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