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).
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. PRIMARY OBJECTIVES 1. To evaluate the safety of administering chimeric antigen receptor T cells targeting CD-19 to patients with relapsed or refractory CD19+ B-cell non-Hodgkin lymphoma (NHL). 2. To determine the recommended phase 2 dose (RP2D) for this cellular therapy. SECONDARY OBJECTIVES 1. 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. 2. To describe the efficacy of chimeric antigen receptor T cells targeting CD-19 in patients with relapsed or refractory CD19+ B cell NHL. 3. 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 Participants will be enrolled to either the dose escalation or dose expansion cohorts. Dose Escalation: CLOSED TO ENROLLMENT Dose Expansion: The dose expansion phase of the study will be limited to two disease-specific cohorts: * Cohort B: Participants with Burkitt lymphoma (B). * Cohort M/W: Participants with Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM). Participants will receive an infusion of Anti-CD19 CAR-T cells during the main study and will be followed for 12 months before being transferred into long term follow-up during years 1 to 15.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Given intravenously (IV)
Given intravenously (IV)
Single infusion
University of California, San Francisco
San Francisco, California, United States
RECRUITINGProportion of participants with treatment-emergent adverse events (AEs)
Participants 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).
Time frame: 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) (Dose escalation)
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.
Time frame: From initiation of study treatment to 30 days following CAR-T infusion
Proportion of participants with CAR-T infusion related adverse events (Dose Escalation)
The proportion of participants with adverse events related to the collection and infusion of CAR-T cells targeting CD19 will be reported.
Time frame: From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days
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.
Time frame: From T-cell collection to end of infusion, approximately 18 days
Overall Response Rate (ORR)
Overall response rates will be reported as proportions of participants by arm. The 2014 Lugano Response for Malignant Lymphoma criteria will be to determine response: Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Relapse and Progression (PD). For the Waldenstrom's Macroglobulinemia cohort, the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) response criteria will be used to determine response: CR, very good partial response (VGPR), PR, minor response (MR), SD, and PD.
Time frame: From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Complete Response Rate
Complete response rates will be reported as will be reported as proportions of participants by arm.
Time frame: From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Partial Response Rate
Partial response rates will be reported as will be reported as proportions of participants by arm.
Time frame: From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Median duration of response
For participants who have been documented to be responders under the 2014 Lugano criteria or the IWWM-11 criteria, and defined as the median time from the documented beginning of response (CR or PR) to the time of relapse.
Time frame: From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Median Progression-free Survival (PFS)
PFS is defined as the median time from entry onto study until a diagnosis of lymphoma progression or death from any cause at 12 months after receiving CAR-T infusion.
Time frame: From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months
Median Overall Survival
Defined as the median time from entry onto study until death from any cause
Time frame: Up to 15 years
Proportion of participants for whom CD19 CAR T-cell therapy is manufactured
The proportion of participants for whom CD19 CAR T-cell therapy is adequately manufactured and meets pre-specified release criteria.
Time frame: 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 participants who are able to complete the study regimen and receive infusion of CAR-T therapy.
Time frame: From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days
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