RATIONALE: PS-341 may stop the growth of tumor cells by blocking the enzymes necessary for
tumor cell growth.
PURPOSE: Phase I trial to study the effectiveness of PS-341 in treating patients who have
OBJECTIVES: I. Determine the maximum tolerated dose and dose-limiting toxicity of PS-341 in
patients with hematologic malignancies. II. Determine the pharmacodynamics of this drug in
these patients. III. Determine response to this drug in these patients. IV. Determine the
correlation between response of malignancies and proteasome inhibition and apoptosis in
peripheral blood mononuclear cells (PBMC) of these patients. V. Determine the correlation
between therapy toxicity and proteasome inhibition and apoptosis in PBMC of these patients.
VI. Determine the effect of this drug on other molecular markers (i.e., BCL-2 in follicular
lymphoma patients and t9;22/BCR/ABL in chronic lymphocytic leukemia patients). VII.
Determine the correlation between interleukin-6 serum levels in multiple myeloma patients
and drug dosing, toxicity of therapy, extent of protease inhibition, response to therapy,
and apoptosis in PBMC of these patients.
OUTLINE: This is a dose-escalation, multicenter study. Patients receive PS-341 IV over 30
minutes on days 1, 4, 8, 11, 15, 18, 22, and 25 followed by a 2-week rest. Treatment repeats
every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6
patients receive escalating doses of PS-341 until the maximum tolerated dose (MTD) is
determined. The MTD is defined as the dose at which 2 of 6 patients experience dose-limiting
PROJECTED ACCRUAL: A total of 3-30 patients will be accrued for this study.
DISEASE CHARACTERISTICS: Histologically confirmed hematologic malignancy including: Acute
myeloid leukemia Chronic myelogenous leukemia Acute lymphoblastic leukemia Chronic
lymphocytic leukemia Hodgkin's disease Non-Hodgkin's lymphoma Multiple myeloma
Myelodysplastic syndrome subtypes: Refractory anemia with excess blasts (RAEB) RAEB in
transformation Refractory to standard treatment or no curative therapy available
Measurable disease Not eligible for higher priority study
PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-2 Life expectancy: At
least 6 weeks Hematopoietic: WBC at least 3,000/mm3 Absolute neutrophil count at least
1,000/mm3 Platelet count at least 50,000/mm3 Hematocrit at least 25% Hepatic: SGOT and
SGPT less than 2.5 times upper limit of normal (ULN) Bilirubin less than 1.5 times ULN
Renal: Creatinine clearance greater than 50 mL/min Cardiovascular: No acute ischemia or
new conduction system abnormalities by EKG No prior myocardial infarction within past 6
months No New York Heart Association class III or IV congestive heart failure Other:
Febrile episodes up to 38.5 degrees C due to tumor fever allowed No concurrent active
infection No grade 1 or greater National Cancer Institute common toxicity criteria No
serious medical or psychiatric condition that would preclude study Not pregnant or nursing
Negative pregnancy test Fertile patients must use effective contraception
PRIOR CONCURRENT THERAPY: Biologic therapy: At least 4 weeks since prior immunotherapy No
concurrent immunotherapy Chemotherapy: At least 4 weeks since prior chemotherapy No other
concurrent chemotherapy Endocrine therapy: Not specified Radiotherapy: At least 4 weeks
since prior radiotherapy No concurrent radiotherapy Surgery: At least 2 weeks since prior