Study of LUCAR-20S in Patients With R/R NHL

Study Overview
=================
Brief Summary
-----------------
An open label, single arm Phase I study to evaluate the safety, tolerability, and pharmacokinetics of LUCAR-20S CAR-T cells in relapsed or refractory CD20+ diffuse large B-cell, follicular, mantle cell and small lymphocytic lymphoma.

Detailed Description
-----------------
This study is an open, dose escalation/dose regimen finding study to assess the safety and pharmacokinetics of donor-derived CD20-directed CAR-T cells administered with lymphodepletion, and to obtain the preliminary efficacy results in subjects who have been diagnosed with relapsed or refractory CD20 positive diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma or small lymphocytic lymphoma. The allo-CAR-T cells will be infused in single-dose.

Official Title
-----------------
A Study Evaluating the Safety, Tolerability, and Pharmacokinetics of LUCAR-20S in Patients With Relapsed/Refractory Diffuse Large B-Cell, Follicular, Mantle Cell or Small Lymphocytic Lymphoma

Conditions
-----------------
Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma, Small Lymphocytic Lymphoma

Intervention / Treatment
-----------------
* Drug: LUCAR-20S CAR-T cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent form (ICF) Age 18 Years to 75 Years Pathological diagnosis of refractory/relapsed CD20+ non-Hodgkin's lymphoma (one of the following): Diffuse large B-cell lymphoma (DLBCL) Follicular lymphoma (FL) Mantle cell lymphoma (MCL) Small lymphocytic lymphoma (SLL) Measurable disease as defined by 2014 Lugano criteria at Screening Refractory/relapsed disease after standard-of- care treatment as following (Undergone at least 2 complete cycle of therapy for each line, unless PD been documented as the best response to the regimen) and not eligible or appropriate for HSCT (Auto/allo). Subject must have documented evidence of progressive disease on or within 12 months of their last regimen. DLBCL: Refractory/relapsed after at least 1 prior line of therapy, must have been treated with anti-CD20 monoclonal antibody FL: Refractory/relapsed after at least 2 prior lines of therapy, must have been treated with anti-CD20 monoclonal antibody MCL: Refractory/relapsed after at least 2 prior lines of therapy SLL: Refractory/relapsed after at least 2 prior lines of therapy Laboratory criteria at Screening ① Blood routine: NE≥1.0×109/L；HGB≥8g/dL；PLT≥50×109/L ② Blood biochemical parameters: Total bilirubin ≤ 1.5 times of the normal upper limit (ULN) Aspartate and alanine aminotransferases (AST, ALT) ≤ 3 times ULN (in the presence of liver metastasis, ULN 5 times) Estimated glomerular filtration rate (eGFR) > 60mL/min Life expectancy > 12 weeks Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0 or 1 Exclusion Criteria: Any malignancy besides the NHL categories under study, exceptions include Any other malignancy curatively treated and disease-free for at least 2 years prior to enrollment History of non-melanoma skin cancer with sufficient treatment and currently no evidence of recurrence Prior treatment with an allogeneic stem cell transplant Prior treatment with genetic therapy Prior treatment with chimeric antigen receptor T (cells) CAR-T therapy directed at CD20 target Those who are positive for any index of hepatitis B surface antigen (HBsAg), hepatitis B virus deoxyribonucleic acid (HBV DNA), hepatitis C antibody (HCV-Ab), hepatitis C virus ribonucleic acid (HCV RNA), and human immunodeficiency virus antibody (HIV-Ab) Prior antitumor therapy with insufficient washout period Targeted therapy, epigenetic therapy, experimental drug therapy or experimental invasive treatment with medical apparatus and instruments 14 days or five half-lives, whichever is shorter before lymphodepletion Use of monoclonal antibodies 21 days prior to lymphodepletion Chemotherapy within 14 days prior to lymphodepletion Radiotherapy within 14 days prior to lymphodepletion Participated in other clinical trials within 30 days prior to lymphodepletion With central nervous system involvement Women in pregnancy or lactation Being fertile and unable to use effective conception during treatment and 100 days after CAR-T infusion Active autoimmune disease or history of autoimmune disease within 3 years With obvious hemorrhagic tendency such as gastrointestinal hemorrhage, coagulation disorders and hypersplenism The following cardiac conditions New York Heart Association (NYHA) stage III or IV congestive heart failure Left ventricular ejection fraction (LVEF) less than (<)45% Uncontrolled cardiac arrhythmia post-medication With a history of myocardial infraction or unstable angina pectoris within the past 6 months Constrictive pericarditis Cardiomyopathy Pulse oximetry of <96% on room air Active or uncontrolled infection requiring parenteral antibiotics, or any evidence of severe active viral/bacterial infection or uncontrolled systemic fungal infection Uncontrolled diabetes mellitus, defined as fast serum glucose > 1.5 times ULN Concurrent use of corticosteroids or other immunosuppressant medications for chronic disease Concurrent use of hematopoietic growth factor Stroke or seizure within 6 months of signing ICF Have received any live, attenuated vaccine within 4 weeks prior to lymphodepletion Have underwent major surgical operation within 2 weeks prior to lymphodepletion, or anticipate to undergo a major surgical operation during the study process or within 2 weeks posterior to study treatment(with the exception of anticipated local anesthesia surgery) Known life threatening allergies, hypersensitivity, or intolerance to LUCAR-20S CAR-T cells or its excipients, including dimethyl sulfoxide (DMSO) Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-CD20 Allogeneic CAR-T Cell Therapy<br>An open label, single arm Phase I study to evaluate the safety, tolerability, and pharmacokinetics of LUCAR-20S CAR-T cells in relapsed or refractory CD20+ diffuse large B-cell, follicular, mantle cell and small lymphocytic lymphoma. | Drug: LUCAR-20S CAR-T cells<br>* An Anti-CD20 Allogeneic CAR-T Cell Therapy in Patients with Relapsed/Refractory Diffuse Large B-Cell, Follicular, Mantle Cell or Small Lymphocytic Lymphoma<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | DLT assessed by NCI-CTCAE 5.0 | 30 days post infusion | 
| Adverse events | Incidence and severity of adverse events as assessed by NCI-CTCAE 5.0 | 90 days post infusion | 
| Concentration of Pharmacokinetics in blood | PK CAR positive T cells in peripheral blood, PK CAR transgene levels in peripheral blood | through study completion, 2 years after infusion of the last subject | 
| Concentration of Pharmacokinetics in bone marrow | PK CAR positive T cells in bone marrow, PK CAR transgene levels in bone marrow | through study completion, 2 years after infusion of the last subject | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II dose (RP2D) | RP2D established through ATD+BOIN design and the DLTs occurring following CAR T-cell infusion | 30 days post infusion | 
| Overall response rate (ORR) after administration | Antitumor efficacy by 2014 Lugano criteria | 3 months post infusion | 
| Time to Response (TTR) after administration | Antitumor efficacy by 2014 Lugano criteria | 3 months post infusion | 
| Duration of remission (DOR) after administration | Antitumor efficacy by 2014 Lugano criteria | through study completion, 2 years after infusion of the last subject | 
| Progress Free Survival (PFS) after administration | Antitumor efficacy by 2014 Lugano criteria | through study completion, 2 years after infusion of the last subject | 
| Overall Survival (OS) after administration | Antitumor efficacy by 2014 Lugano criteria | through study completion, 2 years after infusion of the last subject |