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

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.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: November 2014

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.

Intervention(s) in this Clinical Trial

• Biological: lintuzumab
• Drug: azacitidine
• Other: pharmacological study

Primary Measures

• Complete response rate
  • Safety Issue?: No

Secondary Measures

• Overall response rate
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Diagnosis of myelodysplastic syndromes (MDS) by FAB or WHO criteria (FAB criteria for
• MDS includes ≤ 29% blasts and chronic myelomonocytic leukemia)
• Previously untreated disease
• Patients who have initiated azacytidine (1 course only) are eligible provided that the second course will begin on study within 5 weeks from the initiation of the first course
• Prior cytokine therapy allowed
• Patients with therapy-related MDS are eligible
• No granulocytic sarcoma as the sole site of disease
• Patients with refractory anemia or refractory anemia with ringed sideroblasts must have significant marrow dysfunction as defined by meeting 1 of the following criteria:
• Symptomatic anemia requiring RBC transfusions for ≥ 3 months
• Platelet count < 50,000/mm^3 on 2 occasions or clinically significant hemorrhage requiring transfusion
• Neutrophil count < 1,000/mm^3
• No infection requiring IV antibiotics
• CD33 expression required on ≥ 25% of left-shifted dysplastic myeloid cells, including blasts
• Testing will be done on bone marrow aspirate (testing on peripheral blood is allowed for patients whose CD33 expression in this cellular compartment cannot be ascertained)
• No active CNS disease

PATIENT CHARACTERISTICS:

• See Disease Characteristics
• Life expectancy attributed to a co-morbid medical illness > 6 months (if applicable)
• ECOG performance status 0-2
• Platelet count ≥ 10,000/mm^3 with transfusion
• Total bilirubin < 2.0 mg/dL
• AST/ALT < 2.5 times upper limit of normal
• Creatinine < 2.0 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception before and during study treatment
• No uncontrolled concurrent illness including, but not limited to, any of the following:
• NYHA class III-IV congestive heart failure
• Unstable angina pectoris
• Serious cardiac or ventricular arrhythmia
• Uncontrolled active infection
• Myocardial infarction within the past 6 months
• Electrocardiographic evidence of acute ischemia or active conduction system abnormalities
• Serious medical or psychiatric illness or social situations that are likely to interfere with participation in this study
• No baseline fibrinogen < 100 mg/dL or clinically significant disseminated intravascular coagulation
• More than 3 years since prior diagnosis or treatment of another malignancy except for any of the following:
• Basal cell carcinoma or squamous cell carcinoma of the skin
• In situ malignancy
• Low-risk prostate cancer
• No HIV positivity requiring combination antiretroviral therapy
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to azacitidine or lintuzumab that are not easily managed
• No hypersensitivity to mannitol

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior lenalidomide or thalidomide
• More than 6 months since prior chemotherapy or radiotherapy (for other cancers)
• More than 1 month since prior and no other concurrent investigational agents
• No concurrent ongoing therapeutic anticoagulation with warfarin, Lovenox, or similar agent
• Low-dose prophylaxis therapy allowed
• No concurrent ongoing clopidogrel therapy
• Patients who were using clopidogrel at screening and subsequently discontinued use due to ongoing or future risk of dug- and treatment-related cytopenias are eligible
• No other concurrent anticancer agents or therapies

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Arthur G. James Cancer Hospital & Richard J. Solove Research Institute

Overall Clinical Trial Officials and Contacts

Alison Walker, MD Principal Investigator Arthur G. James Cancer Hospital & Richard J. Solove Research Institute  

Information obtained from ClinicalTrials.gov on February 08, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00997243

Study ID Number: CDR0000656787

ClinicalTrials.gov Identifier: NCT00997243

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database