Azacitidine and Lintuzumab in Treating Patients With Previously Untreated Myelodysplastic Syndromes

Phase 2

Terminated

Conditions: Leukemia
Myelodysplastic Syndromes

Interventions: Biological: lintuzumab
Drug: 5-azacytidine

Registration Number: NCT00997243

Lead Sponsor: Alison Walker

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Not provided

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
5-azacytidine and Lintuzumab	5-azacytidine	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.
5-azacytidine and Lintuzumab	lintuzumab	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.

Primary Outcome Measures

Name	Time	Method
Complete Response Rate	up to 5 years	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.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate	up to 5 years	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.
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
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
Perform Exploratory Studies of AZA-triphosphate With Global DNA Methylation	up to 5 years
Toxicities of the Combination	up to 5 years	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.
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