Safety and Efficacy of PRG-1801 for Refractory Lupus Nephritis and IgG4-Related Disease

Safety and Efficacy of PRG-1801(BCMA-targeting CAR-T Cells) for Refractory Lupus Nephritis and IgG4-Related Disease

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

Study Overview

• Status: Recruiting
• Conditions: Lupus Nephritis; IgG4-related Disease
• Intervention / Treatment: Biological: PRG-1801

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Lingli Dong, MD; Phone Number: 02783665519; Email: tjhdongll@163.com
• Study Contact Backup: Name: Ziwei Hu, MD; Phone Number: 02783665518; Email: 836048368@qq.com

Study Locations

• China
  • Hubei
    • WuHan, Hubei, China, 430030
      • Recruiting
      • Tongji Hospital
      • Contact: Lingli Dong, MD; Phone Number: 02783665519; Email: tjhdongll@163.com
      • Contact: Ziwei Hu; Phone Number: 02783665518; Email: 836048368@qq.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

A. Age ≥ 18 years old; B. If the kidneys are involved, estimate the glomerular filtration rate (eGFR) to be ≥ 15 mL/minute/1.73 m2;

C. 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.
8. 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.

9. 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

A. 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.

B. Positive anti-nuclear antibodies (ANA) and/or anti-dsDNA antibodies during the screening period.

C. 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

A. According to the 2019 ACR/EULAR criteria, diagnosed with IgG4-RD; B. The clinical manifestations were recurrent or refractory IgG4-RD; C. IgG4-RD response index (RI) ≥2, the disease is in the active stage; D. 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 (① subjects with cervical carcinoma in situ who have been completely removed and have not experienced recurrence or metastasis for at least 3 years may participate in this study. ② subjects with basal cell or squamous cell carcinoma who have been completely removed and have not experienced recurrence for at least 3 years may participate in this study);（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-1801 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: BCMA-targeting CAR T cells therapy; The study was divided into two phases: dose exploration phase and dose extension phase. Three dose levels (35×10^6 CAR-T, 100×10^6 CAR-T, 300×10^6 CAR-T) were planned for the dose-exploration phase, and 3 to 6 LN or IgG4-RD subjects were included in each dose group. When 1 out of 3 subjects in a dose group showed DLT, 3 subjects were re-enrolled at that dose level. If DLT occurs in ≥2 of 6 subjects, dose reduction or study termination should be considered. The safe and effective fixed dose of PRG-1801 was determined through the dose-exploration phase, and after evaluation by the investigators, the dose-expansion phase was conducted, in which an additional 3-6 subjects were included in the safe and effective fixed dose for each of the two indications (Lupus Nephritis and IgG4-Related Disease) to further determine the safety and efficacy of this dose for each indications.

