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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

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ClinicalTrials.gov Identifier: NCT00462605
Recruitment Status : Completed
First Posted : April 19, 2007
Results First Posted : April 17, 2017
Last Update Posted : July 18, 2017
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE April 18, 2007
First Posted Date  ICMJE April 19, 2007
Results First Submitted Date  ICMJE March 6, 2017
Results First Posted Date  ICMJE April 17, 2017
Last Update Posted Date July 18, 2017
Study Start Date  ICMJE April 2007
Actual Primary Completion Date March 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2017)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 18, 2007)
Response (complete and partial response)
Change History Complete list of historical versions of study NCT00462605 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2017)
  • Clinical Activity Assessed by Change in Peripheral Blood Counts [ Time Frame: Baseline and after 2 cycles ]
  • Clinical Activity Assessed by Change in Transfusion Requirements [ Time Frame: 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 18, 2007)
  • Improvement of peripheral blood counts
  • Changes in transfusion requirements
  • In vivo induction of terminal differentiation of myeloid progenitor cells as assessed by flow cytometry
  • In vivo changes in detectable chromosomal abnormalities as assessed by FISH
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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  ICMJE
  • Drug: entinostat
    Given PO
    Other Names:
    • HDAC inhibitor SNDX-275
    • SNDX-275
  • Drug: sargramostim
    Given SC
    Other Names:
    • GM-CSF
    • Leukine
    • Prokine
Study Arms  ICMJE 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.
Interventions:
  • Drug: entinostat
  • Drug: sargramostim
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 8, 2013)
24
Original Enrollment  ICMJE
 (submitted: April 18, 2007)
18
Actual Study Completion Date  ICMJE March 2011
Actual Primary Completion Date March 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00462605
Other Study ID Numbers  ICMJE NCI-2009-00195
J06114
U01CA070095 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: B. Smith Johns Hopkins University
PRS Account National Cancer Institute (NCI)
Verification Date June 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP