Gene Therapy for B-Cell Non-Hodgkin Lymphoma Using CD19 CAR Gene Transduced T Lymphocytes

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express anti-CD19 Chimeric Antigen Receptor in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma.

Detailed Description
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Peripheral blood (up to 600 mL) will be collected from a subject after obtaining a written informed consent and completing the 1st registration. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using SFG-1928z retroviral vector. Anti-CD19 CAR expressing T cells (CD19-CAR-T) will be expanded using a medium containing autologous plasma. After the T cells pass in quality control tests, the subject will go into 2nd registration. Subjects will be hospitalized and administered Cyclophosphamide on Day -2 or Bendamustine on Day -3 to Day -2 intravenously as Pre-treatment, and then subjects will receive 1st infusion of CD19-CAR-T on Day 0 and Day 1 (Day 1：1/3 dose, Day 2：2/3 dose) as a split dose. In case the sufficient cell number of CD19-CAR-T is manufactured, DLT is not observed after CD19-CAR-T infusion, certain clinical effect is observed and additional treatment is preferable, the necessity of 2nd infusion will be assessed. In the case that 2nd infusion is necessary, it is allowed to infuse at appropriate timing. This study is conducted based on the 3+3 dose escalation scheme. Three subjects are enrolled in each group of Dose Level. If one of the 3 subjects show DLT during DLT assessment period, another 3 subjects will be added; therefore, decision as to whether the next Dose Level can follow or not is made based on the results obtained from the total of 6 subjects. The investigator assesses the tumor shrinkage effect of CD19-CAR-T in accordance with Revised response criteria malignant lymphoma, at 12 week after the 1st infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the 1st infusion of CD19-CAR-T in reference to guidelines of FDA.

Official Title
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Clinical Research of Gene Therapy for Refractory B-Cell Non-Hodgkin Lymphoma Using Autologous T Cells Expressing a Chimeric Antigen Receptor Specific to the CD19 Antigen

Conditions
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Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide or Bendamustine
* Genetic: Dose Level -1
* Genetic: Dose Level 1
* Genetic: Dose Level 2
* Genetic: Dose Level 3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory B-NHL. Evaluable region can be identified by CT scan and is positive by FDG-PET. 20 ≤ age ≤ 70 years at the time of informed consent. ECOG performance status of 0-2. Well preserved main organ functions. Life expectancy ≥3 months after informed consent. Written informed consent. Exclusion Criteria: Other active malignancy. CNS infiltration of lymphoma. History of allogeneic stem cell transplantation. Already participated in a clinical trial in which CD19-CAR-T are administered within 24 weeks. Concurrent use of systemic steroids or immunosuppressive agents. Concurrent severe heart disease. History of severe cerebrovascular disease or sequela including paralysis. Known active or severe infection. HIV seropositive status. HBsAg-positive or both HBcAb and HBV-DNA positive. Active hepatitis C. Psychiatric disorder or drug addiction that affects the ability of informed consent. Pregnant or breastfeeding women, women who may be pregnant and women desiring to become pregnant. Men who desire impregnating a woman are also excluded (excluded: in case when sperm is cryopreserved prior to gene therapy and a child is born by using the sperm). Any other patients judged by the investigators to be inappropriate for the subject of this study.

Ages Eligible for Study
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Minimum Age: 20 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Level -1<br>Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject. | Drug: Cyclophosphamide or Bendamustine<br>* Cyclophosphamide [1.5 g/m^2 x 1 day Intravenous (IV)] or Bendamustine [120 mg/m^2 x 2 days Intravenous (IV)] is administered as Pre-treatment medication of CD19-CAR-T.<br>Genetic: Dose Level -1<br>* CD19-CAR-T [1 x 10^5 cells/kg x 1 day and 2 x 10^5 cells/kg x 1 day Intravenous (IV)] are administered.<br>|
| Experimental: Dose Level 1<br>Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject. | Drug: Cyclophosphamide or Bendamustine<br>* Cyclophosphamide [1.5 g/m^2 x 1 day Intravenous (IV)] or Bendamustine [120 mg/m^2 x 2 days Intravenous (IV)] is administered as Pre-treatment medication of CD19-CAR-T.<br>Genetic: Dose Level 1<br>* CD19-CAR-T [1/3 x 10^6 cells/kg x 1 day and 2/3 x 10^6 cells/kg x 1 day Intravenous (IV)] are administered.<br>|
| Experimental: Dose Level 2<br>Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject. | Drug: Cyclophosphamide or Bendamustine<br>* Cyclophosphamide [1.5 g/m^2 x 1 day Intravenous (IV)] or Bendamustine [120 mg/m^2 x 2 days Intravenous (IV)] is administered as Pre-treatment medication of CD19-CAR-T.<br>Genetic: Dose Level 2<br>* CD19-CAR-T [1 x 10^6 cells/kg x 1 day and 2 x 10^6 cells/kg x 1 day Intravenous (IV)] are administered.<br>|
| Experimental: Dose Level 3<br>Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject. | Drug: Cyclophosphamide or Bendamustine<br>* Cyclophosphamide [1.5 g/m^2 x 1 day Intravenous (IV)] or Bendamustine [120 mg/m^2 x 2 days Intravenous (IV)] is administered as Pre-treatment medication of CD19-CAR-T.<br>Genetic: Dose Level 3<br>* CD19-CAR-T [1/3 x 10^7 cells/kg x 1 day and 2/3 x 10^7 cells/kg x 1 day Intravenous (IV)] are administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity Profile | Confirm the toxicity profile with CTCAE ver4.0. | 12 weeks | 
| Toxicity Profile | Confirm existence or non-existence of normal B-lymphocytes decrease by flow cytometry. | 12 weeks | 
| Toxicity Profile | Measure immunoglobulin by PCR. | 12 weeks | 
| Toxicity Profile | Confirm replication competent retrovirus (RCR) by PCR. | 12 weeks | 
| Toxicity Profile | Confirm clonality by linear amplification mediated (LAM)-PCR. | 12 weeks | 
| Quality test of CD19-CAR-T | Transduction efficiency, viability, sterility and potency. | Before administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor shrinkage effect | Confirm the efficacy with Revised response criteria for malignant lymphoma J Clin Oncol. 25: 579-586 (2007). | 12 weeks | 
| Lymphocyte subset analysis of CD19-CAR-T | Confirm the state of immune mechanism by flow cytometry. | 12 weeks | 
| Human anti-mouse antibody (HAMA) test | Examine HAMA with ELISA. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, Neoplasms, Experimental, Immune System Diseases, Adoptive Immunotherapy, Anti-CD19 CAR Expressing T cells Therapy, CD19 CAR Gene-Transduced Lymphocyte, Genetically Engineered Lymphocyte Therapy, Retroviral Vector, Burkitt Lymphoma, Lymphoma, Lymphoma, Follicular, Lymphoma, Non-Hodgkin, Lymphomatoid Granulomatosis, Lymphoma, B-Cell, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Large-Cell, Immunoblastic, Lymphoma, B-Cell, Marginal Zone, Lymphoma, Extranodal NK-T-Cell, Lymphoma, Mantle-Cell, Neoplasms by Histologic Type