Phase I/IIA Study of CART19 Cells for Patients With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma

Study Overview
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Brief Summary
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This is a study for children who have been previously treated for Leukemia/Lymphoma. In particular, it is a study for people who have a type of Leukemia/Lymphoma that involves B cells (a type of white cell), which contain the cancer. This is a new approach for treatment of Leukemia/Lymphoma that involves B cells (tumor cells). This study will take the subject's white blood cells (T cells) and modify them in order to target the cancer. The subject's T cells will be modified in one or two different ways that will allow the cells to identify and kill the tumor cells (B cells). Both ways of modifying the cells tells the T cells to go to the B cells (tumor cells) and turn on and potentially kill the B cells (tumor cells). The modification is a genetic change to the T cells, or gene transfer, in order to allow the modified T cells to recognize your tumor cells but not other normal cells in the subject's body. These modified cells are called chimeric antigen receptor 19 (CART19) T-cells.

Detailed Description
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At entry subjects will be staged and the suitability of their T cells for CART-19 manufacturing will be determined. Subjects who have adequate T cells will be leukapheresed to obtain large numbers of peripheral blood mononuclear cells (PBMC) for CART-19 manufacturing. The T cells will be purified from the PBMC, transduced with CART-19 lentiviral vector, expanded in vitro and then frozen for future administration. Chemotherapy will then be given. Following tumor burden reassessment, CART-19 cells will be thawed and infused. Subjects will have blood tests to assess safety, and engraftment and persistence of the CART-19 cells at regular intervals through four weeks after their last infusion of the study. Following the 6 months of intensive follow-up, subjects will be evaluated quarterly for two years with a medical history, a physical examination, and blood tests. Following this evaluation, subjects will enter a roll-over study for annual follow-up by phone and questionnaire for an additional thirteen years to assess for the diagnosis of long-term health problems, such as development of new malignancy. Primary objectives: Determine the safety and feasibility of administration of chimeric antigen receptor T cells transduced with the anti-CD 19 lentiviral vector (referred to as CART-19 cells). Determine duration of in vivio survival of CART-19 cells. Real Time polymerase chain receptor (RT-PCR) analysis of whole blood will be used to detect and quantify survival of CART-19 TCR:4-1BB and TCR cells over time. Secondary objectives: For patients with detectable disease, measure anti-tumor response due to CART-19 cell infusions. To determine if the 4-1BB transgene is superior to the TCR only transgene as measured by the relative engraftment levels of CART-19 TCR:4-1BB and TCR cells over time. For patients with stored or accessible tumor cells (such as patients with active chronic lymphocytic leukemia (CLL), acute lymphoblastic leukema (ALL), etc) determine tumor cell killing by CART-19 cells in vitro. Determine if cellular or humoral host immunity develops against the murine anti-CD19, and assess correlation with loss of detectable CART-19 (loss of engraftment). Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg)

Official Title
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CHP 959 - A Phase I/IIA Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRzeta and 4-1BB Signaling Domains in Patients With Chemotherapy Resistant Or Refractory CD19+ Leukemia and Lymphoma

Conditions
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B Cell Leukemia, B Cell Lymphoma

Intervention / Treatment
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* Biological: CART-19


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects with CD 19+ B cell malignancies in patients with no available curative treatment options (such as autologous or allogeneic SCT) who have limited prognosis (several months to <2 year survival) with currently available therapies will be enrolled: Eligible diseases: CD 19+ leukemia or lymphoma ALL without curative options for therapy, including those not eligible for allogeneic SCT because of: age co-morbid disease other contraindications to TBI-based conditioning (required for ALL SCT) lack of suitable donor prior SCT Declines allo SCT (in CR3) as a therapeutic option after documented discussion about the role of SCT with a BMT physician not part of the study team. Note: Patient may be in any complete response, or patient may have active disease but responding or stable after most recent therapy. The intent is not to enroll patients with no degree of disease control, or rapidly increasing disease burden between enrollment and cell infusion. Follicular lymphoma, previously identified as CD19+ At least 2 prior combination chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Stage III-IV disease. Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval <1 year). Disease responding or stable after most recent therapy (chemotherapy, MoAb). CLL At least 2 prior chemotherapy regimens (not including single agent monoclonal antibody (Rituxan) therapy. Less than 1 year between last chemotherapy and progression (i.e. most recent progression free interval <1 year). Not eligible or appropriate for conventional allogeneic SCT Disease responding or stable after most recent therapy (chemotherapy, MoAb) Mantle cell lymphoma Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT Disease responding or stable after most recent therapy (chemotherapy, MoAb) Relapsed after prior autologous SCT B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least 1 prior therapy and not eligible for allogeneic SCT. Diffuse large cell lymphoma or other high-grade NHL, previously identified as CD19+ Residual disease after primary therapy and not eligible for autologous SCT Relapsed after prior autologous SCT Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or autologous SCT Age 1 to 24 years. Patients ages 22-24 will only be enrolled if they are currently being treated at CHOP or another pediatric facility/oncologist Expected survival > 12 weeks Creatinine < 2.5 mg/dl and less than 2.5x normal for age ALT ≤ 5x normal Bilirubin <2.0 mg/dl Any relapse after prior SCT will make patient eligible regardless of other prior therapy Patients with relapsed disease after prior allogeneic SCT (myeloablative or non-myeloablative) will be eligible if they meet all other inclusion criteria and Have no active GVHD and require no immunosuppression Are more than 4 months from transplant For those patients who require leukapheresis for T cell collection (i.e. no previously collected product exists), adequate venous access for apheresis or eligible for appropriate catheter placement, and no other contraindications for leukapheresis Voluntary informed consent is given Patients with CNS3 disease will be eligible if CNS disease is responsive to therapy (at infusion) Exclusion Criteria: Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion Uncontrolled active infection Active hepatitis B or hepatitis C infection Concurrent use of systemic steroids at the time of cell infusion or cell collection, or a condition, in the treating physician's opinion, that is likely to require steroid therapy during collection or after infusion. Steroids for disease treatment at times other than cell collection or at the time of infusion are permitted. Use of inhaled steroids, or hydrocortisone for physiological replacement in patients with adrenal insufficiency are permitted as well Presence of grade 2-4 acute or extensive chronic GVHD Under treatment for GVHD Previous treatment with any gene therapy products Any uncontrolled active medical disorder that would preclude participation as outlined. HIV infection. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 24 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: CART-19 T Cells<br>The subject's thawed T cells will be modified in one or two different ways that will allow the cells to identify and kill the tumor cells (B cells). The T cells will be infused over 10-15 minutes on days Days 0, and 1. Day 14 is tentative based on response. | Biological: CART-19<br>* Day 0: 10% of total dose Day 1: 30% of total dose if patient is stable (no significant toxicity) from prior dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Study Related Adverse Events. | Inclusive of any events that are possibly, likely, or definitely related to study treatment any time from the first day of study treatment until week 24. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Subjects With a Successful Product Manufactured |  | 24 weeks | 
| Number of Subjects With Complete Remission (CR). | Complete remission rate for subjects with Non-CNS3 ALL. National Comprehensive Cancer Network standard response criteria, which define complete remission (CR) as ,5% bone marrow blasts by morphologic determination, with no evidence of extramedullary disease or refractory disease. | 4 Weeks | 
| Number of Subjects With Complete Remission With Incomplete Blood Count Recovery (CRi). | Complete remission rate for subjects with Non-CNS3 ALL. National Comprehensive Cancer Network standard response criteria, which define complete remission (CR) as ,5% bone marrow blasts by morphologic determination, with no evidence of extramedullary disease or refractory disease. | 4 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biological: CART19