CD19-targeting CAR T Cells in Relapsed or Refractory CD19 Positive B-cell Malignancies

Study Overview
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Brief Summary
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This is a single center, single arm, open-label phase 1 study to determine the safety and efficacy of autologous T cells expressing CD19 chimeric antigen receptors in adults with CD19+ B cell malignancies.

Detailed Description
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This is a single-center, Open Label phase I clinical trial, 9 subjects planned to be enrolled. The subjects will be divided into low-dose group, medium-dose group and high-dose group.Dose CAR+ cells/kg Low 1×105 Medium 2×106 High 6×106

Official Title
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CD19-targeting CAR T Cell Therapy in the Treatment of Relapsed or Refractory CD19 Positive B-cell Malignancies

Conditions
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B-cell Malignancy, B-cell Lymphoma, B-Cell Acute Lymphoblastic Leukaemia

Intervention / Treatment
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* Biological: CD19 CAR T


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CD19+ relapsed or refractory B cell malignancies: Relapsed or refractory B acute lymphocytic leukemia. Relapse was defined as presence of > 5% blasts at screening, or second or subsequent bone marrow relapse, or any bone marrow relapse after allogeneic stem cell transplant and must be ≥ 6 months from stem cell transplant at the time of infusion. Refractory was defined by not achieving an initial complete response after 2 cycles of a standard chemotherapy regimen . Patients who were refractory to subsequent chemotherapy regimens after an initial remission were considered chemorefractory Patients with Ph+ acute lymphocytic leukemia were eligible if they are intolerant to or have not achieved a remission after two lines of tyrosine kinase inhibitor therapy, or if tyrosine kinase inhibitor therapy is contraindicated, or ineligible for allogeneic stem cell transplant because of: Comorbid disease Other contraindications to allogeneic stem cell transplant conditioning regimen Lack of suitable donor Prior hematopoietic stem cell transplant Declined allogeneichematopoietic stem cell transplant as a therapeutic option Relapsed or refractory non-Hodgkin's lymphoma Histopathological CD19+. No response to last line of therapy i. partial response as best response to most recent therapy regimen ii. partial response as best response to most recent therapy with duration no longer than 6 month from last dose of therapy Refractory post-Autologous stem cell transplant i. Disease progression or relapsed less than or equal to 12 months of Autologous stem cell transplant (must have biopsy proven recurrence in relapsed subjects) ii. If salvage therapy is given post-Autologous stem cell transplant, the subject must have had no response to or relapsed after the last line of therapy Subjects must have received adequate prior therapy including at a minimum: anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20-negative and an anthracycline containing chemotherapy regimen for subjects with transformed follicular lymphoma must have received prior chemotherapy for follicular lymphoma and subsequently have chemorefractory disease after transformation to Diffuse large B-cell lymphoma At least one measurable lesion per revised IWG Response Criteria 18-75 years old Expected survival ≥ 12 weeks Adequate renal, hepatic, pulmonary and cardiac function defined as: Creatinine clearance (as estimated by Cockcroft Gault) > 60 mL/min Serum ALT/AST <2.5 ULN Total bilirubin <1.5 mg/dl, except in subjects with Gilbert's syndrome Cardiac ejection fraction >50%, no evidence of pericardial effusion as determined by an echocardiogram, and no clinically significant pleural effusion Baseline oxygen saturation >92% on room air Eastern cooperative oncology group (ECOG) performance status of 0 - 2 Pregnant or lactating women must have a negative pregnancy test before infusion, and agree to take effective contraception during the trial Apheresis product received and accepted Written informed consent Exclusion Criteria: Isolated extra-medullary relapse leukemia Other malignancies Concomitant genetic syndrome, with the exception of Down Syndrome Burkitt's lymphoma/leukemia Treatment with any prior gene therapy product, anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy Active hepatitis B, C, or any uncontrolled infection Grade 2 to 4 Graft versus Host Disease (GVHD) Medications or treatments that were to be excluded: Corticosteroids within 72 hours of infusion, with the exception of physiologic replacement Allogeneic cellular therapy, such as donor lymphocyte infusion within 6 weeks prior to infusion Graft versus Host Disease therapies Chemotherapy stopped prior to lymphodepletion based on clearance central nervous system prophylaxis treatment Active central nervous system disease (central nervous system 2 disease [Cerebral spinal fluid containing blasts, but < 5 WBCs/microliter] patients were eligible) Any condition that investigator considered may increase the risk of the subjects or interfere with the trial results

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: CD19 CAR T<br>CD19 CAR T cells transduced with a lentiviral vector to express anti-CD19 scFv CD3z:CD28 administered by IV infusion. | Biological: CD19 CAR T<br>* CD19 CAR T cells transduced with a lentiviral vector to express anti-CD19 scFv CD3z:CD28 administered by IV infusion. Subjects will receive 0.1-10 x 10^6 transduced CAR T cells as a split dose over three days as follows:Day 1, 10% fraction, Day 2, 30% fraction, Day 3, 60% fraction.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of toxicities and adverse events | To assess the frequency and severity of toxicities and adverse events according to NCI CTC v4.0 | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate | To assess the overall response rate after CD19 CAR T infusion in R/R B cell malignancies | 24 week | 
| overall survival | To assess the overall survival in patients with R/R B cell malignancies | 24 week |