Arsenic Trioxide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia

Roswell Park Comprehensive Cancer Center

Status and phase

Completed

Phase 1

Conditions

Leukemia

Treatments

Drug: idarubicin

Biological: filgrastim

Drug: arsenic trioxide

Drug: cytarabine

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00093483

CDR0000387999

P30CA016056 (U.S. NIH Grant/Contract)

RPCI-RP-0209

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide, cytarabine, and idarubicin, work in different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of arsenic trioxide when given together with cytarabine and idarubicin in treating patients with acute myeloid leukemia.

Full description

OBJECTIVES:

Determine the maximum tolerated dose and/or biologically effective dose of arsenic trioxide followed by high-dose cytarabine and idarubicin in patients with previously untreated de novo or secondary acute myeloid leukemia.

OUTLINE: This is a dose-escalation study of arsenic trioxide. Patients are stratified according to timing of accrual (before November 2002 vs since November 2002).

Patients receive arsenic trioxide IV over 1 hour on day 1 followed by high-dose cytarabine IV over 1 hour every 12 hours on days 1-6 and idarubicin IV over 30 minutes on days 2-4 (immediately after doses 3, 5 and 7 of cytarabine). Patients also receive filgrastim (G-CSF) subcutaneously beginning 12 hours after the last dose of chemotherapy and continuing until blood counts recover.

Cohorts of 3-6 patients receive escalating doses of arsenic trioxide until the maximum tolerated dose (MTD), current dose used for myelodysplastic syndromes or acute promyelocytic leukemia, or biologically effective dose is reached. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. The biologically effective dose is defined as the dose at which 3 patients with constitutive STAT3 activity have the activity negated after the first dose of arsenic trioxide.

PROJECTED ACCRUAL: A maximum of 40 patients (6 for stratum I [accrued before November 2002] and 34 for stratum II [accrued since November 2002] will be accrued for this study within 3 years.

Enrollment

61 patients

Sex

All

Ages

18 to 59 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Histologically confirmed de novo or secondary acute myeloid leukemia with ≥ 20% blasts AND at least 1 of the following characteristics*:
- Auer rods
- Peroxidase or sudan black positive blasts
- Chloroacetate esterase-positive or diffusely non-specific esterase-positive blasts
- Presence of a myeloid immunophenotype by multiparameter flow cytometry, including expression of one or more myeloid markers (CD13, CD33) on blasts NOTE: *Megakaryocytic leukemia can be diagnosed by the detection of platelet antigens (e.g. factor VIII, glycoprotein Ib or IIb/IIIa) using monoclonal antibodies or the presence of ultrastructural platelet peroxidase
No acute promyelocytic leukemia
No Philadelphia-chromosome positive chronic myeloid leukemia
Prior hematologic disorders, including myelodysplastic syndromes, aplastic anemia, paroxysmal nocturnal hemoglobinuria, and myeloproliferative disorders allowed

PATIENT CHARACTERISTICS:

Age

18 to 59

Performance status

Not specified

Life expectancy

More than 4 weeks

Hematopoietic

Not specified

Hepatic

Bilirubin ≤ 2 times normal*
SGOT ≤ 2 times normal*
Alkaline phosphatase ≤ 2 times normal* NOTE: *Unless abnormalities are directly attributable to leukemia

Renal

Creatinine ≤ 1.5 times normal* NOTE: *Unless abnormalities are directly attributable to leukemia

Cardiovascular

Cardiac ejection fraction ≥ 45%*
Absolute QT interval ≤ 460 msec with potassium > 4.0 mEq/L and magnesium > 1.8 mg/dL
No myocardial infarction within the past 6 months
No uncontrolled symptomatic congestive heart failure
No angina pectoris
No multifocal cardiac arrythmias
No other severe cardiovascular disease NOTE: *Unless abnormalities are directly attributable to leukemia

Other

No serious medical or psychiatric illness that would preclude informed consent or limit survival to < 4 weeks
No uncontrolled diabetes mellitus
No other concurrent active malignancy
No known hypersensitivity to E. coli-derived drug preparations
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

No prior chemotherapy for acute leukemia, except hydroxyurea to control white blood cell counts
- Prior chemotherapy for an antecedent malignancy or other medical condition allowed

Endocrine therapy