Bortezomib in Treating Patients With Myelodysplastic Syndromes

• Sponsor: University of Rochester (Other)
• Overall Status: Completed
• CT.gov ID: NCT00262873
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arm: 1
• Duration (Months): 65
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: bortezomib	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Pilot Study of VELCADE in Patients With MDS
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bortezomib	Drug: bortezomib

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced an Adverse Event [For 21 days/course for up to 12 courses]

2. Number of Participants Who Experienced Cytopenias [21 Days/course for up to 12 courses]

Secondary Outcome Measures

1. Interleukin 6 Levels in Serum [day 14]

   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.

2. Vascular Endothelial Growth Factor (VEGF) Levels in Serum [day 14]

   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.

3. Average Percentage of Light Density Cells in Apoptosis [day 14]

   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.

4. Average Number of Colony Forming Unit-granulocyte-macrophages in Bone Marrow [day 14]

   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.

5. Average Number of Erthroid Burst Forming Units in Bone Marrow [day 14]

   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.

6. Average Number of Leukemia Forming Units in Bone Marrow [day 14]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642

Sponsors and Collaborators

• University of Rochester

Investigators

• Study Chair: Jane L. Liesveld, MD, James P. Wilmot Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jane Liesveld, attending physician, University of Rochester
• ClinicalTrials.gov Identifier: NCT00262873
• Other Study ID Numbers: CDR0000449689; URCC-U20403; MILLENNIUM-i34103-042
• First Posted: Dec 7, 2005
• Last Update Posted: May 9, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Jane Liesveld, attending physician, University of Rochester: previously treated myelodysplastic syndromes; refractory anemia with excess blasts; refractory anemia with ringed sideroblasts; refractory anemia; secondary myelodysplastic syndromes; de novo myelodysplastic syndromes
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Bortezomib

Study Results

Participant Flow

Recruitment Details	23 patients were screened for the study.
Pre-assignment Detail	15 patients did not meet study eligibility criteria.

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Period Title: Overall Study
STARTED	8
COMPLETED	0
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 37.5%
>=65 years	5 62.5%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	69
Sex: Female, Male (Count of Participants)
Female	5 62.5%
Male	3 37.5%
Region of Enrollment (participants) [Number]
United States	8 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced an Adverse Event
Time Frame	For 21 days/course for up to 12 courses

Outcome Measure Data

Analysis Population Description

patients enrolled to receive study drug

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	8
Number [participants]	6 75%

2. Primary Outcome

Title	Number of Participants Who Experienced Cytopenias
Time Frame	21 Days/course for up to 12 courses

Outcome Measure Data

Analysis Population Description

This data was not collected.

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	0

3. Secondary Outcome

Title	Interleukin 6 Levels in Serum
Description	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.
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

data was only available on 5 participants

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	5
pre bortezomib	6.8 (1.7)
post bortezomib	8.6 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Vascular Endothelial Growth Factor (VEGF) Levels in Serum
Description	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.
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

data was only available on 5 participants

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	5
pre bortezomib	402 (105)
post bortezomib	254 (69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Average Percentage of Light Density Cells in Apoptosis
Description	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.
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

marrow samples were not available on all participants at baseline

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	5
pre bortezomib	6.68 (2.67)
post bortezomib	11.37 (3.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Average Number of Colony Forming Unit-granulocyte-macrophages in Bone Marrow
Description	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.
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

baseline marrow samples were available only 5 participants

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	5
pre bortezomib	16.1 (12.8)
post bortezomib	28.6 (25.8)

7. Secondary Outcome

Title	Average Number of Erthroid Burst Forming Units in Bone Marrow
Description	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.
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

analysis was performed on only four participants

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	4
pre bortezomib	14.75 (14.98)
post bortezomib	14.75 (25.51)

8. Secondary Outcome

Title	Average Number of Leukemia Forming Units in Bone Marrow
Description	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.
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

baseline bone marrow was only available on 5 participants

Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
Measure Participants	5
pre bortezomib	27.65 (25.15)
post bortezomib	54.28 (59.16)

Adverse Events

Time Frame	4 years
Arm/Group Title	Bortezomib
Arm/Group Description	Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy.
All Cause Mortality
	Bortezomib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bortezomib
	Affected / at Risk (%)	# Events
Total	2/8 (25%)
Gastrointestinal disorders
constipation	1/8 (12.5%)	1
Respiratory, thoracic and mediastinal disorders
pneumonia	1/8 (12.5%)	1
Other (Not Including Serious) Adverse Events
	Bortezomib
	Affected / at Risk (%)	# Events
Total	5/8 (62.5%)
Blood and lymphatic system disorders
Low Platelets	1/8 (12.5%)	1
Cardiac disorders
Hypotension	1/8 (12.5%)	1
Gastrointestinal disorders
Constipation	4/8 (50%)	4
Infections and infestations
Fever	1/8 (12.5%)	1
Nervous system disorders
Neuropathy	3/8 (37.5%)	3

Limitations/Caveats

All study visits were completed and the trial concluded normally for the limited number of enrolled participants; therefore, the study was considered to have been completed. However, the study is under-powered.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.