Donor-derived Mesenchymal Stromal Cells, Alemtuzumab, Co-stimulation Blockade and Sirolimus for Tolerance Induction in Adult Kidney Allograft Recipients (ITN062ST)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Proportion of Participants who Achieve Operational Tolerance
研究概览
简要总结
Anti-rejection medicines, also known as immunosuppressive drugs, are prescribed to organ transplant recipients to prevent rejection of the new organ. Long-term use of these medicines places transplant recipients at higher risk of serious infections and certain types of cancer.
The purpose of this study is to determine if:
- it is safe to give mesenchymal stromal cells (MSCs) to kidney transplant recipients, and
- the combination of the immunosuppressive (anti-rejection) study drugs plus the MSCs can allow a kidney transplant recipient to slowly reduce and/or then completely stop all anti-rejection drugs, without rejection of their kidney (renal) allograft, a process called "immunosuppression withdrawal".
详细描述
Background:The most common problem following a kidney transplant is the development of acute or chronic rejection. Rejection is the immunologic reaction in which the body refuses to accept the transplanted organ. The body's immune system will make destructive antibodies that will attempt to attack the transplanted organ.
In order to prevent organ rejection, all patients receiving an allograft (a graft transplanted between genetically non-identical individuals of the same species) must take anti-rejection (immunosuppressive) therapy. These medications function by lowering the body's natural immune system. Often these medications are associated with significant side effects ranging from infections to cancer.
Study:
This is a single center, open label, dose-escalation clinical trial in 6 adult recipients of Human Leukocyte Antigen (HLA)- non-identical, living-donor renal allografts. All participants will receive induction therapy with alemtuzumab followed by maintenance therapy with sirolimus and belatacept.
A total of 2 dosing cohorts of 2 recipients each will receive 12 infusions of donor-derived MSCs starting on Day 42 post-transplant and every 4 weeks starting on Day 56 post-transplant, with a minimum of 7 days between the first and second MSC infusions.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult candidates of an human leukocyte antigen (HLA)-non-identical, living-donor kidney transplant:
- •-Candidates must meet the United Network for Organ Sharing (UNOS) criteria, including laboratory criteria, for transplant listing;
- •Evidence of established immunity to Epstein-Barr Virus (EBV) as demonstrated by serologic testing;
- •Serological evidence of prior Cytomegalovirus (CMV) infection if donor is CMV positive;
- •For women of child bearing potential:
- •A negative serum or urine pregnancy test with sensitivity of less than 50 mIU/mL within 72 hours of start of study medication; and
- •Agreement to use contraception:
- •--- According to the FDA Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective
- •---Female recipients of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for 18 months after the first dose of study therapy.
- •Meets institutional selection criteria for organ and bone marrow donation:
- •-All donors will be screened and tested in accordance with:
- •(i) FDA 21 CRF 1271.85 requirements for donors of human cells, tissues, and cellular- and tissue-based products (HCT/P); and
- •(ii) standards for living kidney donors testing for infection established by the United Network for Organ Sharing (UNOS).
- •Ability to understand and provide informed consent for all study procedures including kidney transplant and bone marrow harvest.
排除标准
- •History of any immunodeficiency syndrome (including Human Immunodeficiency Virus-1 (HIV-1) and HIV-2);
- •Positive anti-Hepatitis C Virus (HCV) Polymerase Chain Reaction (PCR), anti-Hepatitis C Virus (HBV) PCR, or HBV surface antigen;
- •History of malignancy within 5 years of enrollment or any history of hematogenous malignancy or lymphoma; --Exception: Participants with curatively treated non-melanomatous skin cancer or curatively treated cervical carcinoma in situ may be enrolled.
- •Underlying renal disease with high likelihood of recurrence, including but not limited to:
- •primary focal segmental glomerulosclerosis (FSGS),
- •Type I or II membranoproliferative glomerulonephritis (MPGN),
- •hemolytic-uremic syndrome and
- •thrombotic thrombocytopenic purpura (HUS/TTP) syndrome. ---Subject(s) with end-stage renal disease (ESRD) of unknown etiology and/or has no histologically confirmed diagnosis, may be enrolled into the study as long as there are no clinical signs or symptoms consistent with excluded clinical diagnoses.
- •History of active M. tuberculosis:
- •-Participants with a history of latent M. tuberculosis (LTB) as defined by positive testing for tuberculosis using an approved IGRA blood test, such as QuantiFERON®-Gold TB or T-SPOT-TB assay must:
- •have completed treatment for LTB and
- •have a negative chest x-ray. ----All participants will undergo IGRA testing for M tuberculosis within 3 months prior to transplant.
- •Current or historical evidence of donor-specific antibody;
- •Immunosuppressive drug therapy within one year prior to enrollment.
- •May not be taking or have taken prednisone, cyclosporine A, tacrolimus, azathioprine, Mycophenolate Mofetil (MMF), cyclophosphamide, methotrexate, infliximab, etanercept, or other agents which have a primary therapeutic effect of immunosuppression in the year prior to transplantation.
- •May not have taken depletional anti-lymphocyte agents at any time.
- •--Exceptions:
- •Short (≤ 30 days) courses of topical or inhaled steroids are permitted, as are
- •Short oral or parental pulses for a documented hypersensitivity reaction.
