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Phase I Study of PS-341 in Acute Myeloid Leukemias, Myelodysplastic Syndromes and Chronic Myeloid Leukemia in Blast Phase

Phase 1
18 Years
Not Enrolling
Adult Acute Promyelocytic Leukemia (M3), Blastic Phase Chronic Myelogenous Leukemia, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, Relapsing Chronic Myelogenous Leukemia

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Trial Information

Phase I Study of PS-341 in Acute Myeloid Leukemias, Myelodysplastic Syndromes and Chronic Myeloid Leukemia in Blast Phase


I. Determine the maximum tolerated dose of PS-341 in patients with refractory or relapsed
acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic
myeloid leukemia in blast phase.

II. Assess the plasma pharmacology of this drug, its ability to inhibit proteasome function
and to accelerate apoptosis in circulating blasts in this patient population.

III. Assess the antileukemic effects of this drug in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive PS-341 IV bolus twice weekly for 4 weeks followed by 2 weeks of rest.
Treatment continues for a maximum of 12 courses in the absence of unacceptable toxicity or
disease progression.

Cohorts of 2 patients receive escalating doses of PS-341 until the maximum tolerated dose
(MTD) is determined. The MTD is defined as the dose level associated with toxicity
probability closest to 0.2 after 30 patients are treated.

Inclusion Criteria:

- AML, ALL, or high-risk MDS (R-AEB or RAEB-t) that has:

- Not responded (no CR) to initial induction chemotherapy, or

- Recurred after an initial CR of < 1 year, or

- Recurred after an initial CR of > 1 year and failed to respond to an initial
re-induction attempt, or

- Recurred more than once, OR

- Chronic myeloid leukemia in myeloid blast phase

- Patients with CML blast phase may receive PS-341 as their first therapy for
blast phase or after failing other treatments for blast phase

- Patients with refractory or relapsed acute promyelocytic leukemia are eligible
provided they have failed an ATRA-containing regimen

- Patients who are likely to benefit from allogeneic bone marrow transplantation (i.e.,
age < 60 years of physiological age with histocompatible donor) should be excluded
from this study unless such therapy is not feasible

- ECOG performance status =< 52 (Karnofsky >= 50%)

- Total bilirubin < 1.6 mg/ml

- ALT or AST =< 2.5 times the institutional upper limit of normal

- Creatinine < 1.6 mg/ml or creatinine clearance >= 60 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal

- Patients must have been off chemotherapy for 2 weeks prior to entering this study and
recovered from the toxic effects of that therapy; use of hydroxyurea on patients with
rapidly proliferative disease (i.e., absolute peripheral blood blast count >= 5 x
10^9/L, and increasing by >= 1 x 10^9/L/24 hrs) is allowed up to 24 hours prior to
the start of therapy with PS-341

- The effects of PS-341 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason, women of childbearing potential and men must agree
to use adequate contraception (hormonal or barrier method of birth control) prior to
study entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately

- Because the potential risk of toxicity in nursing infants secondary to PS-341
treatment of the mother is unknown but may be harmful, breastfeeding should be
discontinued if the mother is treated with PS-341

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients undergoing therapy with other investigational agents

- Patients with known brain metastases or CNS disease should be excluded from this
clinical trail because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other toxicities

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, or unstable angina pectoris, or
cardiac arrhythmia

- HIV-positive patients receiving, anti-retroviral thearpy (HAART) are excluded from
the study because of possible pharmacokinetic interactions; appropriate studies will
be undertaken in patients receiving, HAART therapy when indicated

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The occurrence of greater or equal grade 3 toxicity

Outcome Description:

Graded using the NCI CTC version 2.0.

Outcome Time Frame:

35 days

Safety Issue:


Principal Investigator

Jorge Cortes

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

February 2000

Completion Date:

Related Keywords:

  • Adult Acute Promyelocytic Leukemia (M3)
  • Blastic Phase Chronic Myelogenous Leukemia
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Refractory Anemia With Excess Blasts
  • Refractory Anemia With Excess Blasts in Transformation
  • Relapsing Chronic Myelogenous Leukemia
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Blast Crisis
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Promyelocytic, Acute
  • Myelodysplastic Syndromes
  • Preleukemia
  • Anemia, Aplastic



M D Anderson Cancer Center Houston, Texas  77030