FKC288 in Participants With Autoimmune Kidney Diseases

Evaluation of the Safety and Efficacy of FKC288 in Participants With Autoimmune Kidney Diseases: A Single-center Exploratory Clinical Study

This study is a single-center, open-label, dose-escalation exploratory clinical trial, expected to enroll 6 to 12 participants. It will use a BOIN (Bayesian Optimal Interval) design for dose escalation, with four predetermined dose groups (0.3×10^6 cells/kg, 1.0×10^6 cells/kg, 3.0×10^6 cells/kg, and an alternative dose of 0.1×10^6 cells/kg). Each dose group plans to enroll 1-2 or 3-6 participants with relapsed or refractory autoimmune-mediated kidney diseases (such as lupus nephritis, ANCA-associated vasculitis, membranous nephropathy, and IgG4-related diseases).

Study Overview

• Status: Recruiting
• Conditions: Lupus Nephritis; ANCA-associated Vasculitis; Membranous Nephropathy - PLA2R Induced; IgG4-Related Diseases
• Intervention / Treatment: Drug: FKC288

Detailed Description

A leukapheresis procedure will be performed to manufacture FKC288 chimeric antigen receptor (CAR) modified T cells. Bridging therapy is allowed between PBMC collection and lymphodepletion. Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. After 1-day rest, subjects will receive a single dose infusion of FKC288 at 0.1, 0.3, 1.0, or 3.0x 10^6 CAR+ T cells/Kg. Subjects will be followed in the study for a minimum of 2 years after FKC288 infusion.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Xianghua Huang, MD; Phone Number: 13770648824; Email: hxhszb@163.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210016
      • Recruiting
      • Jinling Hospital
      • Contact: Xianghua Huang, MD; Phone Number: 13770648824; Email: hxhszb@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Participants must personally sign an informed consent form approved by the Ethics Committee before the start of the study.
2. Participants must be aged ≥18 and ≤65 years.

3. Disease-specific inclusion criteria:

   Active, relapsing, refractory Lupus Nephritis (LN):

   LN diagnosed by kidney biopsy within the last 2 years, with pathological types III, IV, or V, and a chronicity index (CI) score≤3

   Meets one of the following criteria:

   Refractory LN, defined as no remission after at least one standard regimen (CTX and/or MMF) for 6 months.

   Relapsing LN, defined as a need to increase steroid dosage to control disease activity during maintenance treatment.

   Clinical criteria: eGFR > 45 ml/min/1.73 m²; urinary protein quantification ≥ 1.5g/24h; SLE-DAI score ≥ 8.

   ANCA-associated vasculitis (AAV) patients:

   Diagnosed as AAV according to the 2012 Chapel Hill Consensus Conference criteria, meeting one of the following:

   Newly diagnosed AAV with renal involvement:

   Renal involvement must meet both:

   Kidney biopsy showing pauci-immune necrotizing glomerulonephritis. Urinary red blood cells >30/high power field.

   Relapsing or refractory AAV:

   Relapse: Defined as an increase in BVAS V3.0 score of ≥1 after remission, requiring adjustment of immunosuppressive treatment to regain remission.

   Refractory: Defined as a) less than 50% reduction in BVAS V3.0 after 6 weeks of standard induction treatment; or b) persistent disease activity (BVAS V3.0 ≥3) after 12 weeks of treatment.

   Membranous nephropathy (MN) patients:

   Tissue biopsy diagnosed as aPLA2R-related membranous nephropathy.

   Clinical criteria for high-risk or relapsing/refractory membranous nephropathy:

   High-risk patients:

   Defined as meeting any of the following: eGFR normal, urinary protein >3.5g/d, ACEI/ARB treatment for 6 months with <50% reduction in urinary protein, combined with serum albumin <25g/l or aPLA2R >50RU/ml; or eGFR <60ml/min/1.73m², and/or urinary protein >8g/d for over 6 months.

   Refractory/relapsing membranous nephropathy patients:

   Refractory: Defined as resistance to previous immunosuppressive treatment (persistent urinary protein ≥3.5g/d with <50% reduction compared to baseline).

   Relapse: Defined as complete or partial remission achieved with previous immunosuppressive treatment, followed by reappearance of urinary protein ≥3.5g/d.

   eGFR ≥ 45 ml/min/1.73 m².

   IgG4-related disease patients:

   Meeting the 2019 ACR/EULAR diagnostic criteria for IgG4-related disease, and meeting one of the following:

   Newly diagnosed active IgG4-related disease (Respond Index (RI) ≥3).

   Refractory or relapsed IgG4-related disease:

   Refractory: Defined as no remission with steroid or steroid plus immunosuppressant treatment (no clinical or imaging improvement, RI decrease <2) Relapse: Defined as new progression or recurrence of clinical symptoms or imaging findings in a patient who had achieved remission, with or without elevated blood IgG4 (RI increase≥2)

4. Expected survival ≥ 12 weeks.
5. ECOG performance status ≤ 2.
6. Female participants of childbearing potential must agree to use effective contraception from the day of signing the informed consent until 365 days after the infusion. Effective contraception is defined as abstinence or the use of a contraceptive method with a failure rate of <1% per year.

7. Participants must have adequate organ function, meeting all of the following criteria before enrollment:

   1. Absolute neutrophil count ≥ 1.0×10⁹/L [Granulocyte colony-stimulating factor (G-CSF) support is allowed, but no supportive treatment should be received within 7 days before the assessment].
   2. Platelet count ≥ 50×10⁹/L [No transfusion support (including component transfusion) or treatments aimed

Exclusion Criteria:

1. Participants who have received the following previous treatments:

   1.1 Participants who have received gene therapy before enrollment. 1.2 Participants who have been injected with live vaccines within 4 weeks prior to enrollment.

   1.3 Participants who have received other investigational drug treatments within 12 weeks before apheresis.

2. Participants with active malignancies within the past 5 years, except for tumors deemed curable and cured, such as basal or squamous cell carcinoma, cervical or breast carcinoma in situ, etc.
3. Participants who are positive for Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb) with abnormal peripheral blood HBV DNA tests (defined as HBV DNA quantification above the lower limit of detection or above the normal reference range of the testing center, or qualitative HBV DNA test positive); positive for Hepatitis C virus (HCV) antibodies with positive peripheral blood HCV RNA; positive for Human Immunodeficiency Virus (HIV) antibodies; positive for Cytomegalovirus (CMV) DNA; positive for syphilis test RPR.
4. Participants with uncontrolled active infections (except for < Grade 2 CTCAE urinary reproductive system infections and upper respiratory infections).
5. Participants with severe heart diseases, including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive heart failure (New York Heart Association [NYHA] class ≥ III), severe arrhythmias.
6. Participants with hypertension or diabetes that cannot be controlled with medication.
7. Participants with unresolved toxic reactions from previous treatments to baseline or ≤ Grade 1 (according to NCI-CTCAE v5.0, except for alopecia and clinically insignificant lab abnormalities).
8. Participants who have undergone major surgery within 2 weeks prior to enrollment or plan to have surgery during the waiting period for infusion or within 12 weeks after receiving study treatment (except for planned minor surgeries under local anesthesia).
9. Participants with solid organ transplants.
10. Pregnant or breastfeeding women.
11. Participants with a history of central nervous system diseases (such as cerebral aneurysm, epilepsy, stroke, dementia, psychosis, etc.) or consciousness disorders.
12. Participants with other unstable systemic diseases as judged by the researcher, including but not limited to severe diseases of the liver, kidneys, gastrointestinal tract, or metabolic diseases requiring medication.
13. Participants are known to have life-threatening allergic reactions, hypersensitivity, or intolerance to FKC288 cellular products or their components.
14. Participants judged by the researcher to have bleeding, severe thrombosis, or hereditary/acquired bleeding and severe thrombosis conditions (including hemophilia, coagulation dysfunction, thrombocytopenia, splenomegaly, etc.), or patients currently undergoing thrombolytic or anticoagulant therapy.
15. Participants who have received any B cell-depleting therapy or non-depleting B cell targeted therapy within 6 months.
16. Participants who have received high-dose methylprednisolone treatment (cumulative dose > 1.5g) or cyclophosphamide pulse therapy within a month.
17. Participants judged by the researcher to be unable to discontinue other immunosuppressants one week before apheresis, or those treated with more than 5 mg/day of prednisone (or equivalent dose of other corticosteroids).
18. AAV patients diagnosed with eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) or with active alveolar hemorrhage.
19. Other conditions deemed by the researcher as unsuitable for enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment arm; Administration of FKC288 Four dose groups of 0.1×10^6 CAR-T/kg, 0.3×10^6 CAR-T/kg, 1.0×10^6 CAR-T/kg, and 3.0×10^6 CAR-T/kg FKC288 are designed in this study. Each dose group plans to enroll 1-2 or 3-6 participants with relapsed or refractory autoimmune-mediated kidney diseases (such as lupus nephritis, ANCA-associated vasculitis, membranous nephropathy, IgG4-related diseases) according to observed DLT. FKC288 will be intravenously infused at least 24 hours after lymphodepletion preconditioning. According to the assigned dose group, the designated dose of FKC288 will be infused in a single infusion within 30 minutes on day 0.

Drug: FKC288; The autologous dual target BCMA/CD19-CAR-T cell of this study is obtained by infecting T cells with anti-BCMA/CD19-CAR lentiviral vectors. Administration method: intravenous infusion； Subjects will be treated with Fludarabine and Cyclophosphamide before cell infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of subjects with dose-limiting toxicity	The number of participants with dose limiting toxicity in each dose group and the type of dose limiting toxicity that occurred.	Within 28 days after FKC288 injection infusion
The proportion of subjects with adverse events	All adverse events were evaluated according to NCI-CTCAE v5.0 criteria.	Within 24 weeks after FKC288 injection infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) of all subjects	Time from the first FKC288 infusion to the first assessment of disease progression/relapse or death from any cause.	Within 2 years after FKC288 injection infusion
Overall survival (OS) of all subjects	Time from the first FKC288 infusion to death from any cause.	Within 2 years after FKC288 injection infusion
Proportion of subjects achieving renal response	The proportion of participants who achieve partial remission (PR) or complete remission (CR) of renal.	Within 6 months after FKC288 injection infusion
Duration of response (DoR) of all subjects	The time from FKC288 infusion to the first assessment of CR/PR until the first assessment of disease progression/relapse or death due to the study disease	Within 2 years after FKC288 injection infusion

Collaborators and Investigators

• Sponsor: Nanjing University School of Medicine
• Investigators: Principal Investigator: Zhihong Liu, Jinling Hospital, China

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: February 22, 2024
• First Submitted That Met QC Criteria: February 22, 2024
• First Posted (Actual): February 29, 2024

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Connective Tissue Diseases; Skin Diseases, Vascular; Glomerulonephritis; Lupus Erythematosus, Systemic; Systemic Vasculitis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Nephritis; Lupus Nephritis; Immunoglobulin G4-Related Disease; Vasculitis; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Glomerulonephritis, Membranous
• Other Study ID Numbers: NJCT-2401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No