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