Bortezomib in Treating Patients With Myelodysplastic Syndromes

A Phase II Pilot Study of VELCADE in Patients With MDS

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: bortezomib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bortezomib	Drug: bortezomib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: University of Rochester
• Investigators: Study Chair: Jane L. Liesveld, MD, James P. Wilmot Cancer Center

Publications and helpful links

General Publications

• Liesveld JL, Rosell KE, Bechelli J, Lu C, Messina P, Mulford D, Ifthikharuddin JJ, Jordan CT, Phillips Ii GL. Proteasome inhibition in myelodysplastic syndromes and acute myelogenous leukemia cell lines. Cancer Invest. 2011 Aug;29(7):439-50. doi: 10.3109/07357907.2011.590567.

Study record dates

Study Major Dates

• Study Start: May 1, 2005
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: December 6, 2005
• First Submitted That Met QC Criteria: December 6, 2005
• First Posted (Estimate): December 7, 2005

Study Record Updates

• Last Update Posted (Estimate): May 9, 2016
• Last Update Submitted That Met QC Criteria: April 4, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: refractory anemia; refractory anemia with ringed sideroblasts; refractory anemia with excess blasts; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Antineoplastic Agents; Bortezomib
• Other Study ID Numbers: CDR0000449689; URCC-U20403; MILLENNIUM-i34103-042