## Protocol Section
### Identification Module
**NCT ID:** NCT06421701

**Brief Title:** Anti-CD19 CAR-NK Cells in Refractory/Relapsed Systemic Lupus Erythematosus

**Official Title:** A Clinical Study of Anti-CD19 CAR-NK Cells in the Treatment of Refractory/Relapsed Systemic Lupus Erythematosus

#### Organization Study ID Info
**ID:** 2024-0530
#### Organization
**Class:** OTHER
**Full Name:** Second Affiliated Hospital, School of Medicine, Zhejiang University
### Status Module
#### Completion Date
**Date:** 2026-05-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-20

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-17

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2025-08-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-20
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-13
**Study First Submit QC Date:** 2024-05-17
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Second Affiliated Hospital, School of Medicine, Zhejiang University

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** This study is a single-center, open-label, single-arm, dose-escalation trial. The aim of this study is to investigate the safety and efficacy of anti-CD19 CAR-NK cells in patients with refractory/relapsed systemic lupus erythematosus.

### Conditions Module

**Conditions:**

- Systemic Lupus Erythematosus

### Design Module

#### Design Info

**Allocation:** NA

**Intervention Model:** SINGLE_GROUP

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 10

**Type:** ESTIMATED

**Phases:**

- PHASE1

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** To evaluate the safety and efficacy of anti-CD19 CAR-NK cells in patients with refractory/relapsed systemic lupus erythematosus. All subjects will receive fludarabine/cyclophosphamide lymphodepletion followed by anti-CD19 CAR-NK cells infusion on Day 0, 7, and 14.

**Intervention Names:**

- Drug: anti-CD19 CAR-NK cells

**Label:** anti-CD19 CAR-NK cells

**Type:** EXPERIMENTAL

### Interventions

#### Intervention 1

**Arm Group Labels:**

- anti-CD19 CAR-NK cells

**Description:** Patients will receive Fludarabine (25 mg/m2 per day) and Cyclophosphamide (500mg/m2 per day) on day -5, -4, and -3. Doses of 2×10\^6/kg, 3×10\^6/kg, 4×10\^6/kg anti-CD19 CAR-NK cells will be infused in each group on Day 0, 7, and 14 using the "3 + 3" dose-escalation strategy.

**Name:** anti-CD19 CAR-NK cells

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** DLT definition is dose-limiting toxicity.

**Measure:** The proportion of subjects with DLT

**Time Frame:** Within 28 days after anti-CD19 CAR-NK cells infusion

**Description:** Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs as assessed by CTCAE v5.0.

**Measure:** The proportion of subjects with adverse events

**Time Frame:** 12 months

#### Secondary Outcomes

**Description:** Proportion of patients with SRI-4 response: including SELENA-SLEDAI ≥4-Point improvement, BILAG 2004 with no new A domain score AND no more than 1 new B domain scores, PGA with No worsening (\<0.3-point increase).

**Measure:** Proportion of subjects with Systemic Lupus Erythematosus Responder Index-4 (SRI-4) response

**Time Frame:** 4, 8, 12, 16, 20, 24, 36 and 52 weeks after infusion

**Description:** The Definition of Remission in SLE (DORIS) is a standardized criterion to clearly define what constitutes remission in patients with systemic lupus erythematosus.

**Measure:** Proportion of participants achieving definition of remission in SLE (DORIS) remission

**Time Frame:** 4, 8, 12, 16, 20, 24, 36 and 52 weeks after infusion

**Description:** The Lupus Low Disease Activity State (LLDAS) is a clinical treatment target designed for patients with systemic lupus erythematosus. It represents a state where the disease activity is kept at a low level, aiming to minimize symptoms and prevent long-term damage caused by the disease.

**Measure:** Proportion of participants achieving Lupus Low Disease Activity State (LLDAS)

**Time Frame:** 4, 8, 12, 16, 20, 24, 36 and 52 weeks after infusion

**Description:** Assessment of SLEDAI-2000 from baseline administration at various timepoints up to month 12 follow up visit.

**Measure:** Changes in the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) score from baseline

**Time Frame:** Within 12 months after anti-CD19 CAR-NK cell infusion

**Description:** Assessment of SELENA-SLEDAI from baseline administration at various timepoints up to month 12 follow up visit.

