The Study of Anti-CD19 CAR NK Cells in the Treatment of Relapsed/Refractory Diffuse Large B Cell Lymphoma

Study Overview
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Brief Summary
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A single arm, open-label pilot study is designed to determine the safety and effectiveness of anti-CD19 CAR NK cells in patients with B-cell Non Hodgkin Lymphoma. 9-12 patients are planned to be enrolled in the dose-escalation trial (6×10^8 cells, 1×10^9 cells, 1.5×10^9 cells). The primary endpoints are DLT, MTD. The secondary endpoints are the overall response rates (ORR) and disease control rate (DCR).

Official Title
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An Exploratory Clinical Study of Safety and Efficacy of Anti-CD19 CAR NK Cells in the Treatment of Relapsed/Refractory Diffuse Large B Cell Lymphoma

Conditions
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Diffuse Large B Cell Lymphoma

Intervention / Treatment
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* Biological: anti-CD19 CAR NK cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects voluntarily participate in this clinical study and sign the Informed Consent Form (ICF). Clinical diagnosis of CD19 positive diffuse large B cell lymphoma as defined by the 2017 World Health Organization (WHO) classification of tumors of haematopoietic and lymphoid tissue. Relapsed/Refractory diffuse large B cell lymphoma refers to: not complete response (CR) of 2 lines of standard treatment; PD after treatment or duration of SD less than 6 months after treatment; progress or relapse within 12 months after autologous stem cell transplant. Subjects with a measurable or evaluable lesion (more than one lesion≥15mm) according to IWG criteria. Age≥ 18 years old and ≤ 75 years old, male or female. Subjects with estimated survival > 12 weeks. Serum albumin (ALB) ≥30g/L, Total Bilirubin (TBIL) ≤ 25.7μmol/L, serum creatinine (SCr) ≤ 132.6μmol/L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the upper limit of normal (ULN). Absolute neutrophil count (ANC) ≥ 1.0×109/L, platelet count ≥ 50×109/L. ECOG performance ≤ 1. Left ventricular ejection fraction (LVEF) ≥50% and no clinically significant pericardial effusion. ≥ 4 weeks after subjects received last dose treatment (Radiotherapy, chemotherapy, monoclonal antibody therapy or other treatments). Exclusion Criteria: Subjects with known severe allergic reactions, hypersensitivity, contraindication to any medications during the trial (cyclophosphamide, fludarabine, tozumabs), or subjects with a history of severe allergic reactions. Relapsed after allogenic haemopoietic stem cell transplantation (HSCT). Subjects with active infection receiving intravenous (IV) antibiotic treatment, or received intravenous (IV) antibiotic treatment within one week prior to anti-CD19 CAR NK Cell infusion. Subjects with acquired and congenital immunodeficiency diseases. Subjects with grade III or IV heart failure (NYHA classification). History of epilepsy or other central nervous system (CNS) diseases. Subjects with extranodal lymphoma in Intracranial, lung, or gastrointestinal tract. History of other primary malignant tumors except: Cured non-melanoma skin cancer by surgical excision, for example basal cell carcinoma (BCC); Cured primary malignant tumors, such as cervical cancer, superficial bladder cancer, breast cancer. Systemic corticosteroids are used concomitantly within 2 weeks prior to treatment. Females who are pregnant, lactating, or planning a pregnancy within six months. Subjects who have received other clinical trial treatment within 3 months. Any situation judged by the investigators that may increase the risk of the subjects or interfere with the clinical trial outcome.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: anti-CD19 CAR NK cells<br>CD19-CAR-NK is an allogenic CD19-Targeted chimeric antigen receptor NK-cell (CAR-NK) therapy. | Biological: anti-CD19 CAR NK cells<br>* Patients will receive Fludarabine (30 mg/m2 per day) and Cyclophosphamide (300mg/m2 per day) on day -5, -4, and -3. Doses of 6×10^8, 1×10^9, 1.5×10^9 Anti-CD19 CAR NK cells will infused in each group using the 3 + 3 dose-escalation strategy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicity (DLTs) | To characterize the safety, tolerability, and determine the Maximum tolerated dose (MTD) of Anti-CD19 CAR NK Cells for Relapsed/Refractory diffuse large B cell lymphoma. | within 4 weeks after infusion | 
| Incidence of Treatment Emergent Adverse Events (TEAEs) | To characterize the safety of Anti-CD19 CAR NK Cells for Relapsed/Refractory diffuse large B cell lymphoma | up to 48 weeks after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The overall response rate (ORR) | To characterize the efficacy of Anti-CD19 CAR NK Cell Therapy for Relapsed/Refractory diffuse large B cell lymphoma | 1, 3, 6 and 12 months after infusion | 
| Disease control rate (DCR) | To characterize the efficacy of Anti-CD19 CAR NK Cell Therapy for R/R Non-Hodgkin Lymphoma. | 1, 3, 6, 12 and 12 months after infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-Cell Lymphoma, CD19, CAR-NK, diffuse diffuse large B cell lymphoma