19(T2)28z1xx Chimeric Antigen Receptor (CAR) T Cells in People With B-Cell Cancers

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of 19(T2)28z1xx CAR T cells in people with relapsed/refractory B-cell cancers. The researchers will try to find the highest dose of 19(T2)28z1xx CAR T cells that causes few or mild side effects in participants. Once they find this dose, they can test it in future participants to see if it is effective in treating their relapsed/refractory B-cell cell cancers. This study will also look at whether 19(T2)28z1xx CAR T cells work against participants' cancer.

Official Title
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A Phase I Study of CD19-Targeted 19(T2)28z1xx Chimeric Antigen Receptor (CAR) Modified T Cells in Adult Patients With Relapsed or Refractory B-cell Malignancies

Conditions
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Diffuse Large B Cell Lymphoma, Primary Mediastinal Large B Cell Lymphoma, Transformed Follicular Lymphoma to Diffuse Large B Cell Lymphoma, Chronic Lymphocytic Leukemia, Indolent Non-Hodgkin Lymphoma, Marginal Zone Lymphoma, Waldenstrom Macroglobulinemia, Burkitt's Lymphoma, Primary CNS Lymphoma

Intervention / Treatment
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* Drug: 19(T2)28z1xx CAR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years of age Creatinine ≤2.0 mg/100 ml, direct bilirubin ≤2.0 mg/100 ml, AST and ALT ≤3.0x upper limit of normal (ULN) Adequate pulmonary function as assessed by ≥92% oxygen saturation on room air by pulse oximetry. Histologically confirmed DLBCL and large B cell lymphoma, including DLBCL, not otherwise specified (NOS), or Transformed DLBCL from follicular lymphoma, or High-grade B cell lymphoma (excluding Burkitt's lymphoma), or Primary mediastinal large B cell lymphoma AND Chemotherapy refractory disease, defined as a failure to achieve at least a partial response or disease progression within 12 months to the last therapy, OR Disease progression or recurrence in ≤12 months of prior autologous stem cell transplant (ASCT), OR Relapsed disease after 2 or more prior chemoimmunotherapies with at least one containing an anthracycline and CD20 directed therapy Patients need to have radiographically documented disease Exclusion Criteria: ECOG performance status ≥2. Patients with active CNS disease Pregnant or lactating women. Women and men of childbearing age should use effective contraception while on this study and continue for 1 year after all treatment is finished. Impaired cardiac function (LVEF <40%) as assessed by ECHO or MUGA scan. Patients with the following cardiac conditions will be excluded: New York Heart Association (NYHA) stage III or IV congestive heart failure Myocardial infarction ≤6 months prior to enrollment History of clinically significant ventricular arrhythmia or unexplained syncope, not believed to be vasovagal in nature or due to dehydration ≤6 months prior to enrollment Patients with HIV or active hepatitis B or hepatitis C infection are ineligible. Patients with prior allogeneic hematopoietic stem cell transplant are eligible, if more than 3 months from transplant and if patients have no active graft versus host disease (GvHD) and not on systemic immunosuppressive therapy. Prior CD19-directed therapy including CD19 CAR T cells is allowed, as long as expression of CD19 is confirmed by flow cytometry or immunohistochemistry. Patients with uncontrolled systemic fungal, bacterial, viral or other infection are ineligible. Patients with any concurrent active malignancies as defined by malignancies requiring any therapy other than expectant observation or hormonal therapy, with the exception of squamous and basal cell carcinoma of the skin. Patients with presence of clinically significant neurological disorders such as epilepsy, generalized seizure disorder, severe brain injuries are ineligible. Any other issue which, in the opinion of the treating physician, would make the patient ineligible for the study.

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
Interventional Model Description: This is a standard phase I open-label dose-escalation trial. Cohorts of 3-6 patients will be infused with escalating doses of 19(T2)28z1XX CAR T cells to establish the MTD. There are 4 planned dose levels with one additional de-escalation dose level. A 3+3 design will be used to establish the RP2D. Once the RP2D is determined, the study will open to Dose Expansion phase and up to 12 patients with B-cell non-Hodgkin lymphoma (same eligibility criteria as the dose-escalation phase).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 19(T2)28z1xx CAR T cells<br>Cohorts of 3-6 patients will be infused with escalating doses of 19(T2)28z1XX CAR T cells to establish the RP2D. There are 4 planned flat-dose levels: 25x10^6, 50 x 10^6, 100 x 10^6 and 200 x 10^6 CAR T cells and one de-escalation dose: 12.5 x 10^6 CAR T cells. A standard 3+3 dose escalation design will be implemented starting from dose 1. | Drug: 19(T2)28z1xx CAR T cells<br>* 2-7 days following the completion of the conditioning chemotherapy, patients will receive the CAR- T cells by IV infusion over 1-3 days depending on the dose level and formulation of the final CAR- T cells.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II Dose (RP2D) | Dose escalation will use a 3+3 design. DLT-evaluable participants are defined as those participants who were infused with 19(T2)28z1XX CAR T cells and who were monitored for toxicities during the first 28 days of post infusion. | 28 days post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall response rate (ORR) | Response and progression of the disease will be evaluated in this study using the Lugano Classification | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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19(T2)28z1XX CAR T cells, 20-167