Arsenic Trioxide and Imatinib Mesylate in Treating Patients With Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Memorial Sloan Kettering Cancer Center (MSK)

Status and phase

Completed

Phase 2

Phase 1

Conditions

Leukemia

Treatments

Drug: imatinib mesylate

Drug: arsenic trioxide

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00081133

CDR0000358923 (Registry Identifier)

03-126

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide, work in different ways to stop cancer cells from dividing so they stop growing or die. Imatinib mesylate may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Combining arsenic trioxide with imatinib mesylate may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of arsenic trioxide when given with imatinib mesylate and to see how well they work in treating patients with accelerated phase or blastic phase chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.

Full description

OBJECTIVES:

Primary

Determine the maximum tolererated dose of arsenic trioxide when administered with imatinib mesylate in patients with accelerated or blastic phase chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.
Determine the rate of complete morphologic remission in the bone marrow of patients treated with this regimen.

OUTLINE: This is a phase I dose-escalation study of arsenic trioxide followed by a phase II study.

Phase I:
- Induction therapy: Patients receive oral imatinib mesylate once daily on days 1-35 (weeks 1-5) and arsenic trioxide IV over 1-4 hours on days 1-5, 8-12, 15-19, and 22-26 (weeks 1-4).

Patients undergo bone marrow evaluation on week 5. Patients achieving a morphologic remission proceed to consolidation therapy. Patients not achieving morphologic remission receive a second course of imatinib mesylate as above on weeks 6-10 and arsenic trioxide as above on weeks 6-9. Patients are re-evaluated on week 10. Patients achieving morphologic remission proceed to consolidation therapy. Patients not achieving a morphologic remission are removed from study.

Consolidation therapy: Patients receive oral imatinib mesylate as in induction therapy on approximately weeks 6-11 (or weeks 11-16*) and arsenic trioxide IV over 1-4 hours on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 (approximately weeks 6-9 OR weeks 11-14*).

Patients who remain in morphologic remission receive a second course of imatinib mesylate as in induction therapy on approximately weeks 12-17 (or weeks 17-22*) and arsenic trioxide as above (in consolidation therapy) on approximately weeks 12-15 (or weeks 17-20*).

NOTE: *For patients who receive a second course of induction therapy

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

Phase II: Patients receive arsenic trioxide at the MTD and imatinib mesylate as in phase I.

Treatment in both phases continues in the absence of unacceptable toxicity or disease progression.

After completion of consolidation therapy, patients may continue imatinib mesylate off study at the discretion of the physician. Patients who become candidates for stem cell transplantation at any time during the study are removed from study.

PROJECTED ACCRUAL: A total of 6-43 patients (6-12 for phase I and 37 [including 6 patients from phase I] for phase II) will be accrued for this study within 2 years.

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

Diagnosis of one of the following:
- Chronic myelogenous leukemia (CML) in one of the following phases:
  - Blastic phase*
  - Accelerated phase*
    - No appropriate donors for stem cell transplantation NOTE: *Must have received high-dose (600-800 mg/day) imatinib mesylate of no more than 3 months duration
- Acute lymphoblastic leukemia
  - Philadelphia chromosome positive by cytogenetic confirmation
    - Patients with only bcr-abl-positive disease by polymerase chain reaction are not eligible
  - > 10% blasts in the bone marrow
No isolated extramedullary disease

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

ECOG 0-2

Life expectancy

Not specified

Hematopoietic

Not specified

Hepatic

Bilirubin ≤ 2 times upper limit of normal (ULN)
AST ≤ 2 times ULN
INR and PTT ≤ 1.5 times ULN (except for patients on anticoagulation therapy)

Renal

Creatinine ≤ 2 times ULN

Cardiovascular

Baseline QTc intervals < 480 ms
No chronic arrhythmias
No active coronary artery disease

Other

No chronic electrolyte abnormalities
No prior non-compliance to medical regimens
No patients who are considered potentially unreliable
No active serious infection
No other active malignancies except superficial epithelial cancers
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective barrier contraception during and for at least 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy