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Cyclophosphamide

Fludarabine

Fludarabine phosphate

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Alkylating Agents

CHEMOTHERAPY: Patients receive fludarabine IV over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.

T-CELL INFUSION: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.

Autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T Cells

Partow Kebriaei

This phase I trial investigates the side effects and best dose of CD19 positive (+) specific CAR-T cells in treating patients with CD19+ lymphoid malignancies, such as acute lymphoblastic leukemia, non-Hodgkin lymphoma, small lymphocytic lymphoma, or chronic lymphocytic lymphoma. Sometimes researchers change the genetic material in the cells of a patient's T cells using a process called gene transfer. Researchers then inject the changed T-cells into the patient's body. Receiving the T-cell infusion may help to control the disease.

PRIMARY OBJECTIVE:

I. To determine the safety and maximum tolerated dose (MTD) of donor-derived genetically modified, CD19-specific T cells expressing mbIL15 and HER1t using the Rapid Personalized Manufacture (RPM) process (autologous CD19-CD8-CD28-CD3zeta-chimeric antigen receptor \[CAR\]-mbIL15-HER1t T cells \[CD19-mbIL15-CAR-T cells\]) administered to patients with CD19+ advanced lymphoid malignancies who have previously received an allogeneic hematopoietic stem cell transplantation (HSCT), including haploidentical HSCT.

SECONDARY OBJECTIVES:

I. To demonstrate the feasibility of the RPM process. II. To determine the incidence and grading of cytokine release syndrome (CRS) and neurotoxicity.

III. To determine persistence of genetically modified T cells. IV. To determine if cetuximab can control numbers of infused T cells. V. To screen for the development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t).

VI. To determine cytokine profile of the patient with infused T cells. VII. To demonstrate the homing ability of the infused T cells. VIII. To assess disease response after T-cell infusion. IX. To assess progression-free and overall survival. X. To detect emergence of CD19 negative (neg) malignant B cells.

OUTLINE: This is a dose-escalation study of autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells.

CHEMOTHERAPY: Patients receive fludarabine intravenously (IV) over 1 hour and cyclophosphamide IV over 3 hours on days -5, -4, and -3 in the absence of disease progression or unacceptable toxicity.

T-CELL INFUSION: Patients receive autologous CD19-CD8-CD28-CD3zeta-CAR-mbIL15-HER1t T cells IV over 15-30 minutes on day 0.

After completion of study treatment, patients are followed up within 3 days after T-cell infusion and at 1, 2, 3, 4, 6, and 8 weeks, then at 3, 6, and 12 months, then periodically for up to 15 years.

CD19-Specific T Cells Post AlloSCT

Donor-Derived Very-Rapid Manufactured CD19-Specific T Cells for Lymphoid Malignancies After Allogeneic Hematopoietic Stem-Cell Transplantation

Graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse events will be summarized by frequencies and percentages by dose level.

The MTD is defined as the highest dose at which no more than 1 of 6 patients experiences a DLT. The study will employ a standard 3+3 design to find the MTD of CD19-specific chimeric antigen receptor (CAR) T cell dose.

Persistence of genetically modified T cells will be assessed by the frequency of patients with any detectable CAR-T cells.

For patients receiving cetuximab (i.e., those who experience \>= grade 3 CRS), the change in infused CAR+ T cells from before cetuximab treatment to the nadir of CAR+ T cells after cetuximab summarized by mean, standard deviation, median, and range and days to achieve nadir.

The development of host immune responses against the transgenes (one or more of CAR, mbIL15, HER1t) may be assessed by the percentage of patients with antibody formation against each one of the transgenes.

Individual patient and aggregate cytokine levels (e.g., IL-15, IL-12, IL-8, etc.) will be summarized by means, standard deviations, medians, and ranges.

Homing will be assessed based on presence of infused T cells within biopsied tissue. The frequency and percentage of patients experiencing homing and those who have CD19- malignant B cells will be presented.

Percentage of patients experiencing disease response, defined as partial or complete clearance of disease e.g., by positron emission tomography (PET) and/or bone marrow report will be computed along with a corresponding 95% confidence interval. The percentage of patients who had T cells successfully prepared, released, and infused will be reported. Additional statistical analyses will be performed if deemed appropriate.

Presence of CD19- malignant B cells will be based on flow cytometry staining for CD19 in the context of staining for antigens to detect cancerous B cells. The frequency and percentage of patients experiencing homing and those who have CD19- malignant B cells will be presented.

Will be estimated using the Kaplan-Meier method and presented along with their 95% confidence intervals. Additional statistical analyses will be performed if deemed appropriate.

Spots Global Cancer Trial Database for b acute lymphoblastic leukemia with t(v;11q23.3); kmt2a rearranged