Renal Allograft Tolerance Through Mixed Chimerism (Belatacept)

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02314403
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arm: 1
• Duration (Months): 76.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study will examine the safety and effectiveness of a combination kidney and bone marrow transplant from a haplo-identical related donor. An investigational medication and other treatments will be given prior to and after the transplant to help protect the transplanted kidney from being attacked by the body's immune system

Condition or Disease	Intervention/Treatment	Phase
Kidney Failure, Chronic; Renal Insufficiency	Drug: Belatacept; Drug: ATG; Drug: Rituximab; Radiation: Total Body Irradiation; Radiation: Thymic Irradiation; Procedure: Combined Bone Marrow/Kidney Transplantation	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Mar 1, 2021
• Actual Study Completion Date: Jul 1, 2021

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Combined Bone Marrow and Kidney Transplantation Recipients will receive a conditioning regimen that starts with Rituximab on day -7 (and days -2, 5, 12), Whole Body Irradiation 1.5 Gy x2 on study days -6 and -5, followed by ATG on Days -2, -1, 0. Belatacept 10mg/kg on Days 0, 3, 10, 17, 24, 38, 52. Thymic irradiation (7 Gy) will be given on study day -1, and combined renal and bone marrow transplant will be done on study day 0. Prednisone will be started at 2 mg/kg on day 4 and tapered off by day 20. Tacrolimus will be administered on study days -1 through 60, and then tapered if weaning criteria are met.

Drug: Belatacept; A selective T-cell (lymphocyte) costimulation blocker; Drug: ATG; A T-Cell Depleting Agent; Drug: Rituximab; B-Cell Depleting Agent; Radiation: Total Body Irradiation; Radiation: Thymic Irradiation; Procedure: Combined Bone Marrow/Kidney Transplantation

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Successful Withdrawal of Immunosuppression [5 Years]

   The Primary Outcome is: The induction of transient mixed chimerism and renal allograft tolerance (24 consecutive months off of immunosuppression)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female 18-60 years of age

• Candidate for a living-donor renal allograft from an HLA mismatched donor

• First or second transplant with either a living donor or cadaveric transplant as the first transplant.

• Use of FDA-approved methods of contraception by all recipients from the time that study treatment begins until 104 weeks (24 months) after renal transplantation.

• Ability to understand and provide informed consent.

• Serologic evidence of prior exposure to EBV.

Exclusion Criteria:

• ABO blood group-incompatible renal allograft.

• Evidence of anti-HLA antibody within 60 days prior to transplant as assessed by routine methodology (AHG and/or ELISA)

• Leukopenia or thrombocytopenia.

• Positive for HIV-1, hepatitis B core antigen, or hepatitis C virus; or positivity for hepatitis B surface antigen.

• Cardiac ejection fraction < 40% or clinical evidence of insufficiency.

• Forced expiratory volume FEV1 < 50% of predicted.

• Lactation or pregnancy.

• History of cancer other than basal cell carcinoma of the skin or carcinoma in situ of the cervix.

• Underlying renal disease etiology with a high risk of disease recurrence in the transplanted kidney (such as focal segmental glomerulosclerosis, type I or II membranoprolifertive glomerulonephritis).

• Prior dose-limiting radiation therapy.

• Known genetic disease or family history that may result in greater sensitivity to the effects of irradiation, or a physical deformity that would preclude adequate shielding or appropriate dosing during the irradiation component of the conditioning regimen.

• Enrollment in other investigational drug studies within 30 days prior to enrollment.

• Abnormal (>2 times lab normal) values for (a) liver function chemistries (ALT, AST, AP), (b) bilirubin, (c) coagulation studies (PT, PTT).

• Allergy or sensitivity to any component of belatacept, ATG, tacrolimus, or rituximab.

• Maintenance immunosuppression within 3 months prior to conditioning other than physiological doses of steroids, defined as ≤ 50 mg of hydrocortisone or dose equivalent.

• The presence of any medical condition that the investigator deems incompatible with participation in the trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

Sponsors and Collaborators

• Massachusetts General Hospital

Investigators

• Principal Investigator: Tatsuo Kawai, MD PhD, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol - Mar 8, 2016

More Information

Additional Information:

• Kawai T, Cosimi AB, Sachs DH. Preclinical and clinical studies on the induction of renal allograft tolerance through transient mixed chimerism. Curr Opin Organ Transplant. 2011 Aug;16(4):366-71.
• Sachs DH, Sykes M, Kawai T, Cosimi AB. Immuno-intervention for the induction of transplantation tolerance through mixed chimerism. Semin Immunol. 2011 Jun;23(3):165-73.
• Kawai T, (et.al.) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. 2008 Jan 24;358(4):353-61.

Publications

None provided.

