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Delayed Tolerance Through Mixed Chimerism

Sponsor
Massachusetts General Hospital (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05900401
Collaborator
Ossium Health, Inc. (Industry), ITB-Med LLC (Industry)
20
Enrollment
2
Arms
78
Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This study will examine the safety and effectiveness of a bone marrow transplant after kidney transplant (from either a living or deceased 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
  • Other: Bone Marrow Transplant
  • Procedure: Peripheral Blood Stem Cell Collection
  • Drug: Combination of Fludarabine, Cyclophosphamide, Rituximab & Siplizumab
 Phase 1/Phase 2

Detailed Description

Recipients of previous LD or DD kidney transplants that were maintained on conventional I.S., will receive a conditioning regimen that includes rituximab on study day -6, fludarabine 15 mg/m2/day on days -5 to -3 (3 doses), CP (30 mg/kg/day) on days -5 and -4, followed by local thymic irradiation (7 Gy) on day -1 and Siplizumab (anti-CD2 mAb) on days, -2, -1, 0 and +1. Donor HSCs will be infused on study day 0. Methylprednisolone 250mg/day will be started on day 0 and tapered off by day 20 (Fig. 2). 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 12 months following HSCT. The recipients will undergo renal allograft biopsy at 6 months after HSCT. If the I.S. withdrawal criteria are met, I.S. will be slowly tapered off by 9-12 months

Study Design

Study Type:
Interventional
Anticipated Enrollment :
20 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
Single (Participant)
Primary Purpose:
Treatment
Official Title:
Delayed Tolerance Through Mixed Chimerism
Anticipated Study Start Date :
Jun 1, 2023
Anticipated Primary Completion Date :
Dec 1, 2026
Anticipated Study Completion Date :
Dec 1, 2029

Arms and Interventions

Arm Intervention/Treatment
Experimental: Kidney and Stem Cell Recipients

Months-Years after standard transplant, patients will undergo bone marrow transplant (either from prospective collection of stem cells from their living donor, or from bone marrow collected at the time of deceased donation)

Other: Bone Marrow Transplant
Months-Years after standard transplant, patients will undergo bone marrow transplant (either from prospective collection of stem cells from their living donor, or from bone marrow collected at the time of deceased donation)

Drug: Combination of Fludarabine, Cyclophosphamide, Rituximab & Siplizumab
Combination of Fludarabine, Cyclophosphamide, Rituximab & Siplizumab
Experimental: Kidney and Stem Cell Donors

PBSC will be collected from the LD via leukapheresis 1-4 weeks before the scheduled HSCT. The donor will first undergo standard GCSF mobilization: GCSF (can be TBO-GCSF) dosed at 10 mcg/kg/d (rounded to nearest pre-filled syringe) administered subcutaneously daily for 5 consecutive days. On the 5th day, the donor will undergo standard large volume leukapheresis. The target yield will be 2-3 x 106 CD34+ cells / kg of actual recipient body weight. A maximum of 3 days of pheresis will be allowed. A minimum of 2 x 106 CD34+ cells / kg of actual recipient body weight will be required to proceed

Procedure: Peripheral Blood Stem Cell Collection
PBSC will be collected from the LD via leukapheresis 1-4 weeks before the scheduled HSCT. The donor will first undergo standard GCSF mobilization: GCSF (can be TBO-GCSF) dosed at 10 mcg/kg/d (rounded to nearest pre-filled syringe) administered subcutaneously daily for 5 consecutive days. On the 5th day, the donor will undergo standard large volume leukapheresis. The target yield will be 2-3 x 106 CD34+ cells / kg of actual recipient body weight. A maximum of 3 days of pheresis will be allowed. A minimum of 2 x 106 CD34+ cells / kg of actual recipient body weight will be required to proceed.

