Clinical trial NCT06497361: Safety and Efficacy of PRG-2311 for Refractory Lupus Nephritis and IgG4-Related Disease
Official title: Safety and Efficacy of PRG-2311 (CD19/BCMA-targeting CAR-T Cells) for Refractory Lupus Nephritis and IgG4-Related Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Lupus Nephritis
IgG4-related Disease
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
Collaborators: name: Shenzhen Pregene Biopharma Co., Ltd.
First posted: 2024-07-11
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: A Clinical Study on the Safety and Effectiveness of CD19/BCMA Chimeric Antigen Receptor T Cells in the Treatment of Refractory Lupus Nephritis and IgG4-Related Disease.


Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years old;
2. If the kidneys are involved, estimate the glomerular filtration rate (eGFR) to be ≥ 15 mL/minute/1.73 m2;
3. The following test values within 3 days before the collection of mononuclear cells meet the following standards:

   1. Absolute lymphocyte count: ≥ 0.5 × 10 \^ 9/L \[The use of granulocyte colony-stimulating factor (G CSF) is allowed, but subjects are not allowed to receive this supportive treatment within 7 days before the screening period laboratory examination\];
   2. Absolute neutrophil count: ≥ 1.0 × 10 \^ 9/L \[The use of granulocyte colony-stimulating factor (G-CSF) is allowed, but subjects are not allowed to receive this supportive treatment within 7 days before the screening period laboratory examination\];
   3. Platelets: Subject platelet count ≥ 50 × 10 \^ 9/L (subjects are not allowed to receive blood transfusion support within 7 days before the screening period laboratory examination);
   4. Hemoglobin: ≥ 8.0 g/dL (allowing the use of recombinant human erythropoietin) \[subjects have not received red blood cell (RBC) infusion within 7 days prior to the screening period laboratory examination\];
   5. Creatinine clearance rate: (CrCl) or glomerular filtration rate (GFR) (Cockcroft Gault formula) ≥ 30 mL/min;
   6. Total bilirubin (serum): Total bilirubin (serum) ≤ 1.5 × ULN; Blood bilirubin\>1.5 × Gilbert subjects from ULN can be enrolled with the consent of the sponsor AST and ALT: ≤ 3.0 × ULN;
   7. Plasma prothrombin time (PT), international standardized ratio (INR), partial prothrombin time (APTT): PT ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN, INR ≤ 1.5 × ULN Willing to sign an informed consent form.
4. Fertile men and women of childbearing age must agree to use effective contraception from the time they sign an informed consent and up to 1 year after the study drug is used. Blood pregnancy tests for women of reproductive age at the time of screening and before cell infusion must be negative.
5. The patients or their guardians agree to participate in the clinical study and sign the informed consent, indicating that they understand the purpose and procedure of the clinical study and are willing to participate in the study.

   * for refractory LN

     1. According to the 2019 American Society of Rheumatology (ACR) criteria, diagnosed with systemic lupus erythematosus, within 6 months prior to infusion, confirmed by renal tissue biopsy according to the 2003 International Society of Nephrology (ISN)/Society of Nephropathology (RPS) criteria as active, proliferative lupus nephritis (LN), type III or IV, or type III/IV combined with type V, or type V. And have received standard treatment that is ineffective or relapses after disease remission.
     2. Positive anti-nuclear antibodies (ANA) and/or anti-dsDNA antibodies during the screening period.
     3. The SLE Disease Activity Index (SLEDAI-2000) score during the screening period is ≥ 8. SLEDAI-2000 clinical score ≥ 6 points, but low complement and/or anti ds-DNA positivity can be selected.
   * for refractory IgG4-RD

     1. According to the 2019 ACR/EULAR criteria, diagnosed with IgG4-RD;
     2. The clinical manifestations were recurrent or refractory IgG4-RD;
     3. IgG4-RD response index (RI) ≥2, the disease is in the active stage;
     4. meet the clinical phenotype of Mikulitz/systemic

Exclusion Criteria:

Subjects who meet any of the following criteria should be excluded from this study:

