therapy for this malignancy

- No other concurrent investigational or commercial agents or therapies for this
malignancy

- No concurrent valproic acid

- Hepatic:

- Bilirubin normal unless due to hemolysis or Gilbert's syndrome

- AST and ALT =< 2.5 times upper limit of normal