DT388IL3 Fusion Protein in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

OBJECTIVES:

- Determine the maximum tolerated dose of DT_388IL3 fusion protein in patients with
refractory or relapsed or poor-risk acute myeloid leukemia (AML) or high-risk
myelodysplastic syndromes (MDS).

- Define the dose-limiting toxicities of this regimen in these patients.

- Measure the pharmacokinetics of this regimen in these patients.

- Measure the immune responses in patients treated with this regimen.

- Evaluate response and correlate with disease type (relapsed/refractory or poor-risk de
novo AML or high-risk MDS), pretreatment marrow blast percentage, and leukemia blast
interleukin-3 receptor density.

OUTLINE: This is a phase I, multicenter, dose-escalation study followed by a phase II,
open-label study.

- Phase I: Patients receive DT_388IL3 IV over 15 minutes daily for 5 days in the absence
of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of DT_388IL3 until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.

- Phase II: An additional 15 patients receive DT_388IL3 at the MTD as in phase I. Patients
undergo serum and blast collection periodically for laboratory studies, including
analysis of expression of interleukin-3 receptors and anti-DT_388IL3 antibodies at
baseline. Samples are also analyzed by immunoenzyme assays and flow cytometry.

After completion of study treatment, patients are followed periodically for up to 5 years.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Diagnosis of 1 of the following:

- Histologically or morphologically confirmed acute myeloid leukemia (AML), meeting
1 of the following criteria:

- Relapsed or refractory AML after treatment with ≥ 1 prior conventional
induction therapy

- Patients in early first relapse must not have a matched donor available
and/or be ineligible for allogeneic stem cell transplantation

- Poor-risk AML, as defined by any of the following criteria:

- Treatment-related AML, unless associated with favorable cytogenetics
(e.g., inversion 16, t[16;16], t[8;21], t[15;17]), and ineligible for
stem cell transplantation

- Antecedent hematological disease (e.g., myelodysplastic syndromes,
myelofibrosis, or polycythemia vera) that evolved to AML (≥ 20% blasts)
and ineligible for stem cell transplantation

- De novo AML (must be > 70 years of age)

- AML with unfavorable cytogenetics (e.g., abnormalities of chromosomes
-7, -5, 7q-, or 5q-; complex [≥ 3] abnormalities; or abnormalities of
11q23, excluding t[9;11], t[9;22], inversion 3, t[3;3], and t[6;9]),
regardless of age, and ineligible for allogeneic stem cell
transplantation

- High-risk myelodysplastic syndromes diagnosed by morphologic, histochemical, or
cell surface marker criteria

- Resistant or intolerant to chemotherapy

- Ineligible for or unwilling to undergo immediate allogeneic stem cell
transplantation

- Bone marrow index (i.e., percent cellularity × percent blasts) ≤ 40% at time of
treatment

- No active CNS leukemia

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Bilirubin ≤ 1.5 mg/dL

- ALT and AST < 2.5 times upper limit of normal

- Albumin ≥ 3 mg/dL

- Creatinine ≤ 1.5 mg/dL

- LVEF ≥ 50%

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 2 weeks after
completion of study treatment

- No complicated medical or psychiatric problems that would preclude study compliance

- No concurrent serious uncontrolled infection or disseminated intravascular coagulation

- No myocardial infarction within the past 6 months

- No allergies to diphtheria toxin

- No requirement for oxygen

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No other concurrent antineoplastic drugs

- No concurrent radiotherapy

- No concurrent corticosteroids as antiemetics

- No concurrent hematopoietic growth factors (e.g., epoetin alfa, interleukin-11,
filgrastim [G-CSF], or sargramostim [GM-CSF])

- No concurrent intravenous immunoglobins