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Renal Allograft Tolerance Through Mixed Chimerism - SMC/MGH

Primary Purpose

Renal Failure

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Rituximab, Fludarabine, Cyclophosphamide, Thymic irradiation and Siplizumab

Combined bone marrow and kidney transplant

About this trial

This is an interventional treatment trial for Renal Failure

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female 18-60 years of age.
Candidate for a living-donor renal allograft from an HLA mismatched donor
Subjects with chronic kidney disease stage or ESRD who are treated with either hemodialysis or peritoneal dialysis.
First transplant.
Use of FDA-approved methods of contraception
Ability to understand and provide informed consent.
Serologic evidence of prior exposure to EBV
Negative COVID at screening and 2 days before procedure

Exclusion Criteria:

ABO blood group-incompatible renal allograft.
Evidence of anti-HLA antibody (donor specific or not) within 60 days prior to transplant as assessed by routine methodology (Luminex)
Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (<100,000/mm3).
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.
Active infection
Left ventricular ejection fraction < 40% as determined by TTE or clinical evidence of heart failure
Forced expiratory volume FEV1 or DLCO < 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).
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 Siplizumab, Fludarabine, Cyclophosphamide tacrolimus, MMF or rituximab
The presence of any medical condition that the investigator deems incompatible with participation in the trial.
Subjects who have non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c<7). Subject with severe retinopathy, gastroparesis, or severe neuropathy which prevent subject's normal independent daily activities will be excluded from the study

Sites / Locations

Massachusetts General HospitalRecruiting

Outcomes

Primary Outcome Measures

Incidence of Transient Chimerism

Incidence of Chimerism Transition Syndrome

Incidence of tolerance induction

Secondary Outcome Measures

Full Information

NCT ID

NCT04540380

First Posted

August 18, 2020

Last Updated

October 4, 2023

Sponsor

Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04540380

Brief Title

Renal Allograft Tolerance Through Mixed Chimerism - SMC/MGH

Official Title

Renal Allograft Tolerance Through Mixed Chimerism - SMC/MGH

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 1, 2021 (Actual)

Primary Completion Date

January 2025 (Anticipated)

Study Completion Date

June 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The goal is to investigate the safety of the conditioning regimen, and its ability to induce donor/recipient lymphohematopoietic chimerism without Chimerism Transition Syndrome (CTS), which may result in donor-specific unresponsiveness (tolerance) to the renal allograft in the absence of maintenance immunosuppression.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Renal Failure

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

6 (Anticipated)

8. Arms, Groups, and Interventions

Intervention Type

Drug

Intervention Name(s)

Rituximab, Fludarabine, Cyclophosphamide, Thymic irradiation and Siplizumab

Intervention Description

Conditioning regimen .Patients will receive Rituximab, Fludarabine, Cyclophosphamide, Thymic irradiation and Thymoglobulin

Intervention Type

Procedure

Intervention Name(s)

Combined bone marrow and kidney transplant

Intervention Description

Recipients will receive a conditioning regimen that includes rituximab on study days -7 and -2, fludarabine 10mg/m2/day on days -6 to -3 (4 doses), cyclophosphamide (22.5mg/kg/day) on days -5 and -4, followed by local thymic irradiation (7 Gy) on day -1 and Siplizumabon days -1, 0, and +1. Combined kidney and bone marrow transplant will be performed on study day 0. Methylprednisolone will be started at 250 mg/day on day 0 and tapered to prednisone 20mg by day 10 after which it will be continued until day 20. Prophylaxis will be provided for hemorrhagic cystitis, PCP, fungal infection, CMV, and perioperative infection. All patients who require any 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 without chimerism transition syndrome (CTS) will be assessed.

Primary Outcome Measure Information:

Title

Incidence of Transient Chimerism

Time Frame

36 months after immunosuppression withdrawal

Title

Incidence of Chimerism Transition Syndrome

Time Frame

36 months after immunosuppression withdrawal

Title

Incidence of tolerance induction

Time Frame

36 months after immunosuppression withdrawal

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

55 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female 18-60 years of age. Candidate for a living-donor renal allograft from an HLA mismatched donor Subjects with chronic kidney disease stage or ESRD who are treated with either hemodialysis or peritoneal dialysis. First transplant. Use of FDA-approved methods of contraception Ability to understand and provide informed consent. Serologic evidence of prior exposure to EBV Negative COVID at screening and 2 days before procedure Exclusion Criteria: ABO blood group-incompatible renal allograft. Participant with a (non DSA) PRA > 20% within 6 months prior to transplant Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (<100,000/mm3). 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. Active infection Left ventricular ejection fraction < 40% as determined by TTE or clinical evidence of heart failure Forced expiratory volume FEV1 or DLCO < 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). 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 Siplizumab, Fludarabine, Cyclophosphamide, tacrolimus, DMSO, MMF or rituximab. The presence of any medical condition that the investigator deems incompatible with participation in the trial. Subjects who have non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c<7). Subject with severe retinopathy, gastroparesis, or severe neuropathy which prevent subject's normal independent daily activities will be excluded from the study

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Tatsuo Kawai, MD PhD

Phone

617-726-0289

tkawai@mgh.harvard.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Gabe Impreso Baysa, BS

Phone

617-643-7569

gimpresobaysa@mgh.harvard.edu

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Tatsuo Kawai, MD, PhD

Phone

617-726-0289

tkawai@partners.org

First Name & Middle Initial & Last Name & Degree

Tatsuo Kawai, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD

Undecided

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Renal Allograft Tolerance Through Mixed Chimerism - SMC/MGH

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