Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This study will assess safety and feasibility of infusing genetically modified autologous T cells transduced to express a chimeric antigen receptor targeting the B cell surface antigen Cluster of Differentiation 19 (CD19)

Detailed Description
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This is an open-label, pilot, phase 1 study to determine the safety profile of anti-CD19 CAR-T cell infusion in participants with R/R B-cell NHL. The dose-finding cohorts in this study will evaluate and define the safe dose of anti-CD19 Chimeric antigen receptor T cells (CAR-T) cells. Using a 3+3 design, participants will be enrolled sequentially to each dose level. A dose expansion will then occur at the maximum tolerated dose (MTD) and dose levels that have not exceeded the MTD. PRIMARY OBJECTIVES To evaluate the safety of administering chimeric antigen receptor T cells targeting CD-19 to patients with relapsed or refractory CD19+ B-cell nonHodgkin lymphoma (NHL). To determine the recommended phase 2 dose (RP2D) for this cellular therapy. SECONDARY OBJECTIVES To assess the safety and toxicity of cell collection and infusion of CAR-T cells targeting CD19 in patients with relapsed or refractory CD19+ B cell NHL. To describe the efficacy of chimeric antigen receptor T cells targeting CD-19 in patients with relapsed or refractory CD19+ B cell NHL. To evaluate the feasibility of CD19 CAR T cell manufacturing for patients with relapsed or refractory CD19+ B cell NHL of local manufacturing and ability to produce adequate quantities of vector positive T-cells. OUTLINE Eligible participants will undergo apheresis with collection of autologous peripheral blood mononuclear cells that will be used to generate CAR-T cells. The CAR T cells will be produced using the Miltenyi Prodigy, and an FDA compliant Lentigen Technology, Inc., CD19 targeted lentiviral vector. After successful generation of the anti-CD19 CAR-T cells (drug product (DP)), subjects will undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by 2-5 days of rest. A single infusion of anti-CD19 CAR-T cells at the starting dose of 5 x 105 cells/kg will be given on Day=0. Following treatment with DP, subjects will be followed on this study for 12 months for safety, disease status, and survival. For long term follow-up, participants will be followed for 15 years. For participants whose dose does not meet the target dose, enrollment into a conforming product low-dose cohort, at minimum dose level - 1 and that has not exceeded the MTD will occur. This conforming product low-dose cohort will be evaluated for toxicity and efficacy of those lower dose levels as part of the primary safety and secondary objectives. For participants whose CAR-T product does not meet the pre-specified release criteria, enrollment into a non-conforming product cohort, at a minimum dose level - 1 and that has not exceeded the MTD will occur. This non-conforming product cohort will be evaluated for toxicity and efficacy of the non-conforming product cohort as part of the exploratory objectives

Official Title
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A Phase 1 Clinical Trial of Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma

Conditions
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Refractory Non-Hodgkin Lymphoma, Burkitt Lymphoma, Mantle Cell Lymphoma, Follicular Lymphoma, Lymphoplasmacytic Lymphoma, Primary Mediastinal Large B Cell Lymphoma, Diffuse Large B Cell Lymphoma, Small Lymphocytic Lymphoma, Transformed Lymphoma

