The Impact of Velcade(TM)on Antibody Secreting Cells in Sensitized Renal Allograft Candidates

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00722722
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 18
• Location: 1
• Arms: 3
• Duration (Months): 70
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Patients planning to have kidney transplantation who are sensitized to their donors have high levels of donor specific alloantibodies. High levels of donor specific antibodies put kidney transplant recipients at risk for rejection very early after transplant. This study is trying to determine if the drug bortezomib (Velcade ™) can reduce donor specific alloantibodies to a level that permits kidney transplantation without a high risk for rejection.

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplantation	Drug: Bortezomib	Phase 2

Detailed Description

The study is designed to assess the impact of in vivo treatment of bortezomib on anti-human leukocyte antigen (HLA) production by normal antibody secreting cells (ASC) in sensitized renal allograft candidates. The design involves treatment of subjects with bortezomib using one of three dosing regimens (4 doses, 16 doses or 32 doses of bortezomib). Using novel assays, anti-HLA production is determined by measuring the bone marrow derived ASC at baseline (prior to therapy) and after treatment (at day 14, 3 days after the last bortezomib dose). Paired data are used with patients serving as their own controls. Finally, the safety of bortezomib is evaluated by monitoring total serum antibody levels and the incidence of side effects (primarily neuropathy) at 1 month, the final follow-up point.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Impact of Velcade(TM)on Antibody Secreting Cells in Sensitized Renal Allograft Candidates
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 4 dose group 4 doses of bortezomib (1.3mg/m^2 of body surface area)	Drug: Bortezomib; Velcade given in four-dose cycles intravenously (through a vein).; Other Names: Velcade(TM)
Active Comparator: 16 dose group 16 doses of bortezomib (1.3mg/m^2 of body surface area)	Drug: Bortezomib; Velcade given in four-dose cycles intravenously (through a vein).; Other Names: Velcade(TM)
Active Comparator: 32 dose group 32 doses of bortezomib (1.3mg/m^2 of body surface area)	Drug: Bortezomib; Velcade given in four-dose cycles intravenously (through a vein).; Other Names: Velcade(TM)

Outcome Measures

Primary Outcome Measures

1. Response to Bortezomib Monotherapy [6 months]

   Response to treatment with Bortezomib (BTZ) alone was defined as a reduction in serum Donor Specific Alloantibody (DSA) levels following treatment. DSA levels were measured prior to treatment and after treatment. A good response occurred if all DSA were reduced. A partial response when a reduction was observed in at least one DSA, but not all DSA. No response occurred when no reduction of any DSA was attained.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

• Female subject is post-menopausal, surgically sterilized, or she and/or sexual partner are willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

• Male subject agrees to use an acceptable method for contraception for the duration of the study.

• Renal transplant candidates who otherwise meet our acceptance criteria.

• Evidence of alloantibody in their serum (panel reactive antibody >20% and specificities determined by single antigen flow bead assay).

• Sensitized patients with no living donors or have donor-specific antibody levels too high to undergo successful transplantation using our current protocols (T or B cell crossmatch channel shift >500).

Exclusion Criteria:

• Patient has a platelet count of <30 x 10^9/L within 14 days before enrollment.

• Patient has an absolute neutrophil count (ANC) of <1.0 x 10^9/L within 14 days before enrollment.

• Patient has >Grade 2 peripheral neuropathy within 14 days before enrollment.

• 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. Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the investigator as not medically relevant.

• Patient has hypersensitivity to bortezomib, boron or mannitol.

• Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

• Patient has received other investigational drugs within14 days before enrollment.

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Diagnosed or treated for malignancy within 5 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

• Contraindication to kidney transplantation-active infection, comorbid medical conditions, etc.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Mark D. Stegall, M.D., Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Mayo Clinic Clinical Trials

Publications

• Diwan TS, Raghavaiah S, Burns JM, Kremers WK, Gloor JM, Stegall MD. The impact of proteasome inhibition on alloantibody-producing plasma cells in vivo. Transplantation. 2011 Mar 15;91(5):536-41. doi: 10.1097/TP.0b013e3182081333.

