Refractory/Recurrent Central Nervous System Lymphoma
Conditions
Keywords
Refractory or recurrent, central nervous system lymphoma, Diffuse large B cell lymphoma, CAR-NK
Brief summary
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
BIOLOGICALanti-CD19 CAR-NK cells
lentiviral vector-transducted cord blood-derived NK cells to express anti-CD19 CAR
Sponsors
Second Affiliated Hospital, School of Medicine, Zhejiang University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients with refractory/recurrent CNS lymphoma must meet all of the following criteria to be eligible: 1. Voluntarily participate in the study and sign the informed consent; 2. Age 18-75 years old, male or female; 3. 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. 4. Imaging showed no evidence of systemic lymphoma; 5. 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. 6. Imaging showed the presence of at least one measurable lesion, with a minimum diameter of ≥10mm; 7. Expected survival ≥3 months; 8. ECOG score 0-3 points; 9. 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; 10. Previous autologous hematopoietic stem cell transplantation is allowed, and the interval between stem cell transfusion and CAR-NK transfusion is ≥3 months; 11. Previous CAR-T cell therapy is allowed, and the time interval between CAR-T transfusion and CAR-NK transfusion is ≥3 months; 12. Female subjects of childbearing age must test negative for pregnancy and agree to use effective contraception during the test; 13. 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: 1. Allergic to any of the components of cell products; 2. History of other tumors; 3. 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; 4. Have received gene therapy within the past 3 months; 5. Active infections requiring treatment (except simple urinary tract infections, bacterial pharyngitis), but prophylactic antibiotic, antiviral and antifungal infection treatment is permitted; 6. 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; 7. Subjects with Grade III or IV cardiac dysfunction according to the New York Heart Association's cardiac function grading criteria; 8. 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); 9. Previous history of epilepsy, autoimmune encephalitis, cerebral infarction or cerebral hemorrhage within 6 months; 10. Whole-body enhanced CT or PET/CT suggests evidence of systemic lymphoma; 11. Lactating women who are unwilling to stop breastfeeding; 12. Any other circumstances that the investigator believes may increase the risk to the subject or interfere with the test results; 13. Patients requiring more than 10mg of dexamethasone per day for 3 days prior to enrollment; 14. Patients who cannot tolerate ommaya capsule implantation; 15. Those who cannot tolerate enhanced magnetic resonance imaging.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicity (DLTs) | Up to 28 days | To evaluate the safety, tolerability, and determine the recommended dosage of cord blood-derived Anti-CD19 CAR-NK Cell Therapy for refractory/relapsed central nervous system lymphoma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete response rate (CR) | 3 months | To determine the anti-tumor effectivity of CB CAR-NK019 |
| Overall response rate (ORR) | 3 months | To determine the anti-tumor effectivity of CB CAR-NK019 |
| Progression free survival (PFS) | Up to 2 years | To determine the anti-tumor effectivity of CB CAR-NK019 |
| Overall survival (OS) | Up to 2 years | To determine the anti-tumor effectivity of CB CAR-NK019 |
| Duration of response (DOR) | Up to 2 years | To determine the anti-tumor effectivity of CB CAR-NK019 |
Countries
China
Outcome results
None listed