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Cyclophosphamide
* Biological: anti-CD19 CAR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of relapsed or refractory B-cell NHL: DLBCL, Mantle Cell, Follicular Lymphoma, Lymphoplasmacytic lymphoma, Small Lymphocytic Lymphoma, Primary Mediastinal B-Cell Lymphoma, Burkitt Lymphoma, transformed lymphoma. Subjects with small lymphocytic lymphoma (SLL) must have progressed after at least 2 prior therapies and prior treatment with or intolerance of both ibrutinib and venetoclax. Subjects with DLBCL, primary mediastinal B- Cell lymphoma, Burkitt lymphoma and transformed lymphoma must have relapsed or failed to respond to >= 2 prior lines of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline. Subjects with indolent lymphomas ((nodal or extranodal marginal zone lymphoma, follicular lymphoma and lymphoplasmacytic lymphoma) must have relapsed after or been refractory to >=2 prior lines of multi-agent chemoimmunotherapy including prior exposure to rituximab and at least 2 other chemotherapy agents. For subjects with Mantle cell lymphoma, previous lines of therapy may include multiagent chemotherapy including alkylating agent or anthracycline and anti CD20 antibody therapy and Bruton's tyrosine kinase (BTK) inhibitor therapy. Positron Emission Tomography (PET) -positive disease according to Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification At least one of the following: Primary refractory or early relapse (first remission < 12 months) and not eligible for stem cell transplant Relapsed or refractory disease after two or more lines of systemic therapy No significant circulating disease, defined as an elevated total lymphocyte count above the ULN due to the presence of malignant cells. CD19 positive by either immunohistochemistry or flow cytometry analysis on any biopsy. If prior anti-CD19 therapy has been administered, CD19 positivity has to be re-established on the most recent biopsy. Age >=18 years at the time of consent Absolute lymphocyte count > 100/ (microliter) Eastern Cooperative Oncology Group (ECOG) performance status < 2 Adequate organ function, defined as: Adequate bone marrow function for apheresis and lymphodepleting chemotherapy Hemoglobin (Hgb) >8 grams per deciliter (gm/dl) (transfusions allowed) Platelets >50,000/microliter (uL) (transfusions allowed) Absolute Neutrophil Count (ANC) > 500/uL Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 x institutional upper limit of normal (ULN) and Total bilirubin < 1.5 mg/dl x institutional ULN, except with Gilbert's syndrome Serum Creatinine < 2 x the institutional ULN Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) > 40% as assessed by echocardiogram or multiple uptake gated acquisition (MUGA) within 3 months of screening. Repeat testing may occur at Investigator's discretion. Adequate vascular access for leukapheresis procedure (either peripheral line or surgically placed line). Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must have a negative serum or urine pregnancy test AND agree to use highly effective methods of contraception for 1 year after the last dose of anti-CD19 CAR-T cells Males who have partners of childbearing potential must agree to use an effective barrier contraceptive method Ability to understand a written informed consent document, and the willingness to sign it. Exclusion Criteria: Autologous transplant within 6 weeks of planned CAR-T cell infusion Recipient of prior CAR-T cell therapy targeting CD19 outside of this protocol Active other malignancy, other than non-melanoma skin cancer, carcinoma in situ (e.g., cervix, bladder, or breast). HIV seropositivity Serologic status reflecting active hepatitis B or C infection. Patients that are positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to enrollment. (PCR positive patients will be excluded.) Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant or breastfeeding women are excluded from this study because CAR-T cell therapy may be associated with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with CAR-T cells, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. NOTE: Women of childbearing potential must have a negative serum or urine pregnancy test. Patients with history of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe brain injuries, dementia and Parkinson's disease. History of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus) with requirement of immunosuppressive medication within 6 months. Body weight <40 kilograms(kg) Eligibility for Infusion of Investigational Product: Subjects will undergo an evaluation of eligibility on day 1 prior to infusion of anti-CD19 CAR-T cell product. This eligibility criterion will include the inclusion and exclusion criteria required for enrollment with the following exceptions and additions: No significant laboratory abnormalities. Laboratory result abnormalities that are considered not clinically significant by the principal investigator AND are not the result of a demonstrated active infection or an active central nervous system condition. ECOG performance status < 2 No evidence of uncontrolled intercurrent illness including, but not limited to ongoing or active infection, inflammatory response, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social situations. No new neurologic symptoms suggestive of an active central nervous system condition, or uncontrolled CNS involvement by lymphoma. No corticosteroid use within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy).

