MS-275 in Treating Patients With Hematologic Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. PURPOSE: Phase I trial to study the effectiveness of MS-275 in treating patients who have hematologic cancer.

Detailed Description
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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.

Official Title
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Phase I Clinical-Labratory Study of the Histone Deacetylase (HDA) Inhibitor MS-275 in Adults With Refractory and Relapsed Hematologic Malignancies

Conditions
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Leukemia, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

Intervention / Treatment
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* Drug: entinostat


Participation Criteria
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Eligibility Criteria
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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

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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: entinostat|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory multiple myeloma, recurrent adult acute myeloid leukemia, recurrent adult acute lymphoblastic leukemia, relapsing chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, untreated adult acute lymphoblastic leukemia, untreated adult acute myeloid leukemia, adult acute promyelocytic leukemia (M3), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia, secondary acute myeloid leukemia, de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, atypical chronic myeloid leukemia, myelodysplastic/myeloproliferative disease, unclassifiable, adult acute myeloid leukemia with t(8;21)(q22;q22), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with t(15;17)(q22;q12)