Azacitidine and Arsenic Trioxide in Treating Patients With Myelodysplastic Syndromes

Jonsson Comprehensive Cancer Center

Status and phase

Terminated

Phase 1

Conditions

Leukemia

Myelodysplastic Syndromes

Treatments

Drug: azacitidine

Drug: arsenic trioxide

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00234000

UCLA-0408087

CDR0000442931

Details and patient eligibility

About

RATIONALE: Drugs used in chemotherapy, such as azacitidine and arsenic trioxide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of azacitidine when given together with arsenic trioxide and to see how well they work in treating patients with myelodysplastic syndromes.

Full description

OBJECTIVES:

Primary

Determine the maximum tolerated dose of azacitidine when given in combination with arsenic trioxide in patients with myelodysplastic syndromes (MDS). (Phase I)
Determine the safety and tolerability of this regimen in these patients. (Phase I)
Determine the major hematologic response (erythroid response) rate in patients with transfusion-dependent lower-risk MDS treated with this regimen. (Phase II)
Determine complete and partial remission rates in patients with higher-risk MDS treated with this regimen. (Phase II)
Determine the toxicity profile of this regimen in these patients. (Phase I)

Secondary

Determine time to disease progression in patients treated with this regimen. (Phase I and II)
Determine the overall and progression-free survival of patients treated with this regimen. (Phase I and II)

OUTLINE: This is an multicenter, open-label, phase I, dose escalation study of azacitidine followed by a phase II study. Patients enrolled in the phase II portion are stratified according to baseline International Scoring System score (lower-risk myelodysplastic syndromes [MDS] vs higher-risk MDS).

Phase I: Patients receive azacitidine subcutaneously once daily on days 1-5 and arsenic trioxide IV over 1-4 hours on days 1, 4, 8, 11, 15, 18, 22, and 25. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with stable disease may receive up to 8 courses of therapy. Patients with responding disease may continue to receive study therapy until a major response or a complete remission is achieved.

Cohorts of 3-6 patients receive escalating doses of azacitidine 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: Patients receive arsenic trioxide as in phase I and azacitidine as in phase I at one dose level below the MTD determined in phase I.

After the completion of study treatment, patients are followed at 4 weeks and then every 3-12 months for survival.

PROJECTED ACCRUAL: Approximately 3-18 patients will be accrued for the phase I portion of this study. A total of 60 patients (30 per stratum) will be accrued for the phase II portion of this study.

Enrollment

1 patient

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Confirmed diagnosis of MDS by standard criteria. Patients within each of the FAB diagnostic groups of RA, RARS, RAEB, RAEBt, and CMML are eligible. For patients with lower-risk MDS only: documented red blood cell dependence, defined as the inability to maintain a hematocrit of > 25% without transfusion support.
Adequate marrow iron stores
In patients with serum erythropoietin less than 200 IU/mL at screening, failure to have responded to a 2 to 3 month trial of recombinant erythropoietin
Serum creatinine or serum bilirubin < 1.5 times the upper limit of normal; higher levels are acceptable if ALT levels < 2 x upper limits of normal
Women of childbearing potential must have a negative serum pregnancy test prior to azacitidine/treatment.
Women of childbearing potential should be advised to avoid becoming pregnant and should be advised to not father a child while receiving treatment with azacitidine
Age > 18 years

Exclusion criteria

Treatment with growth factors within the 30 days before first treatment with ATO/Azacitidine, except that patients with serum erythropoietin < 200 IU/mL who failed to respond to a trial with EPO are not excluded regardless of the time since last EPO
Treatment with cytotoxic or experimental agents within 30 days before first treatment with ATO/Azacitidine
Absolute QT interval > 460 msec in the presence of adequate serum potassium and magnesium values
Active serious infections that are not controlled by antibiotics
Pregnant or lactating women
Inability or unwillingness to comply with the treatment protocol, follow-up, or research tests
NYHA Class III or IV heart failure
Poorly controlled hypertension, diabetes mellitus, or other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol