Genetically Engineered Lymphocyte Therapy After Peripheral Blood Stem Cell Transplant in Treating Patients With High-Risk, Intermediate-Grade, B-cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of genetically engineered lymphocyte therapy and to see how well it works after peripheral blood stem cell transplant (PBSCT) in treating patients with high-risk, intermediate-grade, B-cell non-Hodgkin lymphoma (NHL). Genetically engineered lymphocyte therapy may stimulate the immune system in different ways and stop cancer cells from growing. Giving rituximab together with chemotherapy before a PBSCT stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim (G-CSF), or plerixafor helps stem cells move from the bone marrow to the blood so they can be collected and stored. More chemotherapy or radiation therapy is given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Giving genetically engineered lymphocyte therapy after PBSCT may be an effective treatment for NHL.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the safety of cellular immunotherapy utilizing ex vivo expanded autologous central memory T cell (TCM)-enriched cluster of differentiation (CD)8+ T cells genetically-modified to express a CD19-specific chimeric antigen receptor (CAR) in conjunction with a standard myeloablative autologous hematopoietic stem cell transplantation (aHSCT) for research participants with high-risk intermediate grade B-lineage non-Hodgkin lymphomas who have relapsed after primary therapy, or who did not achieve complete remission with primary therapy. (Phase I) II. To determine the maximum tolerated dose (MTD) on dose limiting toxicities (DLTs) and to describe the full toxicity profile. (Phase I) III. To determine the rate of research participants receiving TCM-enriched CD8+ T cells genetically-modified to express a CD19-specific CAR for which the transferred cells are detected in the circulation 28 days (+/- 3 days) by woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) quantitative (Q)-polymerase chain reaction (PCR). (Phase II) SECONDARY OBJECTIVES: I. To determine the tempo, magnitude, and duration of engraftment of the transferred T cell product as it relates to the number of cells infused. (Phase II) II. To study the impact of this therapeutic intervention on the development of CD19+ B-cell precursors in the bone marrow as a surrogate for the in vivo effector function of transferred CD19-specific T cells. (Phase II) III. To describe the progression-free and overall survival of treated research participants on this protocol. (Phase II) OUTLINE: This is a phase I, dose-escalation study of genetically engineered lymphocyte therapy followed by a phase II study. Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with filgrastim and/or plerixafor. Some patients may also receive rituximab intravenously (IV) within 4 weeks of transplant. Patients receive standard myeloablative conditioning followed by autologous PBSCT. Patients then undergo infusion of ex vivo expanded autologous TCM-enriched CD8+ T cells expressing CD19-specific CAR on day 2 or 3 after transplant. After completion of study treatment, patients are followed up periodically for at least 15 years.

Official Title
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Phase I/II Study of Cellular Immunotherapy Using Central Memory-Enriched CD8+ T Cells Lentivirally Transduced to Express A CD19-Specific Chimeric Immunoreceptor Following Peripheral Blood Stem Cell Transplantation for Patients With High-Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma

Conditions
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Recurrent Mantle Cell Lymphoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma

Intervention / Treatment
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* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Biological: Filgrastim
* Biological: Genetically Engineered Lymphocyte Therapy
* Other: Laboratory Biomarker Analysis
* Procedure: Peripheral Blood Stem Cell Transplantation
* Drug: Plerixafor
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: City of Hope (COH) pathology review confirms that research participant's diagnostic material is consistent with history of intermediate grade B-cell NHL (e.g., diffuse B-cell lymphoma, mantle cell lymphoma, transformed follicular lymphoma) History of relapse after achieving first remission with primary therapy, or failure to achieve remission with primary therapy Life expectancy > 16 weeks Karnofsky performance scale (KPS) >= 70% Negative serum pregnancy test for women of childbearing potential Research participant has an indication to be considered for autologous stem cell transplantation Exclusion Criteria: Fails to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I/II study; evidence of understanding includes passing the Protocol Comprehensive Screening given by the Research Subject Advocate (RSA); a legal guardian may substitute for the research participant Any standard contraindications to myeloablative HSCT per standard of care practices at COH Dependence on corticosteroids Currently enrolled in another investigational therapy protocol Human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of enrollment History of allogeneic HSCT or prior autologous HSCT Active autoimmune disease requiring systemic immunosuppressive therapy Research participant(s) who are to receive radioimmunotherapy (Zevalin-based)-based conditioning regimens Research participant(s) with known active hepatitis B or 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: Treatment (cellular adoptive immunotherapy following PBSCT)<br>Patients receive standard salvage chemotherapy per standard practice and undergo standard mobilization for stem cell collection with G-CSF and/or plerixafor. Some patients may also receive rituximab IV within 4 weeks of transplant. Patients receive standard myeloablative conditioning followed by autologous PBSCT. Patients then undergo infusion of ex vivo expanded autologous TCM-enriched CD8+ T cells expressing CD19-specific CAR on day 2 or 3 after transplant. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Stem Cell Transplantation, Autologous;Biological: Filgrastim<br>* Given IV<br>* Other names: Tevagrastim;Biological: Genetically Engineered Lymphocyte Therapy<br>* Receive ex vivo expanded autologous TCM-enriched CD8+ T cells expressing CD19-specific CAR<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo autologous PBSCT<br>* Other names: Peripheral Stem Cell Transplantation;Drug: Plerixafor<br>* Given IV<br>* Other names: SDZ SID 791;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Number of DLTs per dose level are reported. A DLT is defined as: Any grade 3 or higher toxicity, with the exception of expected adverse events; and designated as definitely or probably related (level of attribution) to the infusion of the TCM cells; and occurring within 28 days of T-cell infusion; Any toxicity requiring the use of steroids to ablate side effects attributable to the infusion of the TCM cells, and occurring within 28 days of T-cell infusion; Any toxicity which is a lower grade, but that increases in grade to a grade 3 or higher as a direct result of the TCM, and occurring within 28 days of T-cell infusion; Any grade 2 or greater autoimmune toxicity, and occurring within 28 days of T-cell infusion. | Within 28 days of T-cell infusion | 
| Woodchuck Hepatitis Virus Post-transcriptional Regulatory Element (WPRE) Detection Above Background | Peak expansion of WPRE is expressed in CAR copy number/mL of blood is summarized with median and range | 28 days post T cell infusion | 
| Number of Days of Quantifiable CD19 CAR Post T-cell Infusion | WPRE persistence of quantifiable CD19 CAR summarized with mean and standard deviation | 28 days post T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure to Engraft | Count of participants who fail to engraft post transplant. | Within 21 days post T-cell infusion | 
| Progression-free Survival at 1 Year | Estimated using the Kaplan-Meier methods. Progression is defined using the revised IWG response criteria, as any new lesion or increase by ≥50% of previously involved sites from nadir. | Up to 1 year |