Clinical trial NCT00015925: MS-275 in Treating Patients With Hematologic Cancer
Official title: Phase I Clinical-Labratory Study of the Histone Deacetylase (HDA) Inhibitor MS-275 in Adults With Refractory and Relapsed Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Diseases
Keywords: 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)
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Phase I trial to study the effectiveness of MS-275 in treating patients who have hematologic cancer.

Detailed description: 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.

Eligibility 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

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Greenebaum Cancer Center at University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Judith E. Karp, MD
role: STUDY_CHAIR
References: