A Study of Humanized CD19 CAR-T Cells Therapy for Patients With Relapsed and/or Refractory B-cell ALL and B-cell NHL

Study Overview
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Brief Summary
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A Study of Humanized CD19 CAR-T Cells Therapy for Patients With Relapsed and/or Refractory B-cell Acute Lymphoblastic Leukemia and B-cell Non-Hodgkin's Lymphoma.

Detailed Description
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This is a single arm, open-label, single-center study. This study is indicated for relapsed or refractory CD19+ B-cell hematological malignancies, including acute lymphoblastic leukemia and B-cell non-Hodgkin's lymphoma. The selections of dose levels and the numberof subjects are based on clinical trials of similar foreign products. Two groups of patients will be enrolled, 36 in each group. Primary objective is to explore the safety, main consideration is dose-related safety.

Official Title
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Clinical Trial for the Safety and Efficacy of Humanized CD19 CAR-T Cells Therapy for Patients With Relapsed and/or Refractory B-cell Acute Lymphoblastic Leukemia and B-cell Non-Hodgkin's Lymphoma

Conditions
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Acute Lymphoblastic Leukemia, Non-hodgkin Lymphoma,B Cell

Intervention / Treatment
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* Drug: Humanized CD19 CAR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria only for B-ALL: Male or female aged 3-70 years; Histologically confirmed diagnosis of CD19+ B-ALL per the US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Acute Lymphoblastic Leukemia (2016.v1); Relapsed or refractory CD19+ B-ALL (meeting one of the following conditions): CR not achieved after standardized chemotherapy; CR achieved following the first induction, but CR duration is less than 12 months; Ineffectively after first or multiple remedial treatments; 2 or more relapses; The number of primordial cells (lymphoblast and prolymphocyte) in bone marrow is >5% (by morphology), and/or >1% (by flow cytometry); Philadelphia-chromosome-negative (Ph-) patients; or Philadelphia-chromosome-positive (Ph+) patients who cannot tolerate TKI treatments or do not respond to 2 TKI treatments; Inclusion criteria only for B-NHL: Male or female aged 18-75 years; Histologically confirmed diagnosis of DLBCL (NOS), FL, DLBCL transformed from CLL/SLL, PMBCL, and HGBCL per the WHO Classification Criteria for Lymphoma (2016); Relapsed or refractory B-NHL (meeting one of the following conditions): No response or relapse after second-line or above chemotherapy regimens; Primary drug resistance; Relapse after auto-HSCT; At least one assessable tumor lesion per Lugano 2014 criteria; Common inclusion criteria for B-ALL and B-NHL: Total bilirubin ≤ 51 umol/L, ALT and AST ≤ 3 times of upper limit of normal, creatinine ≤ 176.8 umol/L; Echocardiogram shows left ventricular ejection fraction (LVEF) ≥ 50%; No active infection in the lungs, blood oxygen saturation in indoor air is ≥ 92%; Estimated survival time ≥ 3 months; ECOG performance status 0 to 2; Patients or their legal guardians volunteer to participate in the study and sign the informed consent. Exclusion Criteria: Subjects with any of the following exclusion criteria were not eligible for this trial: History of craniocerebral trauma, conscious disturbance, epilepsy, cerebrovascular ischemia, and cerebrovascular hemorrhagic diseases; Electrocardiogram shows prolonged QT interval, severe heart diseases such as severe arrhythmia in the past; Pregnant (or lactating) women; Patients with severe active infections (excluding simple urinary tract infection and bacterial pharyngitis); Active infection of hepatitis B virus or hepatitis C virus; Concurrent therapy with systemic steroids within 2 weeks prior to screening, except for the patients recently or currently receiving inhaled steroids; Previously treated with any CAR-T cell product or other genetically-modified T cell therapies; Creatinine >2.5mg/dl, or ALT / AST>3 times of normal amounts, or bilirubin>2.0 mg/dl; Other uncontrolled diseases that were not suitable for this trial; Patients with HIV infection; Any situations that the investigator believes may increase the risk of patients or interfere with the results of study.

Ages Eligible for Study
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Minimum Age: 3 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: Administration of Humanized CD19 CAR T-cells<br>Dose escalation follows the standard 3+3 dose escalation design. A total of 3 dose levels are set for subjects. | Drug: Humanized CD19 CAR-T cells<br>* Each subject receive humanized CD19 CAR T-cells by intravenous infusion<br>* Other names: Humanized CD19 CAR-T cells injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | Adverse events assessed according to NCI-CTCAE v5.0 criteria | Baseline up to 28 days after humanized CD19 targeted CAR T-cells infusion | 
| Incidence of treatment-emergent adverse events (TEAEs) | Incidence of treatment-emergent adverse events [Safety and Tolerability] | Up to 2 years after humanized CD19 targeted CAR T-cells infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| B-cell acute lymphocytic leukemia(B-ALL), Overall response rate (ORR) | Assessment of ORR (ORR = CR + CRi) at Month 6, 12, 18 and 24 | At Month 1, 3, 6, 12, 18 and 24 | 
| B-ALL, Overall survival (OS) | From the first infusion of humanized CD19 CAR-T cells to death or the last visit | Up to 2 years after humanized CD19 CAR-T cells infusion | 
| B-ALL, Event-free survival (EFS) | From the first infusion of humanized CD19 CAR-T cells to the occurrence of any event, including death, relapse or gene relapse, disease progression (any one occurs first), and the last visit | Up to 2 years after humanized CD19 CAR-T cells infusion | 
| B cell non-hodgkin's lymphoma (B-NHL), Overall response rate (ORR) | Assessment of ORR (ORR = CR + PR) per Lugano 2014 criteria | At Week 4, 12, and Month 6, 12, 18, 24 | 
| B-NHL, disease control rate (DCR) | Assessment of DCR (DCR=CR+PR+SD) per Lugano 2014 criteria | At Week 12 and Month 6, 12, 18, 24 | 
| Quality of life | Assessment of Quality of life using Research and Treatment of Cancer QOL Core Questionnaire 30 (EORTC QLQ-30) at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| IADL score | Assessment of IADL score at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| ADL score | Assessment of ADL score at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| HADS score | Assessment of Hospital Anxiety and Depression Scale (HADS) score at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lymphoblastic Leukemia, Non-Hodgkin's Lymphoma, CAR T-cell therapy