A Study of CAR-T Cells Therapy for Patients With Relapsed and/or Refractory Central Nervous System Hematological Malignancies

Study Overview
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Brief Summary
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A Study of CAR-T Cells Therapy for Patients With Relapsed and/or Refractory Central Nervous System Hematological Malignancies

Detailed Description
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This is a single arm, open-label, single-center study. This study is indicated for relapsed or refractory central nervous system 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 trialsof similar foreign products. Two groups of patients will be enrolled, 36 in eachgroup. 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 CAR-T Cells Therapy for Patients With the Central Nervous System Involvement of Relapsed and/or Refractory B-cell Acute Lymphoblastic Leukemia or B-cell Non-Hodgkin's Lymphoma

Conditions
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Acute Lymphoblastic Leukemia, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: CAR-T cells
* Procedure: Ommaya Reservoir


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 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 followingconditions): CR not achieved after standardized chemotherapy; CR achieved following the first induction, but CR duration isless 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 flowcytometry); 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 WHOClassification Criteria for Lymphoma (2016); Relapsed or refractory B-NHL (meeting one of the followingconditions): No response or relapse after second-line or abovechemotherapy 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: Highly suspected or confirmed central nervous system involvement of hematological malignancies; Total bilirubin ≤ 51 umol/L, ALT and AST ≤ 3 times of upper limit ofnormal, creatinine ≤ 176.8 umol/L; Echocardiogram shows left ventricular ejection fraction (LVEF) ≥50%; No active infection in the lungs, blood oxygen saturation in indoorair 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 urinarytractinfectionand 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,orbilirubin>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 ofpatients 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 CAR T-cells<br>Dose escalation follows the standard 3+3 doseescalation design. A total of 3 dose levels are set for subjects. | Drug: CAR-T cells<br>* Each subject receive CAR T-cells by intravenous infusion<br>* Other names: CAR-T cells injection;Procedure: Ommaya Reservoir<br>* Surgical catheter placement into the fourth ventricle of the brain<br>|

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 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 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 CAR-T cells to death or the last visit | Up to 2 years after CAR-T cells infusion | 
| B-ALL, Event-free survival (EFS) | From the first infusion of CAR-T cells to the occurrence of any event, including death, relapse orgene relapse, disease progression (any one occurs first), and the last visit | Up to 2 years after 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