A Phase 1 Clinical Trial of Anti-CD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma
概览
- 阶段
- 1 期
- 干预措施
- Fludarabine
- 疾病 / 适应症
- 未指定
- 发起方
- C. Babis Andreadis
- 入组人数
- 36
- 试验地点
- 2
- 主要终点
- Proportion of participants with treatment-emergent adverse events (AEs)
- 状态
- 招募中
- 最后更新
- 3个月前
概览
简要总结
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).
详细描述
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.
研究者
C. Babis Andreadis
Professor of Clinical Medicine
University of California, San Francisco
入排标准
入选标准
- •THE DOSE ESCALATION COHORT IS CLOSED TO FURTHER ENROLLMENT.
- •Inclusion Criteria:
- •Dose expansion Cohorts:
- •Cohort B (Burkitt):
- •Participants must have a diagnosis of relapsed or refractory Burkitt Lymphoma
- •Participants 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 limit of normal (ULN) due to the presence of malignant cells.
- •Participants must have measurable disease as defined below:
- •Participants with Burkitt Lymphoma must have 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"
- •Cohort M/W (Marginal/Waldenström):
排除标准
- •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 virus (HIV) seropositivity.
- •Serologic status reflecting active hepatitis B or C infection. Participants 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 participants will be excluded.)
- •Participants 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.
- •Participants 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).
研究组 & 干预措施
Dose Expansion: Burkitt, Marginal Zone, or Waldenström Macroglobulinemia ONLY (CAR-T Therapy)
Participants with Burkitt lymphoma, or Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM) will undergo Apheresis (1 day) to collect autologous lymphocytes/ mononuclear cells as per University of California, San Francisco (UCSF) institutional practices. CAR-T cell manufacturing (estimated \~13-14 days), during which participants will receive a lymphodepleting regimen of immunosuppressive chemotherapy (Cyclophosphamide 300 mg/m2/IV and fludarabine 30 mg/m2 /IV) followed by the infusion of the maximum tolerated dose of CAR-T cells established in the dose escalation phase, targeting CD19 over 5-30 minutes. Participants will be followed up 30 days after infusion, for up to 12 months, if the participant in continued remission, and for survival up to 15 years.
干预措施: Fludarabine
Dose Expansion: Burkitt, Marginal Zone, or Waldenström Macroglobulinemia ONLY (CAR-T Therapy)
Participants with Burkitt lymphoma, or Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM) will undergo Apheresis (1 day) to collect autologous lymphocytes/ mononuclear cells as per University of California, San Francisco (UCSF) institutional practices. CAR-T cell manufacturing (estimated \~13-14 days), during which participants will receive a lymphodepleting regimen of immunosuppressive chemotherapy (Cyclophosphamide 300 mg/m2/IV and fludarabine 30 mg/m2 /IV) followed by the infusion of the maximum tolerated dose of CAR-T cells established in the dose escalation phase, targeting CD19 over 5-30 minutes. Participants will be followed up 30 days after infusion, for up to 12 months, if the participant in continued remission, and for survival up to 15 years.
干预措施: Cyclophosphamide
Dose Expansion: Burkitt, Marginal Zone, or Waldenström Macroglobulinemia ONLY (CAR-T Therapy)
Participants with Burkitt lymphoma, or Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM) will undergo Apheresis (1 day) to collect autologous lymphocytes/ mononuclear cells as per University of California, San Francisco (UCSF) institutional practices. CAR-T cell manufacturing (estimated \~13-14 days), during which participants will receive a lymphodepleting regimen of immunosuppressive chemotherapy (Cyclophosphamide 300 mg/m2/IV and fludarabine 30 mg/m2 /IV) followed by the infusion of the maximum tolerated dose of CAR-T cells established in the dose escalation phase, targeting CD19 over 5-30 minutes. Participants will be followed up 30 days after infusion, for up to 12 months, if the participant in continued remission, and for survival up to 15 years.
干预措施: anti-CD19 CAR-T cells
CLOSED TO ENROLLMENT: Dose escalation (CART-T Therapy)
Participants will undergo Apheresis (1 day) to collect autologous lymphocytes/ mononuclear cells as per University of California, San Francisco (UCSF) institutional practices. CAR-T cell manufacturing (estimated \~13-14 days), during which participants will receive a lymphodepleting regimen of immunosuppressive chemotherapy (Cyclophosphamide 300 mg/m2/IV and fludarabine 30 mg/m2 /IV) followed by the infusion of CAR-T cells at an initial dose of 5 x 10\^5 cells/kg, targeting CD19 over 5-30 minutes. Participants will be followed up 30 days after infusion, for up to 12 months, if the participant in continued remission, and for survival up to 15 years.
结局指标
主要结局
Proportion of participants with treatment-emergent adverse events (AEs)
时间窗: From initiation of study treatment to 12 months following CAR-T infusion, approximately 15 months
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).
Proportion of participants who experience a dose-limiting toxicity (DLT) (Dose escalation)
时间窗: From initiation of study treatment to 30 days following CAR-T infusion
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.
次要结局
- Proportion of participants with CAR-T infusion related adverse events (Dose Escalation)(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(From T-cell collection to end of infusion, approximately 18 days)
- Complete Response Rate(From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months)
- Median duration of response(From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months)
- Overall Response Rate (ORR)(From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months)
- Median Overall Survival(Up to 15 years)
- Partial Response Rate(From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months)
- Median Progression-free Survival (PFS)(From initiation of study treatment to 12 months after getting CAR-T infusion, approximately 15 months)
- Proportion of participants for whom CD19 CAR T-cell therapy is manufactured(From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days)
- Proportion of participants who complete study treatment(From initiation of CD19 CAR T-cell manufacturing to end of infusion, approximately 18 days)