- •Active autoimmune disease requiring ongoing immunosuppressive therapy or other conditions in which there is an anticipated need for immunosuppressive maintenance therapy;
- •Uncompensated congestive heart failure, pulmonary edema, or symptomatic pulmonary hypertension;
- •Active severe infection within a month of the screening visit;
- •Use of an investigational drug within 30 days of the screening visit;
- •Presence of any medical condition that the investigator deems incompatible with trial participation; or
- •Inability or unwillingness to comply with protocol monitoring and therapy.
- •History of blood donation to the recipient;
- •Evidence of prior Cytomegalovirus (CMV) infection if the recipient is CMV negative;
- •History of HIV-1/HIV-2 infection;
- •Positive HCV PCR, HBV PCR or HBV surface antigen;or
- •Presence of any medical condition that the investigator deems incompatible with trial participation.
研究组 & 干预措施
MSCs 10^4 cells/kg+anti-rejection drugs
The first dosing cohort of 2 participants will receive 12 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg every 4-weeks.
干预措施: mycophenolate acid (Drug)
MSCs 10^4 cells/kg+anti-rejection drugs
The first dosing cohort of 2 participants will receive 12 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg every 4-weeks.
干预措施: Donor-derived Mesenchymal Stromal Cells (Biological)
MSCs 10^4 cells/kg+anti-rejection drugs
The first dosing cohort of 2 participants will receive 12 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg every 4-weeks.
干预措施: alemtuzumab (Drug)
MSCs 10^4 cells/kg+anti-rejection drugs
The first dosing cohort of 2 participants will receive 12 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg every 4-weeks.
干预措施: belatacept (Drug)
MSCs 10^4 cells/kg+anti-rejection drugs
The first dosing cohort of 2 participants will receive 12 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg every 4-weeks.
干预措施: sirolimus (Drug)
MSCs 10^4 cells/kg+anti-rejection drugs
The first dosing cohort of 2 participants will receive 12 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg every 4-weeks.
干预措施: mycophenolate mofetil (Drug)
MSCs 10^4 cells/kg+anti-rejection drugs
The first dosing cohort of 2 participants will receive 12 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg every 4-weeks.
干预措施: prednisone (Drug)
MSCs 10^5 cells/kg+anti-rejection drugs
If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.
干预措施: Donor-derived Mesenchymal Stromal Cells (Biological)
MSCs 10^5 cells/kg+anti-rejection drugs
If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.
干预措施: alemtuzumab (Drug)
MSCs 10^5 cells/kg+anti-rejection drugs
If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.
干预措施: belatacept (Drug)
MSCs 10^5 cells/kg+anti-rejection drugs
If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.
干预措施: sirolimus (Drug)
MSCs 10^5 cells/kg+anti-rejection drugs
If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.
干预措施: mycophenolate mofetil (Drug)
MSCs 10^5 cells/kg+anti-rejection drugs
If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.
干预措施: mycophenolate acid (Drug)
MSCs 10^5 cells/kg+anti-rejection drugs
If the first 3 infusions of 10^4 donor-derived Mesenchymal Stromal Cells (MSCs) cells/kg are well tolerated, this cohort of 2 participants will receive 12 infusions of 10^5 cells/kg every 4-weeks.
干预措施: prednisone (Drug)
结局指标
主要结局
Proportion of Participants who Achieve Operational Tolerance
时间窗: 52 weeks after completion of Immunosuppression Withdrawal (ISW)
Operational tolerance (to their kidney transplant) defined by participant remaining off all immunosuppression for 52 weeks after completion of Immunosuppression Withdrawal (ISW) with: * No evidence of biopsy-proven allograft rejection after initiation of ISW; * Acceptable renal function, defined as an estimated GFR \> 60 ml/min/1.73cm\^2 calculated using the CKD-EPI equation or a serum creatinine that has increased no more than 25% above baseline, as assessed at the week 52 visit after completion of ISW; * No evidence of sustained transplant renal derived pathologic proteinuria, defined as a persistent protein creatinine ratio of greater than 0.5; and * No Donor Specific Antibodies (DSA) at any time after completion of ISW.
次要结局
- Frequency of Antibody-Mediated Chronic Rejection(From kidney transplant to completion of study (up to approximately 7 years))
- Proportion of Participants who Return to Immunosuppression(From ISW completion to end of study participation (up to approximately 5 years))
- Proportion of Participants who Achieve Belatacept Monotherapy(48 weeks from the time of last sirolimus dose)
- Proportion of Participants who Die(From kidney transplant with alemtuzumab induction to to completion of study (up to approximately 6.5 years))
- Incidence of Adverse Events Attributable to Mesenchymal Stromal Cells (MSC) Administration(From initial MCS infusion (day 42 post kidney transplant) to end of study participation (up to 7 years))
- Proportion of Participants who Remain Off Immunosuppression(From ISW completion to end of study participation (up to approximately 5 years))
- Incidence of Participants who Develop Donor Specific Antibody (DSA)(From study enrollment to completion of study (up to approximately 7 years))
- Incidence of Post-Transplant Diabetes(From post kidney transplantation to completion of study (up to approximately 7 years))
- Frequency of Select Adverse Events (AEs)(From kidney transplantation to completion of study (up to approximately 7 years))
- Time from Transplant to the First Episode of Rejection(From kidney transplantation to completion of study (up to approximately 7 years))
- Frequency of Antibody-Mediated Acute Cellular Rejection(From kidney transplant to completion of study (up to approximately 7 years))