1. Pregnant or lactating women;
2. A history of malignant tumors within 5 years （①Carcinoma in situ of the cervix that has undergone curative treatment for more than 12 months prior to screening, ②Basal cell or squamous cell carcinoma of the skin that has been treated therapeutically, ③ Prostate cancer that has been treated with radical prostatectomy or curative radiation therapy for more than 3 years prior to screening has no known recurrence and is not currently receiving treatment；④have had surgery for thyroid cancer, and have not evidence of active disease）;
3. Received any B-cell depletion biologic therapy (for example, rituximab, ocrelizumab, obinutuzumab, ofatumumab, inebilizumab, etc) in the 6 months prior to CAR-T reinfusion, unless B-cell recovery was demonstrated;
4. Received immunosuppressant therapy within 3 days prior to CAR-T reinfusion, or systemic corticosteroid therapy (\>10 mg/ day of prednisone or equivalent doses of other corticosteroids) within 3 days prior to CAR-T reinfusion;
5. Received live vaccine or live therapeutic STDS within 2 weeks prior to screening;
6. The presence of chronic and active hepatitis B (except for HBV DNA testing below 500IU/ml), hepatitis C (HCV), human immunodeficiency virus (HIV) infection, or syphilis infection;
7. With an active infection that requires intravenous antibiotics or hospitalization;
8. Obvious evidence of cardiovascular disease as follows: a N-terminal B-type natriuretic peptide (NT proBNP)\>8500ng/L; b. The New York Heart Association (NYHA) classifies heart failure as Grade IV; c. Patients who received hospitalization for unstable angina or myocardial infarction within 6 months prior to the first administration, or patients who received percutaneous cardiac intervention and received the most recent stent placement within 6 months or coronary artery bypass grafting within 6 months;
9. People who have a known allergy, hypersensitivity, intolerance, or contraindication to any component of PRG-2311 or the drugs that may be used in the study, including fludarabine, cyclophosphamide, tolumab, or albumin, or who have had a prior severe allergic reaction;
10. Patients with other conditions determined by the investigator to be unsuitable for lymphocyte clearance or cell infusion, or who are otherwise unsuitable for study participation.

Primary outcomes:
measure: Safe dose of PRG-2311 infusion
timeFrame: Up to 24 months after PRG-2311 infusion
measure: Occurrence of AE after PRG-2311 infusion
timeFrame: Up to 24 months after PRG-2311 infusion
Secondary outcomes:
measure: LN: Changes of SLE disease activity Index (SLEDAI-2000) score
timeFrame: Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: LN: Changes of FACIT score
timeFrame: Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: LN: Changes of PGA score
timeFrame: Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: LN: Changes of UPCR
timeFrame: Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: LN: Changes of eGFR
timeFrame: Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: LN: overall response rate (complete or partial renal response
timeFrame: Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: IgG4-RD: time to disease relapse
timeFrame: Up to 24 months after PRG-2311 infusion
measure: IgG4-RD: changes in the proportion of patients with improved disease activity (IgG4-RD RI)
timeFrame: Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: IgG4-RD: The annual relapse rate
timeFrame: Up to 24 months after PRG-2311 infusion
measure: IgG4-RD: The proportion of patients achieved a complete response at week 52
timeFrame: 24 months after cell infusion
measure: PK: the feature of copy numbers of CAR-Cmax
timeFrame: Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: PK: the feature of copy numbers of CAR-Tmax
timeFrame: Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: PK: the feature of copy numbers of CAR-AUC0-28d
timeFrame: Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: PK: the feature of copy numbers of CAR-AUC0-90d
timeFrame: Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: PK: the feature of copy numbers of CAR-T last of the copy numbers of CAR
timeFrame: Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: PK: changes of the proportion of CAR-T cells to T cells
timeFrame: Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28, 2nd month, 3rd month
measure: PD: changes of the levels of plasma sBCMA, IgG, IgA, IgM, complement C3 and C4
timeFrame: Screening period, Baseline, Day 14, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: PD: changes of pathogenic antibody titers
timeFrame: Screening period, Baseline, Day 14, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: PD: changes of immunoinflammation related laboratory indices
timeFrame: Screening period, Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28 after cell infusion
measure: PD: changes of T and B lymphocyte subpopulations in peripheral blood
timeFrame: Screening period, Baseline, Day 14, Day 28, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
measure: BCMA expression levels of memory B cells and plasma blast cells
timeFrame: Screening period, baseline, Day 14, Day 28, month 2, month 3, month 6, month 9, month 12 and month 24
measure: Single cell sequencing
timeFrame: Screening period, 3 months after cell infusion (or B cell recovery stage), or depending on the investigator's assessment
measure: The change of national planning vaccine antibody levels
timeFrame: Screening period, 3 months after cell infusion
Other outcomes:
Locations:
city: Wuhan
country: China
facility: Tongji Hospital
state: Hubei
Study officials:
affiliation: Tongji Hospital
name: Lingli Dong
role: PRINCIPAL_INVESTIGATOR
References: