Azacitidine and Lintuzumab in Treating Patients With Previously Untreated Myelodysplastic Syndromes

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as lintuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving chemotherapy together with monoclonal antibodies may be a better way to block cancer growth. PURPOSE: This phase II trial is studying the side effects and how well giving azacitidine together with lintuzumab works in treating patients with previously untreated myelodysplastic syndromes.

Detailed Description
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OBJECTIVES: Primary To determine the complete response rate of the combination of lintuzumab and azacitidine in patients with myelodysplastic syndromes. Secondary To define the specific toxicities of this regimen. To determine the overall response rate. To determine the relationship between pretreatment expression of Syk and clinical response. To determine whether the investigational agents modulate Syk expression and to correlate drug-induced changes in Syk with response to treatment. To provide preliminary data on the biological activity of azacitidine as a demethylating agent (changes in target gene methylation and gene expression, DNMT1 protein expression, global methylation). To perform exploratory studies of azacitidine-triphosphate with global DNA methylation. To explore the biologic role of microRNA in determining clinical response to this regimen and achievement of the other pharmacodynamic endpoints. OUTLINE: Patients receive azacitidine IV or subcutaneously once daily on days 1-7 and lintuzumab IV on days 2, 7, 15, and 22 (days 2 and 15 of course 1 only). Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment modifications may apply according to response. Blood and bone marrow samples are collected periodically for pharmacodynamic studies. After completion of study treatment, patients are followed up for 5 years.

Official Title
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Phase II Study of 5-azacytidine and Lintuzumab in Myelodysplastic Syndromes (MDS)

Conditions
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Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: lintuzumab
* Drug: 5-azacytidine


Participation Criteria
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Eligibility Criteria
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Eligibility Criteria: Age >18 with untreated MDS by FAB or WHO criteria (note: FAB criteria for MDS includes <29% blasts; FAB criteria includes CMML). Patients with therapy related disease (t-MDS). If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months. Eastern Cooperative Oncology Group (ECOG) performance status <2. Must have adequate organ function as defined below: total bilirubin <2.0mg/dL AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal creatinine <2.0mg/dL NYHA CHF(congestive heart failure)Class II or better Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence). Ability to understand and willingness to sign the written informed consent document. CD33 expression is required on at least 25% of left shifted dysplastic myeloid cells, including blasts. This testing will be done on bone marrow aspirate, but for patients whose CD33 expression in this cellular compartment cannot be ascertained, peripheral blood will be allowed to determine this. Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 6 months (for other cancers) prior to entering the study. Patients receiving any other investigational agents or patients that have received other investigational agents within 1 month of enrollment. Patients with active central nervous system disease or with granulocytic sarcoma as sole site of disease. Patients with history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZA or lintuzumab that are not easily managed are excluded. Patients with hypersensitivity to mannitol are excluded. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. As infection is a common feature of MDS, patients with active infection are permitted to enroll provided that the infection is under control. Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Psychiatric conditions that prevent compliance with protocol or consent. Pregnant women or women who are breastfeeding are excluded from this study. HIV-positive patients on combination antiretroviral therapy are ineligible. Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study. Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study. Patients with baseline fibrinogen <100mg/dL, or those with clinically significant disseminated intravascular coagulation, are excluded. Patients who require ongoing therapeutic anticoagulation with warfarin, lovenox, or similar agent are excluded. This does not apply to patients on low dose prophylaxis therapy. Patients who require ongoing clopidogrel therapy are excluded. In cases where clopidogrel use at screening is subsequently discontinued due to ongoing or future risk of drug and treatment related cytopenias, such patients will be eligible. Patients with platelet <10,000/uL who are refractory to platelet transfusion are not eligible (must bump to at least >10,000/uL after transfusion) Patients who have previously received lenalidomide or thalidomide are excluded.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-azacytidine and Lintuzumab<br>Cycle 1- 5-azacytidine (Vidaza, AZA) 75mg/m2 IV/SC(subcutaneous)daily on days 1-7. Subsequent Cycles (cycles to be repeated every 28 days) AZA 75mg/m2 IV/SC daily on days 1-7. | Biological: lintuzumab<br>* Cycle 1 600mg as an IV infusion (flat dose for all), given on days 2, 7, 15, and 22. Subsequent Cycles (cycles to be repeated every 28 days) 600mg as an IV infusion, given every other week, twice during each cycle, including one dose given during AZA therapy. Doses should be given at least 12 days apart. By convention, dosing on days 7 and 22 of each cycle will be encouraged, but due to expected issues of patient convenience (time, travel, etc.), the study requirements are every other week, twice during each cycle, with one dose during AZA treatment.<br>* Other names: SGN-33;Drug: 5-azacytidine<br>* 75mg/m2 IV/SC daily on days 1-7.<br>* Other names: AZA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | Response to therapy was determined based on percentage of blasts in bone marrow, hematopoiesis, and requirement for supportive care (i.e., transfusions or cytokine growth factors). The modified International Working Group response criteria was used, based on Cheson, et al. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Response to therapy was determined based on percentage of blasts in bone marrow, hematopoiesis, and requirement for supportive care (i.e., transfusions or cytokine growth factors). The modified International Working Group response criteria was used, based on Cheson, et al. | up to 5 years | 
| Toxicities of the Combination | All patients who received study drug were closely monitored for adverse events (AEs). All AEs that occured during study period were reported and the investigator determined the severity and relationship to study drug (unrelated, unlikely, possibly, probably, or definitely related). The NCI's CTCAE(Common Toxicity Criteria for Adverse Effects)v3.0 was used for grading AEs. | up to 5 years | 
| Determine the Relationship Between Pretreatment Expression of Syk and Clinical Response; to Determine Whether the Investigational Agents Modulate Syk Expression and Correlate Drug-induced Changes in Syk With Response to Treatment |  | up to 5 years | 
| Provide Preliminary Data on the Biological Activity of AZA as a Demethylating Agent (Changes in Target Gene Methylation and Gene Expression, DNMT1[Deoxyribonucleic Acid Methyltransferase 1 DNA Methyltransferase 1]Protein Expression, Global Methylation) |  | up to 5 years | 
| Perform Exploratory Studies of AZA-triphosphate With Global DNA Methylation |  | up to 5 years | 
| Explore the Biologic Role of microRNAs in Determining Clinical Response to the AZA Plus Lintuzumab Combination and Achievement of the Other Pharmacodynamic Endpoints |  | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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de novo myelodysplastic syndromes, secondary myelodysplastic syndromes, chronic myelomonocytic leukemia, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory anemia, refractory cytopenia with multilineage dysplasia