A Phase I Trial of Donor- Derived 19-28z CAR T Cells Following Allogeneic Transplant for the Treatment of CD19 Malignancies

Study Overview
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Brief Summary
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The purposed of this study is to determine whether an infusion with specialized 'modified T cells' (or CD19 chimeric antigen T cells, also called CD19 CAR T cells) that target the B cell marker will reduce the risk of relapse after transplant.

Official Title
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A Phase I Trial Evaluating the Safety of Consolidative Infusions of CD19-Specific Chimeric Antigen Receptor (CAR) T Cells Following T-cell Depleted Allogeneic Transplantation for High Risk B-cell Malignancies

Conditions
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Leukemia, Lymphoma, Lymphoma, B-Cell

Intervention / Treatment
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* Biological: CAR T-Cell Infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The following criteria must be met prior to the allogenic transplantation: ALL in second remission or greater (≥ CR2) Please refer to section 3.0 for more discussion of ALL in CR1 versus CR2 CLL High risk in any remission status as defined by 17p deletion or Richter's transformation, or All other patients eligible after at least 2 lines of standard or investigational chemotherapy B-NHL Refractory or stable disease to last line of therapy per ICML 2014. Patients should have at least 2 lines of prior therapy. Relapsed disease in patients who are not candidates for autologous transplant Patient's age is ≥ 18 and ≤ 60. KPS ≥ 70% Patients must have CD19 expression (by any detection method) demonstrated on their malignant cells at the time of enrollment on the protocol. Patients relapsed after prior CD19 CAR T cell or blinatumomab are eligible for enrollment as long as CD19 expression is still prese on the malignant cells. Patients who have a matched related donor willing to donate HSC for allograft and PBMC for CAR T cell generation Patients must have adequate organ function measured by: Cardiac: asymptomatic or if symptomatic then LVEF at rest must be > 50% Hepatic: < 3x ULN ALT and < 1.5 total serum bilirubin, unless there is congenital benign hyperbilirubinemia. Renal: serum creatinine <1.3 mg/dl or if serum creatinine is outside the normal range, then CrCl > 60 ml/min (measured or calculated/estimated) Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for hemoglobin) Negative serum pregnancy test for women of child-bearing potential is required Exclusion Criteria: Active and uncontrolled infection at time of transplantation. Please note that patients being actively treated for a viral reactivation may be enrolled on the protocol at the discretion of the investigators. Patients who have undergone a prior allogeneic or autologous stem cell transplant within the previous six months. Pregnant or breast feeding HIV infection Progressive disease at time of transplant Patients with known autoimmune disease. Patients with active or clinically significant neurological disorders, such as seizure disorders.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort -1<br>Cohorts of 3-6 patients each will be treated with escalating doses of consolidative modified T cells at Day 30 (+/- 5 days) post allo-HSCT Total T-Cell Dose: 1 x 10^4 cells/kg | Biological: CAR T-Cell Infusion<br>* Dose Level -1: 1 x 10^4 cells/kg Dose Level 1: 1 x 10^5 cells/kg Dose Level 2: 2 x 10^5 cells/kg Dose Level 3: 4 x 10^5 cells/kg<br>|
| Experimental: Cohort 1<br>Cohorts of 3-6 patients each will be treated with escalating doses of consolidative modified T cells at Day 30 (+/- 5 days) post allo-HSCT Total T-Cell Dose: 1 x 10^5 cells/kg | Biological: CAR T-Cell Infusion<br>* Dose Level -1: 1 x 10^4 cells/kg Dose Level 1: 1 x 10^5 cells/kg Dose Level 2: 2 x 10^5 cells/kg Dose Level 3: 4 x 10^5 cells/kg<br>|
| Experimental: Cohort II<br>Cohorts of 3-6 patients each will be treated with escalating doses of consolidative modified T cells at Day 30 (+/- 5 days) post allo-HSCT Total T-Cell Dose: 2 x 10^5 cells/kg | Biological: CAR T-Cell Infusion<br>* Dose Level -1: 1 x 10^4 cells/kg Dose Level 1: 1 x 10^5 cells/kg Dose Level 2: 2 x 10^5 cells/kg Dose Level 3: 4 x 10^5 cells/kg<br>|
| Experimental: Cohort III<br>Cohorts of 3-6 patients each will be treated with escalating doses of consolidative modified T cells at Day 30 (+/- 5 days) post allo-HSCT Total T-Cell Dose: 4 x 10^5 cells/kg | Biological: CAR T-Cell Infusion<br>* Dose Level -1: 1 x 10^4 cells/kg Dose Level 1: 1 x 10^5 cells/kg Dose Level 2: 2 x 10^5 cells/kg Dose Level 3: 4 x 10^5 cells/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | To determine maximum tolerated dose (MTD) of intravenously administered allogeneic, donor-derived 19-28z CAR T cells administered following TCD allo-HSCT for patients with high-risk CD19+ malignancies | 24 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Lymphoma, Lymphoma, B-Cell, Chimeric Antigen Receptor (CAR) T cells, CART cells, high-risk B-cell malignancies, 17-331, Memorial Sloan Kettering Cancer Center