Bortezomib in Treating Patients With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well bortezomib works in treating patients with myelodysplastic syndromes.

Detailed Description
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OBJECTIVES: Primary Determine the efficacy of bortezomib, in terms of reduced cytopenia, in patients with myelodysplastic syndromes. Determine the safety and toxic effects of this drug in these patients. Secondary Determine changes in marrow blast percentage or karyotypic profile in patients treated with this drug. OUTLINE: This is an open-label study. Patients receive bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 1 year. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

Official Title
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A Phase II Pilot Study of VELCADE in Patients With MDS

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of myelodysplastic syndromes (MDS) Requires treatment or transfusion support for MDS, as indicated by 1 of the following: Demonstrates transfusion or epoetin alfa dependence Transfusion dependence is defined as requiring ≥ 2 units of packed RBCs within an 8-week period prior to study entry Hemoglobin < 11g/dL on 2 separate occasions 2 weeks apart No iron, cyanocobalamin (vitamin B_12), or folic acid deficiency or other causes of anemia Must have 1 of the following FAB subtypes: Refractory anemia Refractory anemia with ringed sideroblasts Refractory anemia with excess blasts Secondary MDS (if ≥ 3 years since active primary cancer) No chronic myelomonocytic leukemia Not refractory to platelet transfusion support (i.e., inability to maintain platelet count > 20,000/mm^3 with transfusion) No current acute myelogenous leukemia (e.g., > 30% blasts) PATIENT CHARACTERISTICS: Performance status Karnofsky 50-100% Life expectancy At least 6 months Hematopoietic See Disease Characteristics Hepatic Bilirubin ≤ 2 mg/dL AST and ALT < 2 times upper limit of normal Renal Creatinine clearance ≥ 30 mL/min Cardiovascular No significant cardiovascular condition that would preclude study participation No uncontrolled hypertension Pulmonary No significant pulmonary condition that would preclude study participation Immunologic No serious concurrent infection Active infections must be adequately treated with antibiotics prior to study entry No hypersensitivity to bortezomib, boron, or mannitol Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for up to 4 weeks after completion of study treatment No peripheral neuropathy ≥ grade 2 No uncontrolled seizure activity, as defined by no activity within the past year on stable anticonvulsant medications No other malignancy within the past 3 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix No endocrine, neurologic, or other systemic disease that would preclude study entry PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics No prior allogeneic bone marrow transplantation Concurrent transfusion support allowed Concurrent epoetin alfa or darbepoetin alfa allowed if initiated before start of study therapy, dose is stable for ≥ 4 weeks, and dose is stable during study participation No concurrent platelet growth factor support No concurrent thalidomide Chemotherapy No concurrent chemotherapy No concurrent hydroxyurea Endocrine therapy Concurrent corticosteroids for chronic autoimmune or inflammatory condition allowed if initiated before start of study therapy and maintained on a stable or decreasing dose Other Recovered from all prior therapies At least 4 weeks since prior MDS therapy, except epoetin alfa, darbepoetin alfa, filgrastim (G-CSF), pegfilgrastim (G-CSF), or transfusion support At least 30 days since prior investigational agents No prior bortezomib No other concurrent investigational agents No other concurrent therapy for MDS

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: Bortezomib<br> | Drug: bortezomib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced an Adverse Event |  | For 21 days/course for up to 12 courses | 
| Number of Participants Who Experienced Cytopenias |  | 21 Days/course for up to 12 courses | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interleukin 6 Levels in Serum | interleukin-6 levels were measured by enzyme-linked immunosorbant assay ELISA in serum from participants exposed to bortezomib. Levels were measured at Day 0 and Day 14 of cycle 1 of the clinical trial. | day 14 | 
| Vascular Endothelial Growth Factor (VEGF) Levels in Serum | VEGF levels were measured by ELISA (R&DSystems) in serum from participants exposed to bortezomib. Levels were measured at Day 0 and Day 14 of cycle 1 of the clinical trial. | day 14 | 
| Average Percentage of Light Density Cells in Apoptosis | The CD34+ fraction of light density marrow obtained from patients at baseline and while receiving bortezomib were assessed through measurement of Annexin V (assay obtained form R&D Systems) and by flow cytometry analysis. | day 14 | 
| Average Number of Colony Forming Unit-granulocyte-macrophages in Bone Marrow | Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as > 20 grouped cells. | day 14 | 
| Average Number of Erthroid Burst Forming Units in Bone Marrow | Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as > 20 grouped cells. | day 14 | 
| Average Number of Leukemia Forming Units in Bone Marrow | Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as > 20 grouped cells. | day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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previously treated myelodysplastic syndromes, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory anemia, secondary myelodysplastic syndromes, de novo myelodysplastic syndromes