**Measure:** Changes in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score from baseline

**Time Frame:** Within 12 months after anti-CD19 CAR-NK cell infusion

**Description:** Assessment of BILAG-2004 from baseline administration at various timepoints up to month 12 follow up visit.

**Measure:** Changes in the British Isles Lupus Assessment Group 2004 index (BILAG-2004) from baseline

**Time Frame:** Within 12 months after anti-CD19 CAR-NK cell infusion

**Description:** Assessment of PGA from baseline administration at various timepoints up to month 12 follow up visit.

**Measure:** Changes in the Physician Global Assessment (PGA) from baseline

**Time Frame:** Within 12 months after anti-CD19 CAR-NK cell infusion

**Description:** Assessment of 24h proteinuria or urine protein creatinine ratio (UPCR) from baseline administration at various timepoints up to month 12 follow up visit.

**Measure:** Change in proteinuria measured by 24h proteinuria or urine protein creatinine ratio (UPCR) from baseline

**Time Frame:** Within 12 months after anti-CD19 CAR-NK cell infusion

**Description:** Assessment of ANA from baseline administration at various timepoints up to month 12 follow up visit.

**Measure:** Changes in level of anti-nuclear antibody (ANA) in peripheral blood from baseline

**Time Frame:** Within 12 months after anti-CD19 CAR-NK cell infusion

**Description:** Assessment of C3 and C4 from baseline administration at various timepoints up to month 12 follow up visit.

**Measure:** Changes in levels of complement C3 and C4 in peripheral blood from baseline

**Time Frame:** Within 12 months after anti-CD19 CAR-NK cell infusion

**Description:** CMAX is defined as the highest concentration of anti-CD19 CAR-NK cell expansion in the peripheral blood.

**Measure:** CMAX of anti-CD19 CAR-NK cells

**Time Frame:** 3 months

**Description:** TMAX is defined as the time to reach the highest concentration of anti-CD19 CAR-NK cell expansion in the peripheral blood.

**Measure:** TMAX of anti-CD19 CAR-NK cells

**Time Frame:** 3 months

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Voluntarily participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up;
* Age range from 18 to 65 years old, regardless of gender;
* Fulfilling the 2019 ACR/EULAR classification criteria of SLE;
* Presence of anti-dsDNA or anti-Sm antibodies and decreased C3 or C4 levels;
* SELENA-SLEDAI≥8；
* Subject has ≥ 1 organ system with BILAG-2004 Class A mobility score or ≥ 2 organ systems with BILAG-2004 Class B mobility score prior to screening;
* Routine treatment is ineffective or the disease relapses after remission. Definition of routine treatment: use more than two drugs, including glucocorticoid (more than 1mg/kg/d), and any two or more of the following immunomodulatory drugs for more than 6 months: cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, leflunomide, tacrolimus, ciclosporin, and biological agents, including rituximab, belizumab, or telitacicept；
* Hemoglobin ≥ 85g/L; white blood cell count ≥ 3 × 10\^9/L；neutrophil count ≥ 1.5 × 10\^9/L; platelets ≥ 50 × 10\^9/L;
* The functions of important organs are basically normal: ALT ≤ 2 × ULN; AST ≤ 2 × ULN; eGFR ≥ 60ml/min/1.73m2; total bilirubin ≤2.0 mg/dL; cardiac function: left ventricular ejection fraction (LVEF) ≥ 50%; non-oxygenated blood oxygen saturation \>94%; prothrombin time (PT) ≤ 1.5 × ULN；international standardized ratio (INR) ≤ 1.5 × ULN；
* Females of childbearing potential must use effective contraception during the study. In addition, subjects must not donate eggs during the study and for at least 90 days after the last dose of study treatment；

Exclusion Criteria:

