An Early-Phase Study of AZD0120 (Also Known as GC012F), a Chimeric Antigen Receptor-T Cell (CAR-T) Therapy Targeting CD19 and B Cell Maturation Antigen (BCMA), for Desensitization in Highly Sensitized Participants With End Stage Kidney Disease Awaiting Kidney Transplant
Overview
- Phase
- Early Phase 1
- Status
- Recruiting
- Sponsor
- Tongji Hospital
- Enrollment
- 12
- Locations
- 2
- Primary Endpoint
- The incidence of treatment-related adverse events AE/SAE
Overview
Brief Summary
The purpose of this study is to assess the safety, tolerability, and efficacy of AZD0120 in highly sensitized adult participants with ESKD awaiting kidney transplant-who, as assessed by investigators, are improbable desensitization through conventional treatments (e.g., plasmapheresis and immunoadsorption)- with or without living donors.
Detailed Description
This is a single-arm, open-label, early-phase clinical study of AZD0120, a dual-directed CD19/BCMA CAR-T therapy in highly sensitized adult participants with ESKD awaiting kidney transplant. This study aims to evaluate the safety, tolerability, and efficacy of AZD0120 in highly sensitized adult participants with end-stage kidney disease (ESKD) awaiting kidney transplantation-who, as assessed by investigators, are improbable desensitization through conventional treatments (e.g., plasmapheresis and immunoadsorption)-with the participants divided into Cohort 1 (with living donors) and Cohort 2 (without living donors).
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 65 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •1\. Adult men or women aged 18 to 65 years with end-stage kidney disease who are waiting for kidney transplant and require desensitization to enable safe kidney transplant.
- •2\. Cohort 1:
- •A living donor who meets criteria for kidney donation based on national and local center-specific guidelines has been identified
- •Highly sensitized participants with a requirement of positive flow cytometry crossmatch, resulting from at least one DSA detected using Luminex SAB during or before Screening
- •A positive virtual crossmatch, using Luminex SAB (MFI ≥ 2000), obtained within 30 days of Screening and during Screening
- •PRA greater than or equal to 80% which is consistent with highly sensitized based on national criteria
- •At least one anti-HLA antibody that is unacceptable for kidney transplantation
- •High-resolution HLA typing for both the recipient and the donor within 2 years of Screening.
- •4\. The participant is currently eligible for transplantation according to local standards if a graft becomes available upon completion of treatment with the study intervention.
- •5\. Hemoglobin ≥ 8 g/dL.
Exclusion Criteria
- •1\. Previous solid organ (except kidney) or bone marrow transplant.
- •Complement 3 glomerulopathy, immune-complex mediated membranoproliferative glomerulonephritis, or focal and segmental glomerulosclerosis as the cause of ESKD in the native kidney.
- •3\. Severe peripheral arterial disease is defined by the presence of resting pain and/or non healing skin ulcers.
- •4\. History of recurrent UTI; 2 in 6 months or 3 in one year.
- •Active invasive bacterial, viral or fungal infection. Additionally, any infection requiring hospitalization and IV antibiotics within 4 weeks of Screening or PO antibiotics within 2 weeks.
- •6\. History of HIV regardless of treatment.
- •Evidence of active hepatitis B infection based on positive HBsAg or positive core antibody (anti HBc): participants with positive anti-HBc but negative HBsAg may be enrolled if the HBV DNA test result is negative during the Screening Period.
- •8\. Evidence of active hepatitis C infection - Positive HCV antibody: Participants with positive HCV antibody and negative HCV RNA test during the Screening Period and absence of cirrhosis may be enrolled.
- •9\. Detectable viral load for CMV, EBV, BKV or SARS-CoV-2, as determined by PCR.
- •CMV serology incompatible with donor (eg, a recipient with a CMV negative serology should not receive an organ from a CMV positive donor).
Arms & Interventions
AZD0120 CAR-T Cell Injection
This study is An Early Exploratory. The main purpose is an IIT clinical trial to evaluate the safety, tolerability, and efficacy of AZD0120 in highly sensitized adult participants with ESKD awaiting kidney transplant.
Intervention: AZD0120 (Drug)
Outcomes
Primary Outcomes
The incidence of treatment-related adverse events AE/SAE
Time Frame: Through study completion, an average of 3 years
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.A SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of the criteria listed:Results in death and life-threatening.
Occurrence of DLTs.
Time Frame: Through study completion, an average of 3 years
Dose toxicity is defined as any TEAE that meets the following criteria which cannot be attributed to the disease under study. Dose toxicity will be evaluated according to the ASTCT criteria, and the NCI CTCAE Version 5.0.
Secondary Outcomes
- Assessment of CAR transgene levels of AZD0120 in peripheral blood over time by ddPCR.(Through study completion, an average of 3 years)
- Maximum plasma concentration (Cmax)(Through study completion, an average of 3 years)
- Time to maximum plasma concentration (Tmax)(Through study completion, an average of 3 years)
- Last detectable time point（AUC0-28d）(Through study completion, an average of 3 years)
- Last detectable time point（Tlast）(Through study completion, an average of 3 years)
- Last quantifiable concentratione (Clast)(Through study completion, an average of 3 years)
- Circulating soluble BCMA protein levels(Through study completion, an average of 3 years)
- Depletion of BCMA-expressing B cells(Through study completion, an average of 3 years)
- Depletion of CD19-expressing B cells(Through study completion, an average of 3 years)
- Lymphocyte subsets(Through study completion, an average of 3 years)
- Time to recovery of lymphocytes and B cells to baseline(Through study completion, an average of 3 years)
- Levels of cytokine in peripheral blood IL1, IL2, IL4, IL6, IL8, IL10, IL12, IL13, IFN-γ, and TNF-α(Through study completion, an average of 3 years)
- Change from baseline in serum immunoglobulin concentration (including IgG, IgM, IgA, and IgE and IgG subclasses 1-4)(Through study completion, an average of 3 years)
- Time to nadir and recovery of IgG(Through study completion, an average of 3 years)
- Change from baseline in vaccination titers for MMR(measles, mumps, and rubella (vaccine))(Through study completion, an average of 3 years)
- Change from baseline in vaccination titers for VZV(varicellazoster virus)(Through study completion, an average of 3 years)
- Change from baseline in vaccination titers for Tetanus(Through study completion, an average of 3 years)
- Change from baseline in vaccination titers for HBV(Through study completion, an average of 3 years)
- Flow cytometry for CD19 (pan B cell marker), CD20 (pan B cell marker), CD138 (plasma cells), CD23 (follicular dendritic cells), CD3 (T cells), BCMA (plasma cells), and CD68 (macrophages)(Through study completion, an average of 3 years)
- The incidence of anti CAR AZD0120 antibody response through the duration of the study(Through study completion, an average of 3 years)
- The incidence of anti CAR AZD0120 antibody titer through the duration of the study(Through study completion, an average of 3 years)
- The incidence of anti CAR AZD0120 antibody category of response through the duration of the study(Through study completion, an average of 3 years)
- Proportion of participants who achieve a negative virtual crossmatch based on anti-HLA antibodies Luminex assay(Through study completion, an average of 3 years)
- Proportion of participants who achieve a negative flow cytometry crossmatch(Through study completion, an average of 3 years)
- Proportion of participants who achieve a negative CDC crossmatch(Through study completion, an average of 3 years)
- Percentage and absolute decrease in MFI of Class I and II anti HLA antibodies from baseline to transplantation or the end of follow-up(Through study completion, an average of 3 years)
- Decline in MFI of Class I and II anti HLA antibodies to MFI < 2000, < 3000, < 5000.(Through study completion, an average of 3 years)
- Number and proportion of anti HLA antibodies unacceptable for kidney transplantation that were removed.(Through study completion, an average of 3 years)
- Number and proportion of DSAs removed(Through study completion, an average of 3 years)
- Proportion of participants achieving ≥ doubling of donor availability based on national PRA.(Through study completion, an average of 3 years)
- Change in national PRA from baseline over time until kidney transplantation or the end of follow-up, with and without serial dilutions.(Through study completion, an average of 3 years)
- Time to anti-HLA antibody nadir.(Through study completion, an average of 3 years)
Investigators
Gang Chen
Ph.D
Tongji Hospital