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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


Phase 2
18 Years
N/A
Not Enrolling
Both
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

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response (complete and partial response) in patients with myeloid disorders

Outcome Time Frame:

Up to 2 years

Safety Issue:

No

Principal Investigator

B. Smith

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00195

NCT ID:

NCT00462605

Start Date:

April 2007

Completion Date:

Related Keywords:

  • 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
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Neoplasms
  • Leukemia
  • Leukemia, Erythroblastic, Acute
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Megakaryoblastic, Acute
  • Leukemia, Monocytic, Acute
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelomonocytic, Acute
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

Johns Hopkins UniversityBaltimore, Maryland  21205