Clinical trial NCT02314403
Conditions: Kidney Failure, Chronic Renal Insufficiency
Keywords: ESRD
Sponsor: Massachusetts General Hospital
Start date: 2015-02-01; Completion date: 2021-07-01
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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

Detailed description:

Arms: arm 1: 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.
Interventions: intervention 1: Belatacept intervention 2: ATG intervention 3: Rituximab intervention 4: Total Body Irradiation intervention 5: Thymic Irradiation intervention 6: Combined Bone Marrow/Kidney Transplantation
Intervention descriptions: intervention 1: A selective T-cell (lymphocyte) costimulation blocker intervention 2: A T-Cell Depleting Agent intervention 3: B-Cell Depleting Agent intervention 4: None intervention 5: None intervention 6: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
Renal Allograft Tolerance Through Mixed Chimerism 
 
 
Version 3.0 (Mar 8, 2016) 
 
 
 
 
Co-Principal Investigator: 
 
A.Benedict Cosimi, MD 
Tatsuo Kawai, MD, PhD 
Nina Tolkoff-Rubin, MD 
 
Coinvestigators: 
 
Gilles Benichou, PhD 
Yi-Bin Chen, M.D. 
Robert B Colvin, MD 
Bimal Dey, M.D. 
Nahel Elias, M.D. 
Jay Fishman, M.D. 
Eliot Heher, M.D.  
James Markmann, MD, PhD 
Steve McAfee, M.D. 
Fred Preffer, PhD 
David H. Sachs, M.D. 
Susan Saidman, Ph.D. 
Thomas Spitzer, MD 
Larry Turka, M.D. 
Winfred Williams, M.D. 
Karen Winkfield, M.D. Ph.D. 
 
 
 
 
 
 
 
 
 
 
 
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Synopsis 
 
Title 
 
 
Renal Allograft Tolerance Through Mixed Chimerism 
 
Short Title 
 
Renal Allograft Tolerance 
 
Trial Phase 
 
Phase I 
 
Conducted by  
MGH, Transplant Surgery  
 
Principal Investigators A. Benedict Cosimi, M.D.     
Tatsuo Kawai, M.D., Ph.D. 
Nina Tolkoff-Rubin, M.D. 
 
Accrual Objective 
5 participants with end-stage renal disease (ESRD) and no evidence of prior 
sensitization, and their donors 
 
Study Design 
 
Pilot study 
 
Pace of Enrollment  
Enrollment will be limited to one patient every three months  
and Study Duration 
  
 
 
Participants will be followed for a total of 3-4 years after combined bone marrow and kidney 
transplantation (24 months after withdrawal of immunusuppression).  Assessments will be performed 
for participant and graft survival, and long term adverse events. 
 
Endpoint 
The primary endpoint is Induction of transient mixed chimerism and renal allograft 
tolerance (24 consecutive months off  of immunosuppression) 
 
 
 
Recipient Inclusion Criteria 
 
 
1.        Male or female 18–60 years of age. 
 
2.        Candidate for a living-donor renal allograft from an HLA mismatched donor 
 
3.         First or second transplant with either a living donor or cadaveric transplant as the first transplant. 
 
4.        Use of FDA-approved methods of contraception (those with less than a 3% failure rate) by all 
recipients from the time that study treatment begins until 104 weeks (24 months) after renal 
transplantation. (For further information on FDA- approved methods of contraception, see  
http://www.fda.gov/ForConsumers/ByAudience/ForWomen/ucm118465.htm 
 
5. 
Ability to understand and provide informed consent. 
 
6. 
Serologic evidence of prior exposure to EBV.  
 
 
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Recipient Exclusion Criteria 
 
1. 
ABO blood group-incompatible renal allograft. 
 
2. 
Evidence of anti-HLA antibody within 60 days prior to transplant as assessed by routine          
methodology (AHG and/or ELISA)  
 
3. 
Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia. 
 
4. 
Seropositivity for HIV-1, hepatitis B core antigen, or hepatitis C virus (confirmed by hepatitis C     
virus RNA); or positivity for hepatitis B surface antigen. 
 
5. 
Cardiac ejection fraction < 40% or clinical evidence of insufficiency.  
 
6. 
Forced expiratory volume FEV1 < 50% of predicted.  
 
7. 
Lactation or pregnancy. 
 
8. 
History of cancer other than basal cell carcinoma of the skin or carcinoma in situ of the cervix.  
 
9. 
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).  
 
10. 
Prior dose-limiting radiation therapy. 
 
11. 
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. 
 
12. 
Enrollment in other investigational drug studies within 30 days prior to enrollment. 
 
13. 
 Abnormal (>2 times lab normal) values for (a) liver function chemistries (ALT, AST, AP), (b) 
bilirubin, (c) coagulation studies (PT, PTT). 
 
14. 
Allergy or sensitivity to any component of belatacept, ATG, tacrolimus, or rituximab. 
 
15. 
Maintenance immunosuppression within 3 months prior to conditioning other than 
physiological doses of steroids, defined as ≤ 50 mg of hydrocortisone or dose equivalent. 
 
16. 
The presence of any medical condition that the investigator deems incompatible with 
participation in the trial. 
 
Donor Inclusion Criteria 
 
 
1.           Male or female 18–65 years of age. 
 
 2.          For females of childbearing potential: a serum pregnancy test showing negative results. 
 
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3.           Excellent health per conventional predonor history (medical and psychosocial evaluation). 
 
4.             Acceptable laboratory parameters (hematology in normal or near-normal range; liver function 
<2 times the upper limit of normal, and normal creatinine). 
 
5.           Negative for viral infection with HbsAg, HIV, HCV, or HTLV-1. 
 
6.           Cardiac/pulmonary function within normal limits (CXR, ECG). 
 
7. 
 Ability to understand and provide informed consent. 
 
8. 
 Meets standard institutional criteria for both bone marrow and kidney donation 
 
Treatment Description  
 
Recipients will receive a conditioning regimen that starts with Rituximab on day –7 (and days –2, 6, 13), 
Whole Body Irradiation 1.5 Gy x2  on study days –5 and –4, followed by ATG on Days -2, -1, 0. Belatacept 
20mg/kg on Days 1, 6 and 10mg/kg on Days 13, 20  34 . 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 20 mg on day 10 and tapered off by day 20. Tacrolimus will be administered on study days –1 
through 60, and then tapered if weaning criteria are met. Leukapheresis will be performed prior to 
initiating the conditioning regimen and these cells will be frozen 
 
All patients who require a blood transfusion will receive only leukocyte-depleted and irradiated blood 
products for a period of at least 52 weeks following transplantation. 
 
The proportion of patients successfully weaned off immunosuppression will be assessed.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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