• Responsible Party: Tatsuo Kawai, MD, PhD, Associate Professor of Surgery, Harvard Medical School, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02314403
• Other Study ID Numbers: MGH Tolerance Trial
• First Posted: Dec 11, 2014
• Last Update Posted: Oct 25, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by Tatsuo Kawai, MD, PhD, Associate Professor of Surgery, Harvard Medical School, Massachusetts General Hospital: ESRD
• Additional relevant MeSH terms: Renal Insufficiency; Kidney Failure, Chronic; Rituximab; Abatacept

Study Results

Participant Flow

Arm/Group Title	Combined Bone Marrow and Kidney Transplantation
Arm/Group Description	Recipients will receive a conditioning regimen that starts with Rituximab on day -7 (and days -2, 5, 12), Whole Body Irradiation 1.5 Gy x2 on study days -6 and -5, followed by ATG on Days -2, -1, 0. Belatacept 10mg/kg on Days 0, 3, 10, 17, 24, 38, 52. Thymic irradiation (7 Gy) will be given on study day -1, and combined renal and bone marrow transplant will be done on study day 0. Prednisone will be started at 2 mg/kg on day 4 and tapered off by day 20. Tacrolimus will be administered on study days -1 through 60, and then tapered if weaning criteria are met. Belatacept: A selective T-cell (lymphocyte) costimulation blocker ATG: A T-Cell Depleting Agent Rituximab: B-Cell Depleting Agent Total Body Irradiation Thymic Irradiation Combined Bone Marrow/Kidney Transplantation
Period Title: Overall Study
STARTED	2
COMPLETED	2
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Combined Bone Marrow and Kidney Transplantation
Arm/Group Description	Recipients will receive a conditioning regimen that starts with Rituximab on day -7 (and days -2, 5, 12), Whole Body Irradiation 1.5 Gy x2 on study days -6 and -5, followed by ATG on Days -2, -1, 0. Belatacept 10mg/kg on Days 0, 3, 10, 17, 24, 38, 52. Thymic irradiation (7 Gy) will be given on study day -1, and combined renal and bone marrow transplant will be done on study day 0. Prednisone will be started at 2 mg/kg on day 4 and tapered off by day 20. Tacrolimus will be administered on study days -1 through 60, and then tapered if weaning criteria are met. Belatacept: A selective T-cell (lymphocyte) costimulation blocker ATG: A T-Cell Depleting Agent Rituximab: B-Cell Depleting Agent Total Body Irradiation Thymic Irradiation Combined Bone Marrow/Kidney Transplantation
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37 (5.5)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	2 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 50%
Not Hispanic or Latino	1 50%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 50%
More than one race	0 0%
Unknown or Not Reported	1 50%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Successful Withdrawal of Immunosuppression
Description	The Primary Outcome is: The induction of transient mixed chimerism and renal allograft tolerance (24 consecutive months off of immunosuppression)
Time Frame	5 Years

Outcome Measure Data

Analysis Population Description

Two subjects underwent conditioning regimen

Arm/Group Title	Combined Bone Marrow and Kidney Transplantation
Arm/Group Description	Recipients will receive a conditioning regimen that starts with Rituximab on day -7 (and days -2, 5, 12), Whole Body Irradiation 1.5 Gy x2 on study days -6 and -5, followed by ATG on Days -2, -1, 0. Belatacept 10mg/kg on Days 0, 3, 10, 17, 24, 38, 52. Thymic irradiation (7 Gy) will be given on study day -1, and combined renal and bone marrow transplant will be done on study day 0. Prednisone will be started at 2 mg/kg on day 4 and tapered off by day 20. Tacrolimus will be administered on study days -1 through 60, and then tapered if weaning criteria are met. Belatacept: A selective T-cell (lymphocyte) costimulation blocker ATG: A T-Cell Depleting Agent Rituximab: B-Cell Depleting Agent Total Body Irradiation Thymic Irradiation Combined Bone Marrow/Kidney Transplantation
Measure Participants	2
Count of Participants [Participants]	2 100%

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	An adverse event is any occurrence or worsening of an undesirable or unintended sign, symptom, laboratory finding, or disease that occurs during participation in the trial. An adverse event will be followed until it resolves or until 30 days after a participant terminates from the study, whichever comes first.
Arm/Group Title	Combined Bone Marrow and Kidney Transplantation
Arm/Group Description	Recipients will receive a conditioning regimen that starts with Rituximab on day -7 (and days -2, 5, 12), Whole Body Irradiation 1.5 Gy x2 on study days -6 and -5, followed by ATG on Days -2, -1, 0. Belatacept 10mg/kg on Days 0, 3, 10, 17, 24, 38, 52. Thymic irradiation (7 Gy) will be given on study day -1, and combined renal and bone marrow transplant will be done on study day 0. Prednisone will be started at 2 mg/kg on day 4 and tapered off by day 20. Tacrolimus will be administered on study days -1 through 60, and then tapered if weaning criteria are met. Belatacept: A selective T-cell (lymphocyte) costimulation blocker ATG: A T-Cell Depleting Agent Rituximab: B-Cell Depleting Agent Total Body Irradiation Thymic Irradiation Combined Bone Marrow/Kidney Transplantation
All Cause Mortality
	Combined Bone Marrow and Kidney Transplantation
	Affected / at Risk (%)	# Events
Total	0/2 (0%)
Serious Adverse Events
	Combined Bone Marrow and Kidney Transplantation
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Renal and urinary disorders
Thrombotic Microangiopathy	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Combined Bone Marrow and Kidney Transplantation
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Immune system disorders
Neutropenia	1/2 (50%)	1
Musculoskeletal and connective tissue disorders
Heel pain	1/2 (50%)	1
Skin and subcutaneous tissue disorders
HSV Lesion	1/2 (50%)	1

Limitations/Caveats

The incidence of adverse events found around 10 days after bone marrow transplant.

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.