* History of severe allergy or known hypersensitivity to any of the active ingredients of the cell product；
* Pregnant (or lactating) women;
* Severe lupus nephritis (defined as serum creatinine \> 2.5 mg/dL or 221 μmol/L), treatment with hemodialysis within 8 weeks prior to screening；
* Other lupus crises, such as active central nervous system lupus, severe hemolytic anemia, severe thrombocytopenic purpura, severe agranulocytosis, severe myocardial damage, severe lupus pneumonia or pulmonary hemorrhage, severe lupus hepatitis, and severe vasculitis within 8 weeks prior to screening；
* Combined with other autoimmune diseases requiring systemic therapy;
* Clinically significant central nervous system diseases or pathological changes not caused by lupus prior to screening, including but not limited to: cerebrovascular accident, aneurysm, epilepsy, convulsions/convulsions, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis;
* Abnormal test results for hepatitis B or C indicate the presence of an active or chronic infection, including positive HBsAg or positive HBcAb with HBV DNA levels exceeding the normal upper limit，positive hepatitis C antibody and detectable HCV RNA；positive serology for human immunodeficiency virus (HIV) or a known history of HIV infection；
* Cytomegalovirus DNA levels and EB (Epstein-Barr) virus DNA levels in the peripheral blood exceeding the normal upper limits；
* Active or latent tuberculosis；
* Presence of uncontrollable bacterial, fungal, viral or other infections, requiring antibiotic therapy;
* Acquired and congenital immunodeficiency diseases；
* IgA deficiency;
* Other uncontrolled diseases: acute or chronic diseases that are clinically unstable or have not been effectively controlled and are not related to SLE；
* History of malignant diseases such as malignant tumors, except for adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, superficial bladder cancer, breast cancer;
* Any active skin disease that may interfere with the study assessment of SLE, including but not limited to psoriasis, dermatomyositis, systemic sclerosis, non-LE cutaneous lupus manifestations (eg, cutaneous vascular disease, periungual telangiectasia, fingertip sclerosis, rheumatoid nodules, erythema multiforme, leg ulcers) or drug-induced lupus；
* Prior treatment with cell therapy or any prior gene therapy product；
* Contraindication to cyclophosphamide in combination with fludarabine;
* Prior CD19-targeted therapy;
* Received live vaccine treatment within 4 weeks prior to screening;
* Subjects who have undergone major surgery within 8 weeks prior to screening, or who are scheduled to have surgery during the trial；
* Have received B-cell targeted therapy within 4 weeks prior to screening;
* Have received immunosuppressants within 1 week prior to screening;
* Have received plasmapheresis or intravenous immunoglobulin within 3 months prior to screening;
* Have participated in other clinical studies within 3 months prior to screening;
* History of vital organ transplantation (eg, heart, lung, kidney, liver) or hematopoietic stem cell/or bone marrow transplantation；
* Situations in which investigators consider it inappropriate to participate in the study.

**Maximum Age:** 65 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** wuhx8855@zju.edu.cn

**Name:** Huaxiang Wu, PhD

**Phone:** 86-13757118395

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Hangzhou

**Contacts:**

***Contact 1:***

- **Name:** Huaxiang Wu, PhD

- **Phone:** 86-13757118395

- **Role:** CONTACT

**Country:** China

**Facility:** The Second Affiliated Hospital of Zhejiang University School of Medicine

**Zip:** 310016

#### Overall Officials

**Official 1:**

**Affiliation:** Second Affiliated Hospital, School of Medicine, Zhejiang University

**Name:** Huaxiang Wu

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000003240

- Term: Connective Tissue Diseases

- ID: D000001327

- Term: Autoimmune Diseases

- ID: D000007154

- Term: Immune System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC17

- Name: Skin and Connective Tissue Diseases

- Abbrev: BC20

- Name: Immune System Diseases

- Abbrev: All

- Name: All Conditions

### Condition Browse Module - Browse Leaves

- ID: M11177

- Name: Lupus Erythematosus, Systemic

- Relevance: HIGH

- As Found: Systemic Lupus Erythematosus

- ID: M6464

- Name: Connective Tissue Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M4629

- Name: Autoimmune Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M10200

- Name: Immune System Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000008180

- Term: Lupus Erythematosus, Systemic

### Intervention Browse Module - Browse Branches

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: ARhu

- Name: Antirheumatic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

### Intervention Browse Module - Browse Leaves

- ID: M6727

- Name: Cyclophosphamide

- Relevance: LOW

- As Found: Unknown

- ID: M283230

- Name: Fludarabine

- Relevance: LOW

- As Found: Unknown

- ID: M225513

- Name: Fludarabine phosphate

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
