MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia

Study Overview
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Brief Summary
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This phase II trial is studying how well giving MS-275 together with GM-CSF works in treating patients with myelodysplastic syndrome and/or relapsed or refractory acute myeloid leukemia. MS-275 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving MS-275 together with GM-CSF may be an effective treatment for myelodysplastic syndrome and acute myeloid leukemia

Detailed Description
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PRIMARY OBJECTIVE: I. Determine clinical response in patients with myelodysplastic syndromes and/or relapsed or refractory acute myeloid leukemia or acute lymphocytic leukemia treated with MS-275 in combination with sargramostim (GM-CSF). SECONDARY OBJECTIVES: I. Determine the clinical activity of this regimen, in terms of changes in peripheral blood counts and changes in individual patient transfusion requirements, in these patients. II. Determine the biologic activity of this regimen, in terms of changes in the peripheral blood and bone marrow phenotype (i.e., induction of markers of myeloid differentiation or lymphoid differentiation) and changes in detectable cytogenetic abnormalities in the blood and marrow compartments, in these patients. III. Determine the toxicity profile of this regimen in these patients. OUTLINE: Patients receive oral MS-275 on days 1, 8, 15, and 22. Patients also receive sargramostim (GM-CSF) subcutaneously once daily on days 1-42 in courses 3 and 5 and on days 1-35 in courses 1, 2, 4, and 6. Treatment repeats every 6 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria. Patients undergo blood and bone marrow (BM) collection at baseline and periodically during study for biologic correlative studies. Peripheral blood and bone marrow samples are assessed for changes in progenitor phenotype and clonogenic growth by flow cytometry and for changes in cytogenetics (i.e., malignant:nonmalignant cell ratio in BM CD34-positive cells, peripheral blood monocytes, peripheral blood neutrophils, and bone marrow and peripheral blood lymphoblasts) by FISH. Terminal differentiation of CD34-positive progenitor cells is studied in vitro in long-term cultures. After completion of study therapy, patients are followed periodically for up to 2 years.

Official Title
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A Phase II Study of and Oral Histone Deacytylase Inhibitor, MS-275 (NSC 706995), in Combination With Sargramostim (GM-CSF, Berlex, Inc.) Treating Relapsed and Refractory Myeloid Malignancies

Conditions
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Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0), Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Adult Acute Myelomonocytic Leukemia (M4), Adult Erythroleukemia (M6a), Adult Pure Erythroid Leukemia (M6b), Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Ringed Sideroblasts, Refractory Cytopenia With Multilineage Dysplasia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Untreated Adult Acute Lymphoblastic Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: entinostat
* Drug: sargramostim


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of 1 of the following diseases by bone marrow aspiration and/or biopsy: Myelodysplastic syndromes (MDS) meeting the following criteria: Must have 1 of the following subtypes: Refractory anemia (RA) (no RA with 5q-syndrome), RA with ringed sideroblasts or Refractory cytopenia with multilineage dysplasia Myelodysplastic syndromes (MDS) meeting the following criteria: Must have 1 of the following subtypes: Refractory cytopenia with multilineage dysplasia and ringed sideroblasts, RA with excess blasts (RAEB)-1, RAEB-2, Myelodysplastic syndromes, unclassified or Chronic myelomonocytic leukemia International Prognostic Scoring System score of intermediate-2 or high-risk Acute myeloid leukemia (AML) meeting 1 of the following criteria: Relapsed or refractory AML, including any of the following subtypes: * AML with recurrent cytogenetic abnormalities (i.e., AML with 11q23 [MLL] abnormalities) AML with multilineage dysplasia AML that is therapy-related AML, not otherwise categorized (M0 [minimally differentiated], M1 [without maturation], M2 [with maturation], M4 [myelomonocytic leukemia], M5 [monoblastic/monocytic leukemia], M6 [erythroid leukemia], and M7 [megakaryoblastic leukemia]) Untreated AML Newly diagnosed patients are eligible provided they do not qualify for potentially curative intensive chemotherapeutic regimens Acute lymphocytic leukemia (ALL) meeting 1 of the following criteria: Relapsed or refractory ALL Patients with any measurable residual disease are eligible, including cytogenetic abnormalities Untreated ALL Newly diagnosed patients are eligible provided they do not qualify for potentially curative intensive chemotherapeutic regimens, including any of the following: Patients who have refused chemotherapy for untreated ALL Patients who are deemed to be poor candidates medically for ALL induction chemotherapy Relatively stable bone marrow function for > 7 days prior to study entry WBC count that has not doubled within the past 7 days WBC =<10,000/mm³ No uncontrolled peripheral leukemia (i.e., blast count > 30,000/mm³) No active CNS disease Lumbar puncture with negative cytology required for patients with clinical symptoms of active CNS disease Not a candidate for a potentially curative allogeneic stem cell transplantation OR considered a poor candidate for such a procedure due to age, medical comorbidities, or lack of a suitable donor Hemoglobin >= 8 g/dL (transfusions allowed) Creatinine =< 2.0 mg/dL Bilirubin =< 1.6 mg/dL (unless secondary to hemolysis) AST or ALT =< 3 times upper limit of normal (unless disease-related) Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No untreated or progressive infections No history of intolerance to sargramostim (GM-CSF) Recovered from all treatment-related toxicities More than 2 weeks since prior therapy for AML, ALL, or MDS, including chemotherapy, hematopoietic growth factors, or biologic therapy such as monoclonal antibodies Concurrent hydroxyurea allowed during course 1 for control of leukocytosis if WBC > 30,000/mm³ ECOG performance status 0-2

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral MS-275 on days 1, 8, 15, and 22. Patients also receive sargramostim (GM-CSF) subcutaneously once daily on days 1-42 in courses 3 and 5 and on days 1-35 in courses 1, 2, 4, and 6. Treatment repeats every 6 weeks for 2-6 courses in the absence of disease progression or unacceptable toxicity. After completion of 2 courses of study therapy, patients who achieve a complete or partial response may receive an additional 4 courses. Patients who maintain stable disease for more than 2 months after completion of 6 courses of study therapy may receive an additional 6 courses at the time of disease progression, provided they meet original eligibility criteria. | Drug: entinostat<br>* Given PO<br>* Other names: SNDX-275;Drug: sargramostim<br>* Given SC<br>* Other names: Prokine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (Complete and Partial Response) in Patients With Myeloid Disorders | Response to treatment was assessed after two cycles, according to International Working Group (IWG) criteria. Cytogenetic responses were monitored in patients with abnormalities at baseline. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Activity Assessed by Change in Peripheral Blood Counts |  | Baseline and after 2 cycles | 
| Clinical Activity Assessed by Change in Transfusion Requirements |  | Baseline and after 2 cycles | 
| Changes in Detectable Chromosomal Abnormalities Measured by Fluorescent in Situ Hybridization (FISH) |  | Baseline and 6, 12, 24, and 36 weeks | 
| Change in the Percentage of Cells With Normal and Abnormal Myeloid Phenotype Measured by Flow Cytometry |  | Baseline and 6, 12, 24, and 36 weeks |