High Dose Therapy and Autologous Stem Cell Transplantation Followed by Infusion of Chimeric Antigen Receptor (CAR) Modified T-Cells Directed Against CD19+ B-Cells for Relapsed and Refractory Aggressive B Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of delivering the patients' own immune cells, called T cells, after the high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT).

Official Title
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A Phase I Trial of High Dose Therapy and Autologous Stem Cell Transplantation Followed by Infusion of Chimeric Antigen Receptor (CAR) Modified T-Cells Directed Against CD19+ B-Cells for Relapsed and Refractory Aggressive B Cell Non-Hodgkin Lymphoma

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Carmustine
* Drug: Etoposide
* Drug: Cytarabine
* Drug: Melphalan
* Biological: Pegfilgrastim
* Biological: 19-28z T CELLS
* Procedure: Autologous Stem Cell Transplantation


Participation Criteria
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Eligibility Criteria
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Transplant eligible patients will be eligible if criteria met per below. Inclusion Criteria: Patients ≥ 18 years of age with aggressive B-cell non-Hodgkin lymphoma subtypes including, relapsed or refractory diffused large B-cell lymphoma (DLBCL), and transformed follicular lymphoma meeting at least one of the following criteria: Bone marrow involvement at the time of relapse or refractory disease and not appropriate for allogeneic transplantation. PET positive disease outside of one radiation port unless single-port disease treated with prior radiotherapy within the port, following > or = to 2 cycles of salvage chemotherapy, still achieving chemosensitive status 1999 IWG criteria (section 12.2 and 12.383). Creatinine ≤ 1.5 mg/100 ml (or measured 24 hour creatinine clearance of ≥ 50 cc/min) Bilirubin <2.0 mg/100 ml, AST and ALT <3x the upper-limit of normal, PT and PTT < 2x normal outside the setting of stable chronic anticoagulation therapy, Adequate cardiac function (LVEF>40%) as assessed by ECHO or MUGA scan performed within 1 month of treatment. Adequate pulmonary function as assessed by DLCO of > or = to 45% adjusted for hemoglobin. Life expectancy of > 3 months. Exclusion Criteria: Karnofsky performance status ≤ 70 (see appendix VI). Patients with other aggressive B-cell malignancies including, but not limited to: Burkitt lymphoma, transformed CLL/SLL and transformed marginal zone lymphoma that are not included in 6.1 inclusion criteria. Patients previously treated with autologous or allogeneic bone marrow or stem cell transplantation are ineligible. Other past or current malignancy unless in the opinion of the investigator it does not contraindicate participation in the study. Uncontrolled bacterial, viral or fungal infection. Patients with HIV, active hepatitis B or hepatitis C infection.

Ages Eligible for Study
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Minimum Age: 18 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: HIGH DOSE CHEMOTHERAPY AND ASCT<br>This is a phase 1 dose escalation study designed to determine the maximum tolerated dose (MTD) of CAR modified T cells in patients with relapsed and refractory aggressive B-NHL. Three dose levels (5 x 106 19-28z T cells/kg, 1 x 107 19-28z T cells/kg, and 2 x 107 19-28z T cells/kg) are considered for the MTD. | Drug: Carmustine<br> <br> Drug: Etoposide<br> <br> Drug: Cytarabine<br> <br> Drug: Melphalan<br> <br> Biological: Pegfilgrastim<br> <br> Biological: 19-28z T CELLS<br> <br> Procedure: Autologous Stem Cell Transplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated dose (MTD) | will be assessed utilizing a standard 3+3 cell dose escalation to determine the maximum tolerated dose of CD19+ CAR T cells | 2 years | 
| safety | Toxicity will be graded on a scale of 1 to 5 as described by the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2 year progression-free (PFS) |  | 2 years | 
| overall survival (os) |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed, Refractory, Autologous Stem Cell Transplantation, HIGH DOSE CHEMOTHERAPY, 19-28z T cells/kg, 12-117