Exploratory Clinical Study of CD19-targeted CAR-T and CAR-DC in the Treatment of Relapsed and Refractory B-cell Lymphoma

Study Overview
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Brief Summary
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This is an open, single-arm, prospective, dose-escalation clinical trial designed to evaluate the safety and the preliminary efficacy of CD19-targeted CAR-T combined with CAR-DC in the treatment of relapsed and refractory B-cell lymphoma

Detailed Description
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6-18 patients are planned to be enrolled in the dose-escalation trial. The dose of CD19-CAR-DC was according to the 3+3 dose-escalation principle (0.25×10^6/kg, 0.5×10^6/kg, 0.75×10^6/kg ( ±20%) . CAR-T was 2×10^6/kg . The primary endpoints are DLT, MTD, and the second endpionts are the overall response rates (CR and PR), overall survival, and progression-free survival. Based on the results in the dose-escalation trial, the recommended dose will be determined. Another 52 patients will be enrolled to continue estimating the safety and efficacy.

Official Title
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Exploratory Clinical Study of CD19-targeted CAR-T and CAR-DC in the Treatment of Relapsed and Refractory B-cell Lymphoma

Conditions
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Relapsed and Refractory B-cell Lymphoma

Intervention / Treatment
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* Biological: CD19 CAR-T and CD19 CAR-DC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants aged 18 to 75 years old at the time enrollment, with ECOG Score of ≤ 3; Patients should provide a written informed consent; Histologically confirmed CD19+ DLBCL, HGBL-DHL, MCL, tFL, PMBL; Confirmation obtained from central pathology review before enrollment; Sufficient formalin-fixed, paraffin-embedded tumor samples were required for histologically confirmed diagnosis and detection of CD19 expression; Relapsed DLBCL and tFL after ≥2 lines of chemotherapy that include rituximab and anthracycline, or refractory disease as defined in the SCHOLAR-1 study: progressive disease after receiving ≥ 4 cycles of first-line therapy or stable disease (received 2 cycles of later-line therapy) as best response to chemotherapy or relapse ≤ 12 months after autologous stem cell transplantation (ASCT); Relapsed/refractory MCL after ≥ 2 lines of prior therapy, including immunochemotheapy and BTK inhibitor such as ibrutinib, or patient did not agree to receive BTK inhibitor treatment; At least one measurable tumor according to revised International Working Group (IWG) Response criteria; Life expectancy ≥ 3 months; Adequate cardiac, pulmonary, liver, renal, and bone marrow functions, with the following laboratory values: an absolute neutrophil count > 1,000/mm3, platelets count ≥ 45,000/mm3, and hemoglobin > 8.0g/dl; alanine aminotransferase and aspartate aminotransferase ≤ 2.5 × the upper limit of the normal range (ULN), and total bilirubin ≤ 2.0 mg/dl; a serum creatinine of ≤ 1.5 × ULN; a left ventricular ejection fraction ≥ 50%; Exclusion Criteria: Prior treatment that included anti-CD19-targeted therapy, CAR T cell therapy, gene therapy, and allogenic hematopoietic stem cell transplantation (allo-HSCT); Chemotherapy other than lymphodepleting chemotherapy, therapeutic doses of steroids, immunosuppressive agent, any radiation therapy or anti-tumor targeted therapy including lenalidomide, bortezomib, ibrutinib, received within 2 weeks before cell collection; Clinical trial with investigational drug was performed within 4 weeks; History of other cancers; Active hepatitis B or hepatitis C. Hepatitis B: HBV-DNA ≥ 1,000 IU/ml; Hepatitis C: HCV RNA positive; HIV infection; Uncontrollable infection of active bacteria and fungi; Currently pregnant or refusal to practice birth control within 1 year; Active autoimmune or inflammatory diseases; Central nervous system lymphoma.

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: Combination therapy of CD19 CAR-T and CD19 CAR-DC<br>6-18 patientsare planned to be enrolled in the dose-escalation trial (0.5×10^6/kg、1×10^6/kg、2×10^6/kg和4×10^6/kg) and 52 patients in the dose-expansion trial. | Biological: CD19 CAR-T and CD19 CAR-DC<br>* Intravenously injected CAR DC cells and followed by CAR T cells 4 hours later<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | To evaluate the safety, tolerability, and determine the recommended dosage of combined therapy of CD19 CAR-T and CD19 CAR-DC for Relapsed/Refractory B-cell Non-Hodgkin Lymphoma | Up to 28 days | 
| MTD | MTD was the highest dose for DLT in ≤1/6 subjects | Up to 28 days | 
| Incidence of abnormalities | Incidence of abnormalities in AE/SAE/AESI/laboratory tests/electrocardiograms/vital signs. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | The proportion of CR or PR patients as assessed by investigators based on Lugano 2014 Response Assessment | Up to 2 years | 
| Duration of Response | The time from the start of the first assessment of CR or PR to the first assessment as disease recurrence or progression or death | Up to 2 years | 
| Progression Free Survival | The length of time that a participant's disease did not progress during or after CAR-T treatment. | Up to 2 years |