CD19-targeting, 3rd Generation CAR T Cells for Refractory B Cells Malignancy

Study Overview
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Brief Summary
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Treatment of patients with B cell lymphoma or leukemia with two doses of CD19-targeting chimeric antigen receptor (CAR) T cells to evaluate for safety and efficacy.

Detailed Description
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Treatment of patients with B cell lymphoma or leukemia with two doses of CD19-targeting chimeric antigen receptor (CAR) T cells to evaluate for safety and efficacy. The CAR consists of a CD19 targeting antibody scFv with three intracellular signaling domains derived from CD3 zeta, CD28 and 4-1BB. Autologous T cells will be gene engineered with the CAR gene using a retrovirus vector. Prior to T cell infusion, the patients will be subjected to preconditioning treatment. After the second infusion patients will be subjected to immunomodulatory treatment. After T cell infusion, the patients will be evaluated for 24 months for adverse reactions, persistence of CAR T cells and efficacy. Primary outcome: - Registration of the safety profile such as inflammation, fever, pain, changes in blood pressure, pulse and other adverse events. Weekly for the first 6 weeks, then at 3, 6, 9, 12, 15, 18, 21 and 24 months. Secondary outcome: Tumor response, CAR T cell persistence and immunological profile Determination of tumor size and the tumor marker CD19. Determination of the levels of circulating B cells. Determination of the level of CAR T cells (mRNA and cells) in blood and biopsies. Determination of activation markers on CAR T cells such as CD107a. Determination of the presence of immunological markers in blood and biopsies. At 1 and 3 weeks then at 3, 6, 9, 12, 15, 18, 21 and 24 months.

Official Title
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CD19-targeting, 3rd Generation CAR T Cells for Refractory B Cells Malignancy - a Phase II Trial.

Conditions
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B-cell Leukemia, B-Cell Lymphoma

Intervention / Treatment
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* Biological: CAR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory CD19+ B-cell lymphoma or leukemia with no other curative treatment option available. Measurable disease. All ages Performance status ECOG 0-2. Fertile females/males must consent to use contraceptives during participation of the trial. Signed informed consent. Exclusion Criteria: Any significant medical or psychiatric illness that would prevent the patient from giving informed consent or from following the study procedures. Patients with primary CNS lymphoma. Known human immunodeficiency virus (HIV) infection. Active and/or severe infection (e.g. tuberculosis, sepsis and opportunistic infections, active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection. Other serious underlying medical conditions, which, in the Investigator's judgment, could impair the ability of the patient to perform the treatment. Treatment with an investigational product within 30 days prior to enrollment, or at least 5 half-lives of that drug, which is longest. Pregnancy Patients that do not consent to that tissue and blood samples are stored in a biobank Patients whose cells cannot be manufactured.

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 100 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: CAR T cells<br>Autologous 3rd generation CD19-targeting CAR T cells | Biological: CAR T cells<br>* Autologous CD19-targeting, 3rd generation CAR T cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response | Determination of tumor size | 24 months. | 
| B cell levels | Determination of circulating CD19+ B cells | 24 months | 
| CAR T cell persistence | Determination of the level of CAR T cells | 24 months | 
| Immunological profile | Determination of frequencies of immune cells in patient blood and tissues | 24 months | 
| Cytokine profile | Determination of cytokine profile in patient blood | 24 months |