Antigen Targeted T Cell Therapy for Relapsed/Refractory B Cell Lymphomas
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Best objective response post CAR-T infusion
研究概览
简要总结
This is a single center, open label, phase 1 lead in to determine Recommended Phase 2 Dose (RP2D), followed by a phase 2 trial to evaluate the safety and efficacy of Epo-R-CD19 CAR T with or without CD22 CAR T-cells infused into patients with B cell lymphoma.
The study will have the following parts:
- Screening
- Pre-infusion (cell product preparation and bridging) and infusion (lymphodepletion)
- Primary efficacy endpoints
- Long term follow up
Patients who have high risk B cell lymphoma or relapsed/refractory B cell lymphoma who fufil the trial inclusion and exