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

Inclusion Criteria

• Dose expansion Cohorts: * Cohort B (Burkitt): ** 1B. Patients must have a diagnosis of relapsed or refractory Burkitt Lymphoma *** Subjects with Burkitt lymphoma must have relapsed or failed to respond to at least 1 prior line of multiagent chemoimmunotherapy with prior exposure to both an anti-CD20 antibody agent and an anthracycline. *** No significant circulating disease, defined as an elevated total lymphocyte count above the upper limits of normal (ULN) due to the presence of malignant cells. ** Patients must have measurable disease as defined below: *** Subjects with Burkitt Lymphoma must have PET-positive disease according to “Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification” * Cohort M/W (Marginal/Waldenström): ** 1MW. Patients must have a diagnosis of relapsed or refractory Marginal Zone Lymphoma, or Lymphoplasmacytic Lymphoma (LPL)/Waldenström Macroglobulinemia (WM): *** Subjects with indolent lymphomas (nodal or extranodal marginal zone lymphoma, and lymphoplasmacytic lymphoma) must have relapsed after or have been refractory to ≥ 2 prior lines of multi-agent chemoimmunotherapy including prior exposure to an anti-CD20 antibody and an alkylating agent. ** 2MW. Subjects must have measurable disease as defined below: *** Subjects with Marginal Zone Lymphoma or Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia: must either have PET-positive disease according to “Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification” or serum monoclonal immunoglobulin M (IgM) paraprotein > 0.5 g/dL ** 3MW. Subjects with indolent lymphoma (Marginal Zone Lymphoma or Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia) must have symptomatic disease necessitating systemic treatment
• 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/uL
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Hemoglobin (Hgb) > 8 gm/dl (transfusions allowed)
• Platelets > 50,000/uL (transfusions allowed)
• Absolute neutrophil count (ANC) > 500/uL
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x institutional upper limit of normal (ULN)
• Total bilirubin =< 1.5 mg/dl x institutional ULN, except with Gilbert’s syndrome
• Serum creatinine =< 2 x the institutional ULN
• 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
• ELIGIBILITY FOR INFUSION OF INVESTIGATIONAL PRODUCT: 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
• ELIGIBILITY FOR INFUSION OF INVESTIGATIONAL PRODUCT: ECOG performance status =< 2
• ELIGIBILITY FOR INFUSION OF INVESTIGATIONAL PRODUCT: 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
• ELIGIBILITY FOR INFUSION OF INVESTIGATIONAL PRODUCT: No new neurologic symptoms suggestive of an active central nervous system condition, or uncontrolled central nervous system (CNS) involvement by lymphoma

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)
• Human immunodeficiency syndrome (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 kg
• ELIGIBILITY FOR INFUSION OF INVESTIGATIONAL PRODUCT: No corticosteroid use within 7 days prior to infusion (with exception of agents used for prevention of emesis during lymphodepletive chemotherapy)