A Phase 2, Multicenter, Open-Label Study of CC-97540 (BMS-986353), CD19-Targeted NEX-T CAR T Cells, in Participants with Active SLE (Including Lupus Nephritis) with Inadequate Response to Glucocorticoids and at Least 2 Immunosuppressants (Breakfree-SLE)

The primary objective is to evaluate the efficacy of CC-97540 in participants with systemic lupus erythematosus (SLE). This assessment is clinically relevant for determining the therapeutic potential of CD19-targeted NEX-T CAR T cells in patients with active disease who have demonstrated inadequate response to standard immunosuppressive therapy, including those with lupus nephritis.

The secondary objectives include:

• Evaluation of additional efficacy parameters in participants with SLE

• Assessment of duration of response and time to response in patients with SLE

• Evaluation of glucocorticoid use for the treatment of SLE

• Assessment of the effects of CC-97540 on SLE-relevant autoantibodies and complement factors

• Evaluation of key patient-reported outcomes (PROs), including SLE symptoms, functioning, and overall health-related quality of life (HRQoL)

• Assessment of the safety profile of CC-97540 in participants with SLE

This clinical trial enrolled a total of **54 participants** diagnosed with **Systemic Lupus Erythematosus** and **Lupus Nephritis**. The study population included both **male** and **female** subjects, with participants required to be at least **16 years of age** and have a minimum body weight of 40 kg or greater. The trial encompassed adolescents, adults, and elderly individuals, representing a **vulnerable population**. Participants were selected based on having confirmed Systemic Lupus Erythematosus according to the EULAR/ACR 2019 criteria and demonstrating **active disease** as measured by the BILAG scoring system and specific serological markers. Eligible individuals had previously received treatment with **glucocorticoids** and at least two different **immunosuppressive agents** for a minimum duration of three months each, with inadequate therapeutic response. Participants with lupus nephritis were required to have undergone a **kidney biopsy** within six months prior to enrollment.

This is a Phase 2, multicenter, open-label clinical trial evaluating the efficacy and safety of **CC-97540** (also known as **BMS-986353**), a **CD19-targeted CAR T cell therapy**, in participants with active **systemic lupus erythematosus** (including **lupus nephritis**) who have demonstrated inadequate response to **glucocorticoids** and at least two **immunosuppressants**. The trial employs an open-label design without randomization or blinding, allowing all enrolled participants to receive the investigational **cell therapy** product. The primary objective is to evaluate the efficacy of CC-97540 in participants with systemic lupus erythematosus, with the trial expected to commence recruitment in August 2025 and conclude in June 2032, representing an overall trial duration of approximately seven years.

The investigational medicinal product CC-97540 consists of **autologous** human T cells transduced with a **lentiviral vector** encoding an anti-CD19 **chimeric antigen receptor** directed against CD19-expressing cells. The product is administered as a **cell suspension for injection** via the **intravenous** route, with a maximum daily and total dose of 10 units (other dose units), delivered over a maximum treatment period of 5 days. Prior to CC-97540 administration, participants receive **lymphodepleting chemotherapy** consisting of **cyclophosphamide** administered intravenously at a maximum daily dose of 300 mg/m² (maximum total dose 900 mg/m²) and **fludarabine** or **fludarabine phosphate** administered intravenously at a maximum daily dose of 30 mg/m² (maximum total dose 90 mg/m²), both given over a maximum treatment period of 3 days. **Tocilizumab**, an auxiliary medicinal product, may be administered via **intravenous infusion** at a maximum daily dose of 24 mg/kg (maximum total dose 32 mg/kg) over a maximum treatment period of 31 days to manage potential adverse events.

Eligible participants must be at least 16 years old with a body weight of at least 40 kg and must fulfill the **EULAR/ACR 2019 criteria** for systemic lupus erythematosus. Participants must have active disease as determined by the **BILAG** scoring system and serological markers, and must have received prior treatment with glucocorticoids and at least two different immunosuppressants for a minimum of three months each without adequate response. Participants with lupus nephritis must have undergone a **kidney biopsy** within six months prior to enrollment. The trial will assess multiple endpoints including the proportion of participants achieving drug-free **DORIS remission** (primary endpoint), **complete renal response** in participants with baseline lupus nephritis, achievement of **Lupus Low Disease Activity State**, and **SLE Responder Index-4** response. Secondary endpoints include assessment of disease flares using the **SLEDAI flare index**, changes in **proteinuria** and **estimated glomerular filtration rate**, damage accrual measured by the **SLICC damage index**, maintenance and duration of responses, cumulative glucocorticoid exposure, changes in serum **autoantibodies** and **complement factors**, and patient-reported outcomes assessed through validated instruments including **FACIT-Fatigue**, **SF-36 v2 Acute**, **EQ-5D-5L**, and Patient Global Impression scales.

