Addition of Nivolumab to Standard of Care With Anti-CD-19 CAR-T Cells in Patients With Stable/Progressive DLBCL at Lymphodepletion
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Overall response at 1 months after CAR-T infusion
研究概览
简要总结
Progression of DLBCL is the major obstacle for the success of chimeric antigen receptor-T cell (CAR-T) with approximately 60% of the patients relapsing in the first year, and 40% within 3 months, after infusion. While patient with DLBCL in Partial Response/Complete Response at lymphodepletion have a 1-year Progression Free Survival (PFS) of 60-80%, those with Stable Disease/Progressive Disease at time of lymphodepletion have a dismal PFS of 20-30%.
Trials showed that better expansion of CAR-T cells, even in patients with a progressive disease, may overcome this grave prognosis and may result in better PFS
详细描述
Factors that may introduce resistance to CAR-T. in addition to the bulk of disease, include also expression of check point molecules that eventually interfere with the CAR-T action. The investigator, have recently shown (EBMT 2022, # LWP-03) a real-life data, that day +7 CAR-T concentration in patients with stable or progressive disease (SD/PD) at lymphodepletion segregates patients to those with high CAR-T blood concentrations that achieve a high CR/PR rate after CAR-T infusion ,those with 20-100 CAR-T cells/microL that achieve a lower CR/PR rate after CAR-T infusion, and those with <20 cells/microL that achieve the lowest CR/PR rate after infusion. Thus, the extent of CAR-T cell expansion on day 7 after treatment is a prognostic marker predicting response to treatment in this patient group. Considering all these - patients with SD/PD at time of lymphodepletion, and specifically those with lower CAR-T blood concentrations on day +7 are at a very high risk for early disease progression after CAR-T infusion and, as such, there is an urgent unmet medical need to improve their outcomes.
Addition of anti PD-1 to patients with low expansion of CAR-T cells may overcome the inhibitory effect of PD-1 expression and may result in a better function of the CAR-T and eventually tumor suppression.
Nivolumab is a human monoclonal antibody targeting (programmed death-1 ) PD-1, a negative regulatory molecule expressed by activated T and B lymphocytes. Anti PD-1 treatment has been administered as a single dose or repeated administration in different time points during CAR-T cell therapy. These studies showed that this treatment is safe, well tolerated and does not result in increased CAR-T associated toxicities, mainly cytokine release syndrome(CRS) and immune effector cell associated neurotoxicity(ICANS). The optimal time window to administer these agents for achieving safety and efficacy is not determined.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant must be at least 18 years of age inclusive, at the time of signing the informed consent.
- •DLBCL treated with CAR-T targeting CD19 (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel)
- •PD/SD by PET-CT on the day of lymphodepletion
- •Capable of giving signed informed consent
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •No active CRS or ICANS at time of nivolumab administration
排除标准
- •Hypersensitivity to checkpoints inhibitors
- •CRS grade 3 and above or ICANS any grade on days 0-5 following CAR-T
- •AST (Aspartate transaminase) or ALT (Alanine transaminase) over 3 times the upper limit of normal (ULN) or total bilirubin over 3 times ULN
- •Serum creatinine over 1.5 times ULN or over 1.5 times baseline
- •History of or active autoimmune disease
- •Uncontrolled seizure activity and/or clinically evident progressive encephalopathy
- •Active diarrhea (more than 4 bowel movements per day)
- •Clinically significant uncontrolled illness
- •Active infection requiring antibiotics
- •Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
- •Other active malignancy
- •Females only: Pregnant or breastfeeding
研究组 & 干预措施
NIVOLUMAB
All patients enrolled will be given nivolumab ( 3mg/kg IV) on day +5 Patients with CAR-T expansion<100 cells/microL on day +7 will be given 1 additional dose of nivolumab (3mg/kg IV) on day +19 (two weeks after first dose of nivolumab).
干预措施: Nivolumab Injection [Opdivo] (Drug)
结局指标
主要结局
Overall response at 1 months after CAR-T infusion
时间窗: One month post CAR-T infusion
Complete or partial remission rate assessed by PET-CT (Positron Emission Tomography ) at 1 month after combination therapy with nivolumab and CAR-T.
次要结局
- Neurotoxicity(One year post CAR-T infusion)
- Hemophagocytic lymphohistiocytosis (HLH)(One year post CAR-T infusion)
- Cytokine release syndrome(One year post CAR-T infusion)
- Overall survival at 1 year after CAR-T infusion and nivolumab(One year post CAR-T infusion)
- Duration of response(One year post CAR-T infusion)