Biological: PRG-1801; PRG-1801 (BCMA-targeting CAR-T Cells)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safe dose of PRG-1801 infusion	To evaluate the safe dose of PRG-1801 infusion, 3 dosage group were designed in this trial, they are 35×10^6 CAR-T, 100×10^6 CAR-T, and 300×10^6 CAR-T	Up to 24 months after PRG-1801 infusion
Occurrence of AE after PRG-1801 infusion	To evaluate the occurrence of AE after PRG-1801 infusion based on CTCAE v5.0	Up to 24 months after PRG-1801 infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LN: Changes of SLE disease activity Index (SLEDAI-2000) score	SLEDAI-2000 is the most commonly used SLE assessment scale. A total of 24 items, the total score is 105 points, scores ≤6 points indicates mild activity, ≥7 but ≤12 is classified as moderate activity, >12 is classified as severe activity.	Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
LN: Changes of FACIT score	FACIT score is used to assess the fatigue status of patient	Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
LN: Changes of PGA score	PGA score is used to assess the disease activity status of patient by physician	Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
LN: Changes of UPCR	UCPR: urinary protein creatinine ratio (ug/mg)	Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
LN: Changes of eGFR	eGFR : estimated glomerular filtration rate (ml/min/1.73m^2)	Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
LN: overall response rate (complete or partial renal response	complete renal response rate or partial renal response rate	Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
IgG4-RD: time to disease relapse	Definition:The number of days between the date of CAR-T infusion and the date of IgG4-RD recurrence determined by a clinical professional physician during the follow-up period	Up to 24 months after PRG-1801 infusion
IgG4-RD: changes in the proportion of patients with improved disease activity (IgG4-RD RI	IgG4-RD (IgG4-RD RI) responder index is the most commonly used IgG4-RD assessment scale	Baseline,1st month, 2nd month, 3rd month, 6th month, 9th month, 12th month, 18th month, and 24th month after cell infusion
IgG4-RD: The annual relapse rate	The annual recurrence rate	Up to 24 months after PRG-1801 infusion
IgG4-RD: The proportion of patients achieved a complete response at week 52	The proportion of complete response	24 months after cell infusion
PK: the feature of copy numbers of CAR-Cmax	Cmax	Screening period, 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
PK: the feature of copy numbers of CAR-Tmax	Tmax	Screening period, 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
PK: the feature of copy numbers of CAR-AUC0-28d	AUC0-28d	Screening period, 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
PK: the feature of copy numbers of CAR-AUC0-90d	AUC0-90d	Screening period, 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
PK: the feature of copy numbers of CAR-T last of the copy numbers of CAR	T last of the copy numbers of CAR	Screening period, 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
PK: changes of the proportion of CAR-T cells to T cell	Flow cytometry is used to detect the proportion of CAR-T cells to T cells	Screening period, Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28, 2nd month, 3rd month after cell infusion
PD: changes of the levels of plasma sBCMA, IgG, IgA, IgM, complement C3 and C4	Immunology-related index	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
PD: changes of pathogenic antibody titers	Changes of ANA, anti-JO1, anti-SSA, anti-SSB, anti-Ro52, anti-centromerin B, anti-histone, anti-rRNP, anti-Scl70, anti-smith, anti-ul-RNP and anti-dsDNA antibody titers in peripheral blood (only for enrolled lupus nephritis patients), and changes of IgG1, IgG2, IgG3, IgG4, and IgE (only for enrolled IgG4-RD patients)	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
PD: changes of immunoinflammation related laboratory indices	Changes of laboratory indices related to immune responses and inflammation in peripheral blood, including ESR, hsCRP, LDH, and serum cytokines	Screening period, Baseline, Day 2, Day 6, Day 10, Day 14, Day 21, Day 28 after cell infusion
PD: changes of T and B lymphocyte subpopulations in peripheral blood	changes of T and B lymphocyte subpopulations in peripheral blood	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
BCMA expression levels of memory B cells and plasma blast cell	BCMA expression levels of memory B cells and plasma blast cells in peripheral blood	Screening period, baseline, Day 14, Day 28, month 2, month 3, month 6, month 9, month 12 and month 24
Single cell sequencing	Single cell sequencing of peripheral blood T cells, B cells and CAR-T	Screening period, 3 months after cell infusion (or B cell recovery stage), or depending on the investigator's assessment
The change of national planning vaccine antibody levels	To evaluate the effect of CAR-T clearance of B cell on immunological protection after vaccination	Screening period, 3 months after cell infusion

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Collaborators: Shenzhen Pregene Biopharma Co., Ltd.
• Investigators: Principal Investigator: Lingli Dong, MD, Tongji Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2024
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: June 27, 2024
• First Submitted That Met QC Criteria: July 4, 2024
• First Posted (Actual): July 11, 2024

Study Record Updates

• Last Update Posted (Actual): July 11, 2024
• Last Update Submitted That Met QC Criteria: July 4, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Nephritis; Lupus Nephritis; Immunoglobulin G4-Related Disease
• Other Study ID Numbers: S113

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