Azacitidine and Arsenic Trioxide in Treating Patients With Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

Study Overview
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Brief Summary
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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 II trial is studying how well giving azacitidine together with arsenic trioxide works in treating patients with myelodysplastic syndromes or chronic myelomonocytic leukemia.

Detailed Description
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OBJECTIVES: Primary Determine the response rate in patients with myelodysplastic syndromes or chronic myelomonocytic leukemia treated with azacitidine and arsenic trioxide. Secondary Determine time to treatment failure in patients treated with this regimen. Determine the tolerability and toxicity of this regimen in these patients. Determine progression-free survival of patients treated with this regimen. OUTLINE: This a multicenter, non-randomized, open-label, study. Patients receive azacitidine subcutaneously once daily on days 1-5 and arsenic trioxide IV over 1-2 hours on days 1, 2, 8, 9, 15, 16, 22, and 23. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients are evaluated for response on day 113 (week 17). Patients with disease progression or no response are removed from the study. Patients achieving a complete response (CR) receive 2 additional courses of therapy and then undergo observation. Patients achieving a partial response receive 2 additional courses of therapy and then receive arsenic trioxide alone twice weekly in the absence of CR, disease progression, or unacceptable toxicity. After completion of study treatment, patients are followed every 2 months for at least 1 year. PROJECTED ACCRUAL: A total of 19-41 patients will be accrued for this study within 18 months.

Official Title
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A Phase II Study of Arsenic Trioxide in Combination With 5-Azacitidine in Myelodysplastic Syndromes

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: arsenic trioxide
* Drug: azacitidine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of myelodysplastic syndrome or chronic myelomonocytic leukemia International Prognostic Scoring System (IPSS) score ≥ intermediate-1 Low IPSS score allowed provided patient meets ≥ 1 of the following criteria: Platelet count ≤ 50,000/mm^3 Required platelet or packed red cell transfusions within the past 4 weeks Neutropenic (i.e., absolute neutrophil count < 1,000/mm^3) AND has infections requiring antibiotic treatment No prior leukemia or refractory anemia with excess blasts in transformation PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-2 Life expectancy More than 12 weeks Hematopoietic See Disease Characteristics Hepatic Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Renal Creatinine ≤ 1.5 times ULN Cardiovascular No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Baseline QTc < 500 msec QTc interval < 460 msec with potassium > 4.0 mEq/L and magnesium > 1.8 mg/L Immunologic No history of allergic reaction attributed to compounds of similar chemical or biologic composition to study drugs No ongoing or active infection HIV negative Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after study participation No psychiatric illness or social situation that would preclude study compliance No other uncontrolled illness No other malignancy within the past 12 months PRIOR CONCURRENT THERAPY: Biologic therapy More than 4 weeks since prior administration of any of the following: Interferon Filgrastim (G-CSF), sargramostim (GM-CSF), epoetin alfa, or other hematopoietic cytokines Thalidomide or thalidomide analogs No concurrent epoetin alfa Chemotherapy More than 4 weeks since prior chemotherapy No prior arsenic trioxide or azacitidine No other concurrent chemotherapy Endocrine therapy More than 4 weeks since prior steroids No concurrent androgenic steroids Concurrent steroids for adrenal failure or as prophylaxis for nausea allowed Radiotherapy Not specified Surgery Not specified Other More than 4 weeks since prior retinoids No other concurrent investigational agents No other concurrent anticancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: arsenic trioxide|nan|
|Drug: azacitidine|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (overall and confirmed) as measured by International Working Group (IWG) standardized criteria for MDS at day 113 and then every 4 weeks until completion of study treatment |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to treatment failure as assessed by the Kaplan-Meier method at completion of study treatment |  |  | 
| Progression-free survival as assessed by the Kaplan-Meier method at completion of study treatment |  |  | 
| Toxicity as assessed by the Kaplan-Meier method and NCI-CTCAE version 3.0 during treatment until 30 days after completion of study treatment |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, chronic myelomonocytic leukemia