Outcome Measures

Primary Outcome Measures

  1. Incidence of transient mixed chimerism [3 months]

  2. Incidence of renal allograft tolerance [2 years after immunosuppression withdrawal]

Secondary Outcome Measures

  1. Incidence of Participant Survival [2 years after immunosuppression withdrawal]

  2. Incidence of Graft Survival [2 years after immunosuppression withdrawal]

  3. Incidence of Chimeric Transition Syndrome [3 months]

  4. Incidence of Allograft Rejection [2 years after immunosuppression withdrawal]

    Measuring incidence of acute or chronic rejection free survival

  5. Incidence of DSA [2 years after immunosuppression withdrawal]

  6. Incidence of GvHD [2 years after immunosuppression withdrawal]

  7. Incidence of infections [2 years after immunosuppression withdrawal]

    Clinically significant, invasive or resistant opportunistic infection

  8. Incidence of thymic irradiation toxicities [2 years after immunosuppression withdrawal]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No

Recipient Inclusion Criteria

  1. Male or female 18-65 years of age.

  2. Kidney transplant recipients from either LD or DD, with cryo-preserved HSCs available, good renal function (GFR>45 ml/min/1.73m2), normal current allograft biopsy, and no history of documented rejection episodes.

  3. First or second renal 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 https://www.fda.gov/media/150299/download

  5. Ability to understand and provide informed consent.

  6. Serologic evidence of prior exposure to EBV.

  7. Negative COVID-19 test during screening and two days prior to HSC transplantation (HSCT).

Deceased Donor (DD)

  1. Male or female 18-70 years of age.

  2. Consent to donate vertebral bones is obtained from the donor family.

  3. HSCs are successfully cryopreserved and saved >2X106/kg (CD34+ cells) of the recipient.

  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. Negative COVID-19 test at the time of HSC procurement.

Living Donor (LD)

  1. Willingness to provide HSCs by leukapheresis or bone marrow aspiration.

  2. Negative serologic pregnancy test for females of childbearing potential

  3. Good general health as per conventional evaluation for kidney donation.

  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 PBSC collection.

  9. Negative COVID-19 test during screening and two days prior to PBSC collection.

Recipient Exclusion Criteria

  1. ABO blood group-incompatible renal allograft.

  2. Evidence of anti-HLA antibody (donor specific with an MFI >1000) as assessed by routine methodology (Luminex)

  3. Previous history of biopsy proven rejection.

  4. Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (<100,000/mm3).

  5. Seropositivity for HIV-1, hepatitis B surface or core antigen, or hepatitis C virus (confirmed by hepatitis C virus RNA).

  6. Active infection

  7. Left ventricular ejection fraction < 40% as determined by TTE or clinical evidence of heart failure.

  8. Forced expiratory volume FEV1 or DLCO < 50% of predicted.

  9. Lactation or pregnancy.

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

  11. Underlying renal disease etiology with high risk of disease recurrence in the transplanted kidney (such as focal segmental glomerulosclerosis). Autoimmune diseases such as Lupus and Thrombotic Thrombocytopenic Purpura.

  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), or any patients on chronic anticoagulation therapy.

  14. Allergy or sensitivity to any component of Siplizumab, fludarabine, CP, tacrolimus, MMF or rituximab.

  15. Any medical condition that the investigator deems incompatible with participation in the trial. This includes a history of alcohol abuse or illicit drug use/dependence.

  16. Non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c<7). Severe retinopathy, gastroparesis, or severe neuropathy which prevent subject's normal independent daily activities.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

  • Massachusetts General Hospital
  • Ossium Health, Inc.
  • ITB-Med LLC

Investigators

  • Principal Investigator: Tatsuo Kawai, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Tatsuo Kawai, MD, PhD, MD, PhD -- Professor of Surgery, Harvard Medical School, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT05900401
Other Study ID Numbers:
  • 2023P000486
First Posted:
Jun 12, 2023
Last Update Posted:
Jun 12, 2023
Last Verified:
Jun 1, 2023
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Tatsuo Kawai, MD, PhD, MD, PhD -- Professor of Surgery, Harvard Medical School, Massachusetts General Hospital
Tolerance
Transplant
Additional relevant MeSH terms:
Renal Insufficiency
Cyclophosphamide
Rituximab
Fludarabine

Study Results

No Results Posted as of Jun 12, 2023