• Responsible Party: Mark Stegall, PI, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00722722
• Other Study ID Numbers: 08-000556
• First Posted: Jul 28, 2008
• Last Update Posted: May 9, 2016
• Last Verified: Apr 1, 2016

• Additional relevant MeSH terms: Bortezomib

Study Results

Participant Flow

Arm/Group Title	4 Dose Group	16 Dose Group	32 Dose Group
Arm/Group Description	4 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).	16 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).	32 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).
Period Title: Overall Study
STARTED	3	5	10
COMPLETED	3	5	10
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	4 Dose Group	16 Dose Group	32 Dose Group	Total
Arm/Group Description	4 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).	16 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).	32 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).	Total of all reporting groups
Overall Participants	3	5	10	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.3 (3.5)	40.4 (11.4)	39.5 (6.6)	39.1 (7.6)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	5 100%	7 70%	14 77.8%
Male	1 33.3%	0 0%	3 30%	4 22.2%
Region of Enrollment (participants) [Number]
United States	3 100%	5 100%	10 100%	18 100%

Outcome Measures

1. Primary Outcome

Title	Response to Bortezomib Monotherapy
Description	Response to treatment with Bortezomib (BTZ) alone was defined as a reduction in serum Donor Specific Alloantibody (DSA) levels following treatment. DSA levels were measured prior to treatment and after treatment. A good response occurred if all DSA were reduced. A partial response when a reduction was observed in at least one DSA, but not all DSA. No response occurred when no reduction of any DSA was attained.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

In the 32 dose group, one patient received a kidney transplant with a B-cell flow cytometric crossmatch channel shift of less than 300 after dose 20 and was transplanted with a positive crossmatch donor. This patient was then excluded from further DSA analysis.

Arm/Group Title	4 Dose Group	16 Dose Group	32 Dose Group
Arm/Group Description	4 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).	16 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).	32 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).
Measure Participants	3	5	9
Good Response	0 0%	0 0%	0 0%
Partial Response	1 33.3%	1 20%	6 60%
No Response	2 66.7%	4 80%	3 30%

Adverse Events

Time Frame	Subjects were followed for 6 months. Before each drug dose, subjects were evaluated for possible toxicities that may have occurred after the previous doses(s).
Arm/Group Title	4 Dose Group		16 Dose Group		32 Dose Group
Arm/Group Description	4 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).		16 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).		32 doses of bortezomib (1.3mg/m^2 of body surface area) Bortezomib: Velcade given in four-dose cycles intravenously (through a vein).
All Cause Mortality
	4 Dose Group		16 Dose Group		32 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	4 Dose Group		16 Dose Group		32 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/5 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	4 Dose Group		16 Dose Group		32 Dose Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		5/5 (100%)		10/10 (100%)
Blood and lymphatic system disorders
Anemia Grade 1	2/3 (66.7%)	2	1/5 (20%)	1	4/10 (40%)	4
Anemia Grade 2	0/3 (0%)	0	4/5 (80%)	4	6/10 (60%)	6
Thrombocytopenia Grade 1	1/3 (33.3%)	1	3/5 (60%)	3	7/10 (70%)	7
Thrombocytopenia Grade 2	0/3 (0%)	0	0/5 (0%)	0	1/10 (10%)	1
Leukopenia Grade 1	0/3 (0%)	0	0/5 (0%)	0	1/10 (10%)	1
Leukopenia Grade 2	0/3 (0%)	0	0/5 (0%)	0	2/10 (20%)	2
Gastrointestinal disorders
Nausea/Vomiting Grade 1	0/3 (0%)	0	3/5 (60%)	3	5/10 (50%)	5
Diarrhea Grade 1	1/3 (33.3%)	1	1/5 (20%)	1	4/10 (40%)	4
Diarrhea Grade 2	0/3 (0%)	0	1/5 (20%)	1	2/10 (20%)	2
General disorders
Flu-like symptoms Grade 1	0/3 (0%)	0	2/5 (40%)	2	6/10 (60%)	6
Chills Grade 1	0/3 (0%)	0	0/5 (0%)	0	5/10 (50%)	5
Fatigue Grade 1	0/3 (0%)	0	0/5 (0%)	0	3/10 (30%)	3
Fatigue Grade 2	0/3 (0%)	0	0/5 (0%)	0	1/10 (10%)	1
Musculoskeletal and connective tissue disorders
Myalgias Grade 1	0/3 (0%)	0	2/5 (40%)	2	7/10 (70%)	7

Limitations/Caveats

[Not Specified]

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.