Autoimmune Diseases, Lupus Nephritis (LN), Systemic Lupus Erythematosus (SLE)
Conditions
Keywords
Lupus Nephritis, Systemic Lupus Erythematosus, CAR T, CAR-T Cell Therapy, CD20, BCMA, Autoimmune Disease, Cell Therapy, CAR-T, CAR-T Therapy, LN, SLE, CAR T-cell therapy, CAR T-cell, chimeric antigen receptor T-cell therapy, lupus, Lupus Nephritis (LN), adolescent
Brief summary
This Phase 2, multicenter, open-label study will evaluate the safety and efficacy of a single infusion of autologous anti-CD20/BCMA chimeric antigen receptor T cells (C-CAR168) following lymphodepleting chemotherapy in participants with refractory lupus nephritis who are not responding to standard therapy. Approximately 50 participants will undergo leukapheresis, lymphodepletion with fludarabine and cyclophosphamide, and infusion of C-CAR168. Participants will be followed for 104 weeks (approximately 2 years) to evaluate renal response, safety, CAR T-cell persistence, pharmacokinetics/pharmacodynamics, and biomarkers. Long-term safety follow-up for gene therapy-related events will continue for up to 15 years following CAR T-cell infusion.
Detailed description
This is a global, multicenter, single-arm, open-label Phase 2 study evaluating C-CAR168, an autologous dual-targeted anti-CD20/BCMA CAR T-cell therapy, in participants with biopsy-confirmed refractory lupus nephritis who are not responding to standard therapy. Participants will undergo screening, leukapheresis, manufacture of autologous C-CAR168, lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide, followed by a single intravenous infusion of C-CAR168. The study begins with a safety run-in involving the first five participants. Following review by the Safety Monitoring Committee (SMC), enrollment of the remaining participants may proceed if predefined safety criteria are met. Participants will be followed for 104 weeks after infusion for evaluation of efficacy, safety, pharmacokinetics, pharmacodynamics, immunologic biomarkers, and patient-reported outcomes. Participants will subsequently be invited to enroll in a separate long-term follow-up study for continued safety monitoring consistent with FDA recommendations for gene-modified cellular therapies.
Interventions
DRUGC-CAR168
Autologous anti-CD20/BCMA chimeric antigen receptor T-cell therapy administered as a single intravenous infusion at a target dose of 1 × 10\^6 CAR-positive T cells/kg (maximum dose 100 × 10\^6 CAR-positive T cells).
Sponsors
AbelZeta Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All enrolled participants receive lymphodepleting chemotherapy followed by a single infusion of C-CAR168.
Eligibility
Sex/Gender
ALL
Age
14 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Able to provide informed consent or assent where applicable. * Male or female aged 14-70 years, weighing at least 40 kg. * Diagnosis of systemic lupus erythematosus according to the 2019 EULAR/ACR classification criteria. * Biopsy-confirmed ISN/RPS Class III or IV lupus nephritis, with or without Class V, within 6 months before screening. * Proteinuria meeting protocol-defined thresholds. * Refractory to standard therapy. * Meets corticosteroid taper requirements. * Positive ANA and/or anti-dsDNA and/or anti-Smith antibody. * Meets all protocol eligibility requirements.
Exclusion criteria
* Active uncontrolled infection * Active hepatitis B, hepatitis C, or HIV infection * Active tuberculosis * Pregnancy or breastfeeding * Prior gene therapy or CAR T-cell therapy * Active malignancy * Severe cardiovascular disease * Significant pulmonary disease * CNS disease precluding participation * Any condition that would interfere with study participation or safety
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Renal Response (CRR) | Week 65 (Month 15) | Proportion of participants achieving Complete Renal Response according to protocol-defined criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and severity of adverse events (AEs) | Through Week 104 (Month 24) | Evaluate the incidence, severity, and relationship of adverse events following C-CAR168 infusion, graded according to NCI CTCAE Version 6.0. |
| incidence of serious adverse events (SAEs) | Through Week 104 (Month 24) | Evaluate the incidence of serious adverse events following treatment. |
| Incidence and severity of cytokine release syndrome (CRS) | Through Week 104 (Month 24) | Assess CRS according to American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria. |
| Incidence and severity of immune effector cell-associated neurotoxicity syndrome (ICANS) | Through Week 104 (Month 24) | Assess ICANS according to ASTCT consensus grading criteria. |
| Duration of Complete Renal Response (CRR) | Through Week 104 (Month 24) | Evaluate the maintenance of complete renal response without relapse, flare, or rescue medication. |
| Partial Renal Response (PRR) | Through Week 104 (Month 24) | Evaluate the proportion of participants achieving partial renal response. |
| Primary Efficacy Renal Response (PERR) | Through Week 104 (Month 24) | Evaluate the proportion of participants achieving Primary Efficacy Renal Response. |
| Reduction in proteinuria | Through Week 104 (Month 24) | Evaluate the proportion of participants achieving at least a 75% reduction in urine protein-to-creatinine ratio (uPCR). |
| Time to renal response | Through Week 104 (Month 24) | Evaluate the time to achievement of Complete Renal Response, Partial Renal Response, and Primary Efficacy Renal Response. |
| Pharmacokinetics of C-CAR168 measuring quantitative polymerase chain reaction (qPCR) | Through Week 104 (Month 24) | Characterize CAR T-cell expansion and persistence using qPCR |
| Pharmacokinetics of C-CAR168 utilizing flow cytometry | Through Week 104 (Month 24) | Characterize T-cell expansion and persistence utilizing flow cytometry |
| Change in patient-reported outcomes (PROs) | Through Week 104 (Month 24) | Evaluate changes in health-related quality of life using PROs. |
| DORIS remission | Though Week 104 (Month 24) | Evaluate the proportion of participants achieving the Definition of Remission in SLE (DORIS). |
| Progressive renal failure | Through Week 104 (Month 24) | Evaluate the proportion of participants experiencing progressive renal failure as measured by estimated glomerular filtration rate (eGFR). |
| Corticosteroid reduction | Through Week 104 (Month 24) | Evaluate the proportion of participants receiving less than 5 mg/day prednisone equivalent. |
| Lupus disease flare | Through Week 104 (Month 24) | Evaluate the proportion of participants experiencing disease flare according to the SELENA-SLEDAI Flare Index. |
| Immunologic response | Through Week 104 (Month 24) | Evaluate changes in anti-double stranded DNA antibodies, circulating B cells, plasma cells, and complement C3/C4 levels. |
Contacts
CONTACTKirstin Liechty
CONTACTNurat Quadri
PRINCIPAL_INVESTIGATORScott Antonia, MD, PhD
Duke University
Outcome results
None listed