Allogeneic Regulatory Dendritic Cell (DCreg) Therapy in Live-Donor Renal Transplant Recipients
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 28
- 试验地点
- 2
- 主要终点
- Composite Outcome: Proportion of Participants who Experience any of the Pre-Specified Safety Events
研究概览
简要总结
This study will evaluate the safety and feasibility of treatment involving a single infusion of donor-derived regulatory dendritic cells (DCreg) in first time, living donor renal transplant recipients.
DCreg will be prepared from monocytes obtained by leukapheresis from prospective (non-mobilized) living kidney donors and infused into the respective recipients 7 days before renal transplantation. This study will enroll 28 subjects (14 recipients, 14 donors). The duration of follow-up will be:
- 1 week following the leukapheresis procedure for donors and
- 2 years following their DCreg infusion for kidney recipients.
详细描述
This clinical trial is a single-center, open-label, dose-escalation, phase 1 study, enrolling N=14 de novo kidney transplant recipients and their respective living donors. The study objective is to evaluate the safety and feasibility of a single infusion of donor-derived regulatory dendritic cell (DCreg) treatment.
Transplant recipients will receive combination immunosuppressive agents according to the site's Standard of Care (SOC) regimen, with two exceptions:
- mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
- the pre-transplant dose of MPA will be half the standard post-transplant dose, due to increased drug bioavailability in recipients with low kidney function defined by glomerular filtration rate (GFR).
Consequently, participants will be maintained on triple immunosuppressive therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.
Note: Participants will not be withdrawn from known effective therapy for the purpose of participating in this research.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Donor Eligibility Criteria:
- •Able to understand and provide informed consent;
- •Male or female >/= 18 years of age
- •Meets all standard institutional criteria for kidney donation and Health Agency criteria for kidney donation;
- •For females of childbearing potential, a negative urine or serum pregnancy test;
- •Negative for Human Immunodeficiency Virus type 1 (HIV) -1 (antigen and Nucleic Acid Testing (NAT)), HIV-2, Human T-cell leukemia virus type 1 (HTLV-1), and HTLV-2;
- •Negative for hepatitis C (antibody and NAT), hepatitis B (surface antigen and core antibody), and Treponema pallidum infection;
- •Negative for West Nile Virus;
- •Negative health history for Creutzfeldt-Jakob disease;
- •No live vaccines within 8 weeks prior to leukapheresis;
- •No medical condition(s) that the investigator deems incompatible with participation in the trial; and
- •No use of investigational drugs within 12 weeks of participation.
- •Recipient Inclusion Criteria:
- •Must be able to understand and provide informed consent;
- •Is >/= 18 years old at the time of informed consent;
- •Is undergoing a living donor renal transplant;
- •For females of childbearing potential, a negative urine or serum pregnancy test upon study entry
- •The candidate agrees to use contraception with a method that is more than 80% effective (see FDA Office of Women's Health (http://www.fda.gov/birthcontrol). Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) to be used from one month before study treatment begins until one month after study completion;
- •Cytomegalovirus (CMV) seropositive or, if CMV seronegative must be receiving a kidney from a CMV seronegative donor;
- •Has a negative purified protein derivative (PPD) or negative testing for tuberculosis using an approved IGRA blood test, such as QuantiFERON®-Gold TB or T-SPOT-TB assay OR has completed treatment for latent tuberculosis and has a negative chest x-ray. PPD or IGRA testing must occur within 52 weeks before transplant. These requirements apply as well to prior recipients of Bacille Calmette-Guérin (BCG) vaccination;
- •Meets all standard institutional and Health Agency criteria for kidney transplant.
- •Vaccines up to date as per DAIT guidance for patients in transplant trials (Refer to Manual of Operations).
