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

June 16, 2017 updated by: National Cancer Institute (NCI)

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287-8936
        • Johns Hopkins University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm I
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
Given PO
Other Names:
  • HDAC inhibitor SNDX-275
  • SNDX-275
Drug: sargramostim
Given SC
Other Names:
  • Leukine
  • Prokine
  • GM-CSF

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response (Complete and Partial Response) in Patients With Myeloid Disorders
Time Frame: Up to 2 years
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
Time Frame
Clinical Activity Assessed by Change in Peripheral Blood Counts
Time Frame: Baseline and after 2 cycles
Baseline and after 2 cycles
Clinical Activity Assessed by Change in Transfusion Requirements
Time Frame: Baseline and after 2 cycles
Baseline and after 2 cycles
Changes in Detectable Chromosomal Abnormalities Measured by Fluorescent in Situ Hybridization (FISH)
Time Frame: Baseline and 6, 12, 24, and 36 weeks
Baseline and 6, 12, 24, and 36 weeks
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
Baseline and 6, 12, 24, and 36 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: B. Smith, Johns Hopkins University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2007

Primary Completion (Actual)

March 1, 2011

Study Completion (Actual)

March 1, 2011

Study Registration Dates

First Submitted

April 18, 2007

First Submitted That Met QC Criteria

April 18, 2007

First Posted (Estimate)

April 19, 2007

Study Record Updates

Last Update Posted (Actual)

July 18, 2017

Last Update Submitted That Met QC Criteria

June 16, 2017

Last Verified

June 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00195
  • U01CA070095 (U.S. NIH Grant/Contract)
  • J06114

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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