MS-275 in Treating Patients With Hematologic Cancer

OBJECTIVES:

• Determine the toxic effects and pharmacokinetics of MS-275 in patients with poor-risk hematologic malignancy.
• Determine whether this drug induces changes in hematologic differentiation, in terms of changes in morphology, cell surface marker expression, and acetylation status, in these patients.
• Determine whether this drug induces clinical response in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive oral MS-275 on days 1, 8, 15, and 22. Courses repeat every 6 weeks 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. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: Approximately 25-30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• One of the following histologically confirmed diagnoses:

• Acute myeloid leukemia (AML)

• Newly diagnosed de novo AML in patients over 60 years old with the following poor-risk features:

• Antecedent hematologic disorder
• Complex karyotype or other adverse cytogenetics
• Stem cell immunophenotype
• AML arising from myelodysplastic syndromes (MDS)
• Secondary AML
• Relapsed or refractory AML, including primary induction failure
• MDS

• Poor-risk, defined as the following:

• International Performance Score at least 1.5
• More than 10% marrow blasts
• Cytopenias in at least 2 lineages
• Refractory anemia with excess blasts (RAEB)
• RAEB in transformation
• Chronic myelomonocytic leukemia
• Acute lymphoblastic leukemia (ALL)

• Newly diagnosed de novo ALL in patients over 60 years old with the following poor-risk features:

• Complex karyotype or other adverse cytogenetics
• Mixed lineage immunophenotype
• Relapsed or refractory ALL, including primary induction failure
• Chronic myelogenous leukemia (CML)

• CML in accelerated phase or blast crisis
• Interferon-refractory CML in chronic phase
• Multiple myeloma (MM)

• Relapsed or refractory, including prior autologous stem cell transplantation
• Acute promyelocytic leukemia

• Prior treatment with tretinoin
• Ineligible for arsenic trioxide
• No evidence of active coagulopathy
• Low-risk for developing clinically significant coagulopathy during study

• Low tumor burden by marrow aspiration at time of relapse
• No prior coagulation-related sequelae (deep vein thrombosis, pulmonary embolism, or CNS thrombosis or bleed)
• Failure after primary induction therapy or relapse after complete remission allowed if patient received no more than 3 courses of prior induction/reinduction therapy
• Not eligible for curative stem cell transplantation
• No hyperleukocytosis with at least 50,000/mm^3 leukemic blasts
• No active CNS leukemia
• No plasma cell leukemia
• No amyloidosis resulting in major organ dysfunction

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics
• No disseminated intravascular coagulation
• No hyperviscosity

Hepatic:

• AST/ALT no greater than 2 times normal
• Alkaline phosphatase no greater than 2 times normal
• Bilirubin no greater than 1.5 times normal

Renal:

• Creatinine no greater than 1.5 times normal
• No uncorrected hypercalcemia

Cardiovascular:

• See Disease Characteristics
• LVEF at least 45% by MUGA or echocardiogram
• No intrinsic impaired cardiac function, including any of the following:

• Myocardial infarction within the past 3 months
• Prior severe coronary artery disease
• Cardiomyopathy
• Congestive heart failure

Other:

• No active uncontrolled infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics
• At least 1 week since prior growth factors (epoetin alfa, filgrastim [G-CSF], sargramostim [GM-CSF], interleukin [IL]-3, or IL-11)
• At least 4 weeks since prior autologous stem cell transplantation
• No prior allogeneic stem cell transplantation
• No concurrent immunotherapy

Chemotherapy:

• See Disease Characteristics
• At least 3 weeks since prior chemotherapy and recovered
• At least 24 hours since prior hydroxyurea or mercaptopurine for prevention of leukostasis
• No concurrent chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 2 weeks since prior emergency radiotherapy to large soft tissue or lytic bony lesions for MM
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• At least 24 hours since other prior noncytotoxic agents for prevention of leukostasis
• No other concurrent antitumor therapy