排除标准
- •Panel Reactive Antibody (PRA >20%);
- •Positive T or B Cell Flow Crossmatch prior to transplant;
- •Presence of donor specific antibody (DSA) ≥ to mean fluorescence intensity (MFI) of 1000, or DSA between 500 and 1000, if a specific shared epitope pattern is present;
- •Recipient of multi-organ transplant;
- •Any prior renal or extra-renal transplant with HLA class II antigen mismatch shared with prior organ;
- •Epstein-Barr Virus (EBV) Immunoglobulin G (IgG) negative if the donor is EBV positive;
- •Seropositivity for HIV-1, hepatitis B core antigen, or hepatitis C virus (HCV) antibody (if hepatitis C antibody positive, confirm negative infection by HCV RNA), or positivity for hepatitis B surface antigen;
- •History of malignancy witin the past 5 years unless standard institutional criteria detailed in Appendix 6 have been met;
- •High risk for recurrence of renal disease: Hemolytic Uremic Syndrome Thrombotic Thrombocytopenic Purpura (HUS-TTP); Focal Segmental Glomerular Sclerosis (FSGS); or Aggressive native kidney disease.
- •Compensated and decompensated cirrhosis of liver and/or portal hypertension;
- •Chronic Obstructive Pulmonary Disease requiring nasal oxygen, and/or pulmonary hypertension (mean pulmonary pressure >45mm/hg);
- •Any history of stroke with neurological deficit;
- •Any condition that, in the opinion of the investigator, confers excessive risk for participation in this phase 1 study;
- •Presence of a condition that requires treatment with an immunosuppressive agent, other than a physiologic dose of corticosteroid;
- •Live vaccines within 8 weeks prior to transplant;
- •Use of investigational drugs within 12 weeks of participation;
- •Woman receiving a kidney from a man who has fathered her child(ren), whether or not carried to term; or
- •Woman receiving a kidney from her biological child.
研究组 & 干预措施
DCreg: 0.5 million cells/kg+SOC
N=3 participants will receive 0.5 (± 0.1) million cells/kg body weight as a single infusion.
Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:
- mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
- the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).
Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.
干预措施: DCreg: 0.5 million cells/kg+SOC (Biological)
DCreg: 1.2 million cells/kg+SOC
N=3 participants will receive 1.2 (± 0.2) million cells/kg body weight as a single infusion.
Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:
- mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
- the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).
Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.
干预措施: DCreg: 1.2 million cells/kg+SOC (Biological)
DCreg:2.5 to 5.0 million cells/kg+SOC
N=8 participants will receive 25 to 5.0 million cells /kg body weight as a single infusion.
Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:
- mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
- the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).
Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.
干预措施: DCreg:2.5 to 5.0 million cells/kg+SOC (Biological)
结局指标
主要结局
Composite Outcome: Proportion of Participants who Experience any of the Pre-Specified Safety Events
时间窗: Seven Days Prior to Transplant Surgery(e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant
Safety will be assessed by summarizing the proportion of participants who experience any of the following events from the initiation of the regulatory dendritic cells (DCreg) infusion administered 7 days prior to kidney transplant to 1 year post-transplant: * Recipient death attributed to receipt of DCreg, * NCI-CTCAE Grade 4 or higher DCreg infusion reaction, * NCI-CTCAE Grade 4 or higher infection, * Malignancy other than non-melanoma skin cancer, * Pre-transplant Donor Specific Antibodies (DSA), * Post-transplant DSA, * Biopsy-proven acute rejection (BPAR) by BANFF 2017 criteria (grade ≥2A), or * Non-surgical graft loss. * Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).
次要结局
- Incidence of Adverse Event:CTCAE Grade 4 or Higher Infection(Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant)
- Incidence of Non-Surgical Graft Loss(Day 0 (Transplant Surgery) up to 1-Year Post-Transplant)
- Incidence of Adverse Event: Malignancy(Seven Days Prior to Transplant Surgery(e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant)
- Incidence of Pre-Transplant Donor Specific Antibodies (DSA)(Baseline (Seven Days Prior to Transplant Surgery, "Pre" -Regulatory Dendritic Cells (DCreg)) Infusion) up to within 48 Hours of Transplant)
- Incidence of Death Attributed to Participant Receipt of Regulatory Dendritic Cells (DCreg)(Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant)
- Incidence of Post-Transplant Donor Specific Antibodies (DSA)(Day 0 (Transplant Surgery) up to 1-Year Post-Transplant)
- Incidence of Biopsy-Proven Acute Rejection(Day 0 (Transplant Surgery) up to 1-Year Post-Transplant)
- Incidence of Adverse Event: CTCAE Grade 4 or Higher Infusion Reaction(Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant)
研究者
Angus W. Thomson PhD DSc
Professor
University of Pittsburgh