Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

MS-275 in Treating Patients With Hematologic Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 18 and over NCI JHOC-J0253 MSGCC-0050, NCI-2791, NCT00015925

Objectives

1. Determine the toxic effects and pharmacokinetics of MS-275 in patients with poor-risk hematologic malignancy.
2. 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.
3. Determine whether this drug induces clinical response in these patients.

Entry 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/mm³ leukemic blasts



• No active CNS leukemia



• No plasma cell leukemia



• No amyloidosis resulting in major organ dysfunction

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

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

Expected Enrollment

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

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.

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Judith Karp, MD, Protocol chair		Ph: 410-502-7726

Registry Information
Official Title		Phase I Clinical-Labratory Study of the Histone Deacetylase (HDA) Inhibitor MS-275 in Adults with Refractory and Relapsed Hematologic Malignancies
Trial Start Date		2001-02-15
Registered in ClinicalTrials.gov		NCT00015925
Date Submitted to PDQ		2001-03-02
Information Last Verified		2005-05-07
NCI Grant/Contract Number		CA69854

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