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

Sponsors and Collaborators:	Sidney Kimmel Comprehensive Cancer Center National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00462605

Purpose

RATIONALE: 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.

PURPOSE: 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.

Condition	Intervention	Phase
Leukemia Myelodysplastic Syndromes Myelodysplastic/Myeloproliferative Diseases	Drug: entinostat Drug: sargramostim Procedure: cytogenetic analysis Procedure: flow cytometry Procedure: fluorescence in situ hybridization	Phase II

MedlinePlus related topics: Anemia Cancer Leukemia, Adult Acute Leukemia, Adult Chronic

Drug Information available for: Sargramostim Granulocyte-macrophage colony-stimulating factor

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Open Label
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

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Response (complete and partial response) [ Designated as safety issue: No ]

Secondary Outcome Measures:

Improvement of peripheral blood counts [ Designated as safety issue: No ]
Changes in transfusion requirements [ Designated as safety issue: No ]
In vivo induction of terminal differentiation of myeloid progenitor cells as assessed by flow cytometry [ Designated as safety issue: No ]
In vivo changes in detectable chromosomal abnormalities as assessed by FISH [ Designated as safety issue: No ]

Estimated Enrollment:	18
Study Start Date:	April 2007
Estimated Primary Completion Date:	January 2008 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

Determine clinical response in patients with myelodysplastic syndromes and/or relapsed or refractory acute myeloid leukemia treated with MS-275 in combination with sargramostim (GM-CSF).

Secondary

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.
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) and changes in detectable cytogenetic abnormalities in the blood and marrow compartments, in these patients.
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, and peripheral blood neutrophils) 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.

PROJECTED ACCRUAL: A total of 18 patients will be accrued for this study.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosis of 1 of the following diseases by bone marrow aspiration 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
    - Refractory cytopenia with multilineage dysplasia
    - Refractory cytopenia with multilineage dysplasia and ringed sideroblasts
    - RA with excess blasts (RAEB)-1
    - RAEB-2
    - Myelodysplastic syndromes, unclassified
    - Chronic myelomonocytic leukemia
  - International Prognostic Scoring Sytem 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
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

PATIENT CHARACTERISTICS:

ECOG performance status 0-2
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)

PRIOR CONCURRENT THERAPY:

Recovered from all treatment-related toxicities
More than 2 weeks since prior therapy for AML 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00462605

Locations

United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Recruiting
Baltimore, Maryland, United States, 21231-2410
Contact: Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce 410-955-8804 jhcccro@jhmi.edu

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center

National Cancer Institute (NCI)

Investigators

Study Chair:

B. Douglas Smith, MD

Sidney Kimmel Comprehensive Cancer Center

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000540608, JHOC-NA_00006989
Study First Received:	April 18, 2007
Last Updated:	December 2, 2008
ClinicalTrials.gov Identifier:	NCT00462605
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

refractory anemia with ringed sideroblasts
refractory anemia
refractory cytopenia with multilineage dysplasia
refractory anemia with excess blasts
previously treated myelodysplastic syndromes
secondary myelodysplastic syndromes
secondary acute myeloid leukemia
de novo myelodysplastic syndromes
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
recurrent adult acute myeloid leukemia
adult acute minimally differentiated myeloid leukemia (M0)
adult acute myeloblastic leukemia with maturation (M2)
adult acute myeloblastic leukemia without maturation (M1)

adult acute myelomonocytic leukemia (M4)
adult acute monoblastic leukemia (M5a)
adult acute monocytic leukemia (M5b)
adult erythroleukemia (M6a)
adult pure erythroid leukemia (M6b)
chronic myelomonocytic leukemia
untreated adult acute myeloid leukemia
adult acute megakaryoblastic leukemia (M7)
myelodysplastic/myeloproliferative disease, unclassifiable
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)

Study placed in the following topic categories:

Leukemia, Monocytic, Acute
Precancerous Conditions
Chronic myelomonocytic leukemia
Refractory anemia
Acute myelomonocytic leukemia
Di Guglielmo's syndrome
Leukemia, Myeloid, Acute
Leukemia
Preleukemia
Anemia, Refractory
Neoplasm Metastasis
Acute erythroblastic leukemia
Acute myeloid leukemia, adult
Congenital Abnormalities
Acute myelocytic leukemia

Myelodysplastic syndromes
Hematologic Diseases
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Myelodysplasia
Anemia
Myeloproliferative Disorders
Acute myelogenous leukemia
Leukemia, Myeloid
Recurrence
Leukemia, Myelomonocytic, Acute
Myelodysplastic myeloproliferative disease
Leukemia, Erythroblastic, Acute
Anemia, Refractory, with Excess of Blasts
Myelodysplastic-Myeloproliferative Diseases

Additional relevant MeSH terms:

Neoplasms
Pathologic Processes
Disease
Neoplasms by Histologic Type
Syndrome

ClinicalTrials.gov processed this record on January 16, 2009