CAR-T Cells Combined With Dasatinib for Patients With Relapsed and/or Refractory B-cell Hematological Malignancies

Study Overview
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Brief Summary
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A Study of CD19/BCMA-targeted CAR-T Cells Combined With Dasatinib for Patients With Relapsed and/or Refractory B-cell Acute Lymphoblastic Leukemia, B-cell Non-Hodgkin's Lymphoma and Multiple Myeloma.

Detailed Description
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This is a double-arm, single-center study. This study is indicated for relapsed and/or refractory B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin's lymphoma and multiple myeloma, the selections of dose levels and the number of subjects are based on clinical trials of similar foreign products. 120 patients will be enrolled for this trial. Primary objective is to explore the safety.

Official Title
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Clinical Trial for the Safety and Efficacy of CD19/BCMA-targeted CAR-T Cells Combined With Dasatinib for Patients With Relapsed and/or Refractory B-cell Acute Lymphoblastic Leukemia, B-cell Non-Hodgkin's Lymphoma and Multiple Myeloma

Conditions
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Multiple Myeloma in Relapse, Multiple Myeloma, Refractory, Acute Lymphoblastic Leukemia, in Relapse, Acute Lymphocytic Leukaemia Refractory, Non-Hodgkin's Lymphoma, Relapsed, Non-Hodgkin's Lymphoma Refractory

Intervention / Treatment
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* Drug: CD19/BCMA Targeted CAR T-cells and dasatinib
* Drug: CD19/BCMA Targeted CAR T-cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of CD19+ ALL, CD19+ NHL, or BCMA+ MM per the US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (2020.v2); Relapsed or refractory B cell hematological malignancies (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; Relapse after hematopoietic stem cell transplantation; Extramedullary leisions which were ineffective to radiotherapy or chemotherapy; 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 ≥ 12 weeks; ECOG performance status 0 to 2; Women of childbearing age had negative pregnancy test during screening period and before administration, and agreed to take effective contraceptive measures at least one year after infusion. Patients 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 toscreening, except for the patients recently or currently receiving in haledsteroids; 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: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of CD19/BCMA Targeted CAR T-cells and dasatinib<br>Dose levels of CAR-T cells are based on clinical trials of similar foreign products. Meanwhile, dasatinib would be combined as the following regimens: 1) Dasatinib preconditioning CAR-T cells during the manufacturing; 2) Dasatinib for the intervention of cytokine release storm after CAR-T cell infusion; 3) Dasatinib for the intervention of neurotoxicities after CAR-T cell infusion; 4) Dasatinib for the phase of CAR-T cell decreasing. | Drug: CD19/BCMA Targeted CAR T-cells and dasatinib<br>* Each subject receive CS1 Targeted CAR T-cells by intravenous infusion, and the dasatinib was combined according to the presumed regimens.<br>* Other names: Administration of CD19/BCMA Targeted CAR T-cells and dasatinib;|
| Experimental: Administration of CD19/BCMA Targeted CAR T-cells<br>Dose levels of CAR-T cells are based on clinical trials of similar foreign products. | Drug: CD19/BCMA Targeted CAR T-cells<br>* Each subject receive CS1 Targeted CAR T-cells by intravenous infusion.<br>* Other names: CD19/BCMA Targeted CAR T-cells infusion;|

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 | 
| Multiple myeloma (MM), Overall response rate (ORR) | Assessment of ORR at Day 28 | At Day 28 | 
| MM, Overall survival (OS) | Assessment of OS at Month 6, 12, 24 | At Month 6, 12, 24 | 
| Quality of life | Assessment using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scale [For item1-28: max score: 112, min score: 28, higher scores mean a better outcome; for item 28-29: max score: 14, min score: 2, higher scores mean a worse outcome] to measure Quality of life at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| Activities of Daily Living (ADL) score | Assessment using Activities of Daily Living (ADL) scale (Barthel Index) [max score: 100, min score: 0, higher scores mean a better outcome] at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| Instrumental Activities of Daily Living (IADL) score | Assessment of Instrumental Activities of Daily Living (IADL) scale [max score: 56, min score: 14, higher scores mean a worse outcome] at Baseline, Month 1, 3, 6, 9 and 12 | At Baseline, Month 1, 3, 6, 9 and 12 | 
| Hospital Anxiety and Depression Scale (HADS) score | Assessment using Hospital Anxiety and Depression Scale (HADS) [max score: 42, min score: 0, higher scores mean a worse outcome] 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, Multiple Myeloma, CAR T-cell therapy, Dasatinib