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

Primary Purpose

Adult Acute Lymphoblastic Leukemia in Remission, Adult Acute Megakaryoblastic Leukemia (M7), Adult Acute Minimally Differentiated Myeloid Leukemia (M0)

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
entinostat
sargramostim
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Lymphoblastic Leukemia in Remission

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Johns Hopkins University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Clinical Activity Assessed by Change in Peripheral Blood Counts
Clinical Activity Assessed by Change in Transfusion Requirements
Changes in Detectable Chromosomal Abnormalities Measured by Fluorescent in Situ Hybridization (FISH)
Change in the Percentage of Cells With Normal and Abnormal Myeloid Phenotype Measured by Flow Cytometry

Full Information

First Posted
April 18, 2007
Last Updated
June 16, 2017
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00462605
Brief Title
MS-275 and GM-CSF in Treating Patients With Myelodysplastic Syndrome and/or Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphocytic Leukemia
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
April 2007 (undefined)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
March 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
entinostat
Other Intervention Name(s)
HDAC inhibitor SNDX-275, SNDX-275
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
sargramostim
Other Intervention Name(s)
GM-CSF, Leukine, Prokine
Intervention Description
Given SC
Primary Outcome Measure Information:
Title
Response (Complete and Partial Response) in Patients With Myeloid Disorders
Description
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.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Clinical Activity Assessed by Change in Peripheral Blood Counts
Time Frame
Baseline and after 2 cycles
Title
Clinical Activity Assessed by Change in Transfusion Requirements
Time Frame
Baseline and after 2 cycles
Title
Changes in Detectable Chromosomal Abnormalities Measured by Fluorescent in Situ Hybridization (FISH)
Time Frame
Baseline and 6, 12, 24, and 36 weeks
Title
Change in the Percentage of Cells With Normal and Abnormal Myeloid Phenotype Measured by Flow Cytometry
Time Frame
Baseline and 6, 12, 24, and 36 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
B. Smith
Organizational Affiliation
Johns Hopkins University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287-8936
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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