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Phase I Clinical-Labratory Study of the Histone Deacetylase (HDA) Inhibitor MS-275 in Adults With Refractory and Relapsed Hematologic Malignancies


Phase 1
18 Years
N/A
Not Enrolling
Both
Leukemia, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases

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Trial Information

Phase I Clinical-Labratory Study of the Histone Deacetylase (HDA) Inhibitor MS-275 in Adults With Refractory and Relapsed Hematologic Malignancies


OBJECTIVES:

- Determine the toxic effects and pharmacokinetics of MS-275 in patients with poor-risk
hematologic malignancy.

- Determine whether this drug induces changes in hematologic differentiation, in terms of
changes in morphology, cell surface marker expression, and acetylation status, in these
patients.

- Determine whether this drug induces clinical response in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive oral MS-275 on days 1, 8, 15, and 22. Courses repeat every 6 weeks in the
absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of MS-275 until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3
or 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: Approximately 25-30 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- One of the following histologically confirmed diagnoses:

- Acute myeloid leukemia (AML)

- Newly diagnosed de novo AML in patients over 60 years old with the
following poor-risk features:

- Antecedent hematologic disorder

- Complex karyotype or other adverse cytogenetics

- Stem cell immunophenotype

- AML arising from myelodysplastic syndromes (MDS)

- Secondary AML

- Relapsed or refractory AML, including primary induction failure

- MDS

- Poor-risk, defined as the following:

- International Performance Score at least 1.5

- More than 10% marrow blasts

- Cytopenias in at least 2 lineages

- Refractory anemia with excess blasts (RAEB)

- RAEB in transformation

- Chronic myelomonocytic leukemia

- Acute lymphoblastic leukemia (ALL)

- Newly diagnosed de novo ALL in patients over 60 years old with the
following poor-risk features:

- Complex karyotype or other adverse cytogenetics

- Mixed lineage immunophenotype

- Relapsed or refractory ALL, including primary induction failure

- Chronic myelogenous leukemia (CML)

- CML in accelerated phase or blast crisis

- Interferon-refractory CML in chronic phase

- Multiple myeloma (MM)

- Relapsed or refractory, including prior autologous stem cell
transplantation

- Acute promyelocytic leukemia

- Prior treatment with tretinoin

- Ineligible for arsenic trioxide

- No evidence of active coagulopathy

- Low-risk for developing clinically significant coagulopathy during study

- Low tumor burden by marrow aspiration at time of relapse

- No prior coagulation-related sequelae (deep vein thrombosis, pulmonary
embolism, or CNS thrombosis or bleed)

- Failure after primary induction therapy or relapse after complete remission allowed
if patient received no more than 3 courses of prior induction/reinduction therapy

- Not eligible for curative stem cell transplantation

- No hyperleukocytosis with at least 50,000/mm^3 leukemic blasts

- No active CNS leukemia

- No plasma cell leukemia

- No amyloidosis resulting in major organ dysfunction

PATIENT CHARACTERISTICS:

Age:

- 18 and over

Performance status:

- ECOG 0-2

Life expectancy:

- Not specified

Hematopoietic:

- See Disease Characteristics

- No disseminated intravascular coagulation

- No hyperviscosity

Hepatic:

- AST/ALT no greater than 2 times normal

- Alkaline phosphatase no greater than 2 times normal

- Bilirubin no greater than 1.5 times normal

Renal:

- Creatinine no greater than 1.5 times normal

- No uncorrected hypercalcemia

Cardiovascular:

- See Disease Characteristics

- LVEF at least 45% by MUGA or echocardiogram

- No intrinsic impaired cardiac function, including any of the following:

- Myocardial infarction within the past 3 months

- Prior severe coronary artery disease

- Cardiomyopathy

- Congestive heart failure

Other:

- No active uncontrolled infection

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

- See Disease Characteristics

- At least 1 week since prior growth factors (epoetin alfa, filgrastim [G-CSF],
sargramostim [GM-CSF], interleukin [IL]-3, or IL-11)

- At least 4 weeks since prior autologous stem cell transplantation

- No prior allogeneic stem cell transplantation

- No concurrent immunotherapy

Chemotherapy:

- See Disease Characteristics

- At least 3 weeks since prior chemotherapy and recovered

- At least 24 hours since prior hydroxyurea or mercaptopurine for prevention of
leukostasis

- No concurrent chemotherapy

Endocrine therapy:

- Not specified

Radiotherapy:

- At least 2 weeks since prior emergency radiotherapy to large soft tissue or lytic
bony lesions for MM

- No concurrent radiotherapy

Surgery:

- Not specified

Other:

- At least 24 hours since other prior noncytotoxic agents for prevention of leukostasis

- No other concurrent antitumor therapy

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Principal Investigator

Judith E. Karp, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Sidney Kimmel Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

CDR0000068574, J0253

NCT ID:

NCT00015925

Start Date:

February 2001

Completion Date:

Related Keywords:

  • Leukemia
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Diseases
  • refractory multiple myeloma
  • recurrent adult acute myeloid leukemia
  • recurrent adult acute lymphoblastic leukemia
  • relapsing chronic myelogenous leukemia
  • chronic phase chronic myelogenous leukemia
  • accelerated phase chronic myelogenous leukemia
  • blastic phase chronic myelogenous leukemia
  • untreated adult acute lymphoblastic leukemia
  • untreated adult acute myeloid leukemia
  • adult acute promyelocytic leukemia (M3)
  • refractory anemia with excess blasts
  • refractory anemia with excess blasts in transformation
  • chronic myelomonocytic leukemia
  • secondary acute myeloid leukemia
  • de novo myelodysplastic syndromes
  • previously treated myelodysplastic syndromes
  • atypical chronic myeloid leukemia
  • myelodysplastic/myeloproliferative disease, unclassifiable
  • adult acute myeloid leukemia with t(8;21)(q22;q22)
  • adult acute myeloid leukemia with t(16;16)(p13;q22)
  • adult acute myeloid leukemia with inv(16)(p13;q22)
  • adult acute myeloid leukemia with 11q23 (MLL) abnormalities
  • adult acute myeloid leukemia with t(15;17)(q22;q12)
  • Neoplasms
  • Leukemia
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma
  • Myelodysplastic Syndromes
  • Preleukemia
  • Myeloproliferative Disorders
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Greenebaum Cancer Center at University of Maryland Medical CenterBaltimore, Maryland  21201