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 Regimen<br>Apheresis (1 day): Autologous lymphocytes/ mononuclear cell collection will be collected through standard apheresis procedures as per University of California, San Francisco (UCSF) institutional practices CAR-T cell manufacturing (estimated  13-14 days) Lymphodepleting chemotherapy: 3 days of immunosuppressive chemotherapy. Cyclophosphamide given at a dose of 300 mg/m2/IV and fludarabine given at 30 mg/m2 /IV on days -5, -4, and -3. CAR-T cell infusion (1 day): The infusion of CAR-T cells targeting CD19 will occur over 5-30 minutes. | Drug: Fludarabine<br>* Given intravenously (IV)<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Given intravenously (IV)<br>* Other names: Cycloblastin;Biological: anti-CD19 CAR-T cells<br>* Single infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with treatment-emergent adverse events (AEs) | Subjects treated with conforming product who received the target doses of anti-CD19 CAR-T infusion will be included in the analysis. Proportion of participants with treatment-emergent adverse events of CAR-T in B-cell NHL, as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0), revised Cytokine Release Syndrome (CRS) grading criteria, and American Society for Transplantation and Cellular Therapy (ASTCT) immune effector cell (IEC) -associated neurotoxicity syndrome (ICANS) Consensus Grading for Adults (for neurotoxicity grading). | From initiation of study treatment to 12 months following CAR-T infusion, approximately 15 months | 
| Proportion of participants who experience a dose-limiting toxicity (DLT) | A DLT includes AEs graded according to CTCAE version 5.0, with the exceptions of CRS and neurotoxicity, which are graded using CRS and ICANS criteria. DLTs must 1) be suspected to be secondary to CAR-T cell infusion, 2) occur during the first 30 days after infusion and 3) meet the following criteria: 1. Grade 3 or 4 non-hematologic toxicities of any duration, with following exceptions: Grade 3 laboratory abnormalities without associated symptomatology or clinical consequence that resolve in < 7 days; AEs associated with Grade <= 2 CRS; Toxicities associated with Grade 3 CRS (except cardiac or pulmonary organ toxicity) that improves to grade <= 2 within 3 days of intervention; isolated renal or hepatic grade 3 organ toxicity that does not resolve within 7 days; Laboratory abnormalities compatible with tumor lysis syndrome; Grade 4 hematological toxicity that persists at grade >= 3 despite maximum supportive care for >21 days. | From initiation of study treatment to 30 days following CAR-T infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with delayed infusion due to study-related adverse events | The proportion of participants who have their infusion delayed due to and AE will be reported. | From T-cell collection to end of infusion, approximately 18 days | 
| Table of adverse events related to collection and infusion of CAR-T cells | Frequency and severity for each adverse event of collection and infusion of CAR-T cells targeting CD19 in participants with relapsed B cell Non-Hodgkins Lymphoma | From T-cell collection to end of infusion, approximately 18 days | 
| Overall Response rates over time | Overall response rates will be reported as proportions at different time points across the study | From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months | 
| Complete Response rates over time | Complete response rates will be reported as proportions at different time points across the study | From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months | 
| Partial Response rates over time | Partial response rates will be reported as proportions at different time points across the study | From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months | 
| Duration of response | This is measured, only in responders, from the documented beginning of response (CR or PR) to the time of relapse | From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months | 
| Progression-free survival (PFS) | PFS is defined as the time from entry onto study until lymphoma progression or death from any cause at 12 months after receiving CAR-T infusion. | From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months | 
| Overall Survival | Defined as the time from entry onto study until death from any cause | Up to 15 years | 
| Proportion of subjects for whom CD19 CAR T-cell therapy is manufactured | Feasibility will be assessed by the proportion of subjects for whom the ability to produce adequate quantities of vector. | From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days | 
| Proportion of participants who complete study treatment | Feasibility will be assessed by the proportion of subjects who complete the study regimen | From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Hodgkin Lymphoma, Anti-CD19 autologous CAR-T cells