Study of Cord Blood-derived CAR NK Cells Targeting CD19/CD70 in Refractory/Relapsed B-cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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To find the highest tolerable dose of dualCAR-NK19/70 (a type of cell therapy) that can be given to patients who have B-cell lymphoma that is relapsed or refractory.

Detailed Description
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Primary Objectives: --The primary objective is to determine the safety and identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of dualCAR-NK19/70 in patients with r/r B-cell lymphomas. Hypothesis: DualCAR-NK19/70 will be safe, well-tolerated, and effective in patients with r/r B-cell lymphomas. Secondary Objectives: --The secondary objective is to determine the efficacy in adults with r/r LBCL and FL grade 3B treated at the MTD or RP2D of dualCAR-NK19/70. Although the clinical benefit of dualCAR-NK19/70 has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. Secondary endpoints include overall response rate (ORR; including CR + PR) and CR rate as defined by the Lugano Classification response criteria for malignant lymphoma, DOR, PFS, and OS. Exploratory Objectives: --The exploratory objectives are to assess the cellular kinetics and pharmacodynamic effects of dualCAR-NK19/70 and to evaluate biomarkers associated with response, resistance, and toxicity after administration of dualCAR-NK19/70 in blood and tumor samples.

Official Title
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Study of Cord Blood-derived CAR NK Cells Targeting CD19/CD70 in Refractory/Relapsed B-cell Non-Hodgkin Lymphoma

Conditions
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Refractory or Relapsed B-cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: dualCAR-NK19/70 cell


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily participate in the study and sign the informed consent; Age 18-75, male and female; Histologically confirmed diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and other Indolent B-cell NHL transforming types: （A） Relapsed or Refractory DLBCL and tFL after 2 lines Immunotherapy or chemotherapy ; （B） Definition of Refractory large B cell lymphoma (SCHOLAR - 1 Research Standard) : disease progression after more than 4 courses of standard Immunotherapy or chemotherapy; Or the time of disease stabilization ≤ 6 months; Or disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation (auto-HSCT); （C） Relapsed or Refractory MCL must be 1 line with immune chemotherapy; BTK inhibitors are resistant or intolerant as 2-line therapy; （D） Relapsed or Refractory disease after chemotherapy including rituximab and anthracycline. There was at least one measurable lesion with the longest diameter ≥ 1.5cm; Estimated life expectancy of more than 12 weeks other than primary disease; Previously confirmed diagnosis as CD19+ or CD70+ B-NHL. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3. Adequate reserve of organ function: （A） Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤2.5 times the Upper Limit of Normal (ULN) for age; （B） A creatinine clearance (as estimated either by a direct urine collection or Cockcroft-Gault Equation) > 60mL/min; （C） Total bilirubin and alkaline phosphatase ≤1.5 times the Upper Limit of Normal (ULN) for age; （D） glomerular filtration rate > 50 ml/min （E） Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA); （F） Baseline oxygen saturation >92% on room air （G） Absolute neutrophil count > 1000/μL, Platelet count > 45,000/μL ,Hemoglobin > 80g/L; Once previous autologous hematopoietic stem cell transplantation (auto-HSCT) is allowed; For systemic therapy(Such as systemic chemotherapy, systemic radiotherapy and immunotherapy), at least 3 weeks，for Targeted drug therapy alone，at least 2 weeks，must have elapsed at the time of cell infusion; Either having failed or Relapsed after CAR-T therapy at 3 months of assessment; Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study. Women of childbearing potential must have a negative serum or urine pregnancy test. The viral load of severe coronavirus disease 2019 (COVID-19) is undetectable per quantitative PCR and/or nucleic acid testing for two tests. Exclusion Criteria: Allergic to any of the components of cell products; Previous or concurrent of other type of maligant tumors; Acute GvHD or generalized chronic GvHD with grade II-IV (Glucksberg standard) after previous autologous hematopoietic stem cell transplantation (auto-HSCT); Or receiving of anti-GVHD therapy; Known history of systemic gene therapy within the prior 3 months; Active systemic fungal, viral, or bacterial infection (except for simple urinary tract infections and bacterial pharyngitis), however, Preventive treatment is permitted; Known history of infection with hepatitis B (HBsAg positive, but HBV-DNA<1000 is not excluded) or hepatitis C virus (including virus carriers), syphilis and other acquired and congenital immunodeficiency diseases, including but not limited to HIV infection; Class III or IV heart failure as defined by the New York Heart Association; Persisting toxicities (>grade 1, except for clinically non-significant toxicities such as alopecia, fatigue, and anorexia) due to prior trerapy; Known history of active seizures or presence of seizure activities or other central nervous system disease; Have evidence of central nervous system lymphoma(CNS lymphoma) on CT or MRI; Breast-feeding woman; Any circumstances that possibly increase the risk of subjects or interfere with study results, which judged by investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Part 1 (dose escalation) and Part 2 (dose expansion)<br>Part 1 (dose escalation) the dose of dualCAR-NK19/70 participants receive will depend on when you join this study. Up to 3 dose levels of dualCAR-NK19/70 will be tested. About 3-6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level of dualCAR-NK19/70. Each new group will receive a higher dose of dualCAR-NK19/70 than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of dualCAR-NK19/70 is found. Part 2 (dose expansion) Participants will receive dualCAR-NK19/70 at the recommended dose that was found in Part 1. | Drug: dualCAR-NK19/70 cell<br>* Given by IV (vein)<br>* Other names: CAR-NK cell;|

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 evaluate the safety,tolerabitility,and determine the recommended dosage of cord blood-derived CAR NK cells targeting CD19/CD70 | up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate（ORR） | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | 6 months | 
| Complete Remission Rate(CRR) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | 3 months | 
| Overall survival(OS) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 3 years | 
| Duration of Response(DOR) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 3 years | 
| progression-free survival(PFS) | To determine the anti-tumor effectivity of CB dualCAR-NK19/70 | Up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-cell Non-Hodgkin Lymphoma, CAR NK Cells Targeting CD19/CD70, Cord Blood-derived