The trial involves a screening visit to assess eligibility criteria, followed by lymphodepletion chemotherapy administration, CC-97540 infusion, and structured follow-up visits to monitor efficacy and safety outcomes. Participants will undergo regular assessments of disease activity, renal function, serological parameters, and safety monitoring throughout the study period. The expected duration of participant involvement extends from screening through long-term follow-up, with assessments continuing for several years post-infusion to evaluate durability of response and long-term safety. Participants may be withdrawn from the study early due to disease progression, unacceptable toxicity, participant withdrawal of consent, investigator decision, protocol non-compliance, pregnancy, or other safety concerns. The trial will evaluate time-dependent outcomes including time to first response, duration of response, and time to loss of response for key efficacy endpoints, as well as the proportion of participants maintaining drug-free status over time.

CC-97540 (also known as BMS-986353), designated as CD19-Targeted NEX-T CAR T, constitutes the experimental medicinal product in this clinical trial. This product consists of autologous homo sapiens T cells transduced with a lentiviral vector which encodes an anti-CD19 Chimeric Antigen Receptor (CAR) directed against CD19-expressing cells. The investigational product is supplied as a cell suspension for injection and is administered via the intravenous route. The maximum daily dose is 10 units, with a maximum total dose of 10 units administered over a treatment period of up to 5 days. The product is classified as an advanced therapy medicinal product, specifically a cell therapy of autologous origin, and contains genetically modified cells.

Cyclophosphamide is administered as part of the lymphodepleting chemotherapy regimen prior to CAR T cell infusion. This agent is supplied as a powder for solution for injection/infusion and is administered via the intravenous route. The maximum daily dose is 300 mg/m² (milligrams per square meter), with a maximum total dose of 900 mg/m² administered over a treatment period of 3 days. The product will be over-labeled and repackaged for use in this clinical trial.

Fludarabine phosphate and fludarabine serve as additional components of the lymphodepleting chemotherapy regimen. Fludarabine phosphate is supplied as a powder for solution for injection or infusion, while fludarabine is provided as a solution for injection/infusion. Both formulations are administered via the intravenous route. The maximum daily dose for either formulation is 30 mg/m², with a maximum total dose of 90 mg/m² administered over a treatment period of 3 days. These products will be over-labeled and repackaged for use in the study.

Tocilizumab is utilized as an auxiliary medicinal product for the management of potential cytokine release syndrome following CAR T cell administration. The product is supplied as a concentrate for solution for infusion and is administered via intravenous infusion. The maximum daily dose is 24 mg/kg (milligrams per kilogram), with a maximum total dose of 32 mg/kg administered over a treatment period of up to 31 days. The product will be over-labeled and repackaged for use in this clinical trial.

Efficacy will be assessed through multiple parameters measured at specified timepoints throughout the study. The primary efficacy endpoint is the proportion of participants achieving drug-free Definition of Remission in Systemic Lupus Erythematosus (DORIS) remission. Secondary efficacy endpoints include complete renal response (CRR) for participants with baseline lupus nephritis, participants with drug-free DORIS remission, modified CRR for participants with baseline lupus nephritis, the number of participants achieving Lupus Low Disease Activity State (LLDAS) with baseline Systemic Lupus Erythematosus Disease Activity Questionnaire (SLEDAI) score ≥6, and the number of participants achieving SLE Responder Index (SRI)-4 with baseline SLEDAI ≥6. Additional efficacy parameters include the number and severity of participants with flares as assessed by SLEDAI flare index, change from baseline in proteinuria and estimated glomerular filtration rate (eGFR), and change from baseline in Systemic Lupus International Collaborating Clinics (SLICC) damage.

Further secondary endpoints encompass the number and frequency of participants achieving maintenance of drug-free DORIS remission, LLDAS, and SRI-4, time from first response to loss of response for drug-free DORIS remission, LLDAS, and SRI-4, time from baseline to first drug-free DORIS remission, LLDAS, and SRI-4, duration of drug-free status, and the percentage of participants achieving DORIS remission regardless of drug-free status. Additional assessments include cumulative glucocorticoid dose post-infusion used for SLE treatment, change of serum autoantibodies and complement factors from baseline, and change from baseline in patient-reported outcomes assessed by FACIT-Fatigue, SF-36 v2 Acute, EQ-5D-5L, Patient Global Impression of Severity (PGI-S) Pain, and PGI-S Fatigue, as well as Patient Global Impression of Change (PGI-C) Pain and PGI-C Fatigue.