Cord Blood-derived CAR-NK Cells Targeting CD19 for Refractory/Relapsed Central Nervous System Lymphoma

Official title

Clinical Study of Cord Blood-derived CAR-NK Cells Targeting CD19 in the Treatment of Refractory/Relapsed Central Nervous System Lymphoma

Overview

This study is designed to evaluate the safety and efficacy of cord blood-derived CAR-NK019 in the treatment of refractory/relapsed central nervous system lymphoma.

Detailed description

This study is a single-center, open, single-arm incremental, exploratory study designed to evaluate the safety and efficacy of cord blood-derived CAR-NK019 in the treatment of refractory/relapsed central nervous system lymphoma.

The study will be divided into two stages: Phase I is the dose escalation study, which is strictly based on the "3+3" dose escalation principle, and three dose groups are set up, which are administered through the ommaya capsule ventricle, and each dose is infused once a week for 3 weeks. Three to six subjects are intended to be enrolled in each dose group, with each subject observed for at least 28 days after receiving the initial infusion and a long-term follow-up period of two years after each infusion. Phase II is the dose expansion phase: The recommended dose and administration mode for this phase will be determined after comprehensive consideration based on safety data obtained in phase I, the proliferation and survival of CAR-NK cells in vivo, and clinical efficacy data, and 24 effective subjects will be recruited for further evaluation of efficacy and safety. Long-term follow-up lasted up to 2 years after the first CAR-NK transfusion in each patient.

Interventions

• Biological anti-CD19 CAR-NK cells
  lentiviral vector-transducted cord blood-derived NK cells to express anti-CD19 CAR

Primary outcome measures

• Incidence of dose limiting toxicity (DLTs) [Time frame: Up to 28 days]

Secondary outcome measures (5)

• Complete response rate (CR) [Time frame: 3 months]
• Overall response rate (ORR) [Time frame: 3 months]
• Progression free survival (PFS) [Time frame: Up to 2 years]
• Overall survival (OS) [Time frame: Up to 2 years]
• Duration of response (DOR) [Time frame: Up to 2 years]

Eligibility criteria

Inclusion criteria

• Patients with refractory/recurrent CNS lymphoma must meet all of the following criteria to be eligible:

• Voluntarily participate in the study and sign the informed consent;
• Age 18-75 years old, male or female;
• Diffuse large B-cell lymphoma (DLBCL) was confirmed by histology. CD19 expression was positive by lymphoma pathology or flow cytometry, and CD19 expression was ≥20% by IHC.
• Imaging showed no evidence of systemic lymphoma;
• Meets any of the following definitions for refractory/relapsed CNS lymphoma: no complete response has been achieved with prior 2-line regimen including methotrexate or cytarabine-based regimen; Disease progression during any treatment; The stable time of disease after effective treatment is less than 6 months; Disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation.
• Imaging showed the presence of at least one measurable lesion, with a minimum diameter of ≥10mm;
• Expected survival ≥3 months;
• ECOG score 0-3 points;
• Adequate organ function reserve:

• alanine aminotransferase, ASpartate aminotransferase ≤ 2.5× UNL (upper limit of normal);
• Creatinine clearance (Cockcroft-Gault method) ≥60 mL/min;
• Serum total bilirubin and alkaline phosphatase ≤1.5× UNL;
• Glomerular filtration rate >50ml/min
• cardiac ejection fraction (EF) ≥45%;
• Basic oxygen saturation >92% in indoor natural air environment;
• Blood routine: absolute number of neutrophils >×109/L, platelet count 45×109/L, hemoglobin 80g/L;
• Previous autologous hematopoietic stem cell transplantation is allowed, and the interval between stem cell transfusion and CAR-NK transfusion is ≥3 months;
• Previous CAR-T cell therapy is allowed, and the time interval between CAR-T transfusion and CAR-NK transfusion is ≥3 months;
• Female subjects of childbearing age must test negative for pregnancy and agree to use effective contraception during the test;
• Approved anti-tumor therapies, such as systemic chemotherapy, whole body radiotherapy and immunotherapy, have been discontinued for at least 3 weeks before the study; Discontinuation of targeted drug regiments without chemotherapy for at least 2 weeks;

Exclusion criteria

• Subjects who meet any of the following criteria will not be admitted to the study:

• Allergic to any of the components of cell products;
• History of other tumors;
• Acute grade II-IV (Glucksberg standard) GvHD or generalized chronic GvHD occurred after previous allogeneic hematopoietic stem cell transplantation; Or are receiving anti-GVHD treatment;
• Have received gene therapy within the past 3 months;
• Active infections requiring treatment (except simple urinary tract infections, bacterial pharyngitis), but prophylactic antibiotic, antiviral and antifungal infection treatment is permitted;
• Persons infected with hepatitis B (HBsAg positive, but HBV-DNA<103 is not excluded) or hepatitis C virus (including virus carriers), syphilis and other acquired and congenital immunodeficiency diseases, including but not limited to HIV-infected persons;
• Subjects with Grade III or IV cardiac dysfunction according to the New York Heart Association's cardiac function grading criteria;
• Patients who received antitumor therapy in the early stage but did not recover toxicity (CTCAE 5.0 toxicity did not recover to ≤ grade 1, except fatigue, anorexia, alopecia);
• Previous history of epilepsy, autoimmune encephalitis, cerebral infarction or cerebral hemorrhage within 6 months;
• Whole-body enhanced CT or PET/CT suggests evidence of systemic lymphoma;
• Lactating women who are unwilling to stop breastfeeding;
• Any other circumstances that the investigator believes may increase the risk to the subject or interfere with the test results;
• Patients requiring more than 10mg of dexamethasone per day for 3 days prior to enrollment;
• Patients who cannot tolerate ommaya capsule implantation;
• Those who cannot tolerate enhanced magnetic resonance imaging.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• 2nd Affiliated Hospital, School of Medicine, Zhejiang University — Hangzhou

Identifiers

NCT: NCT06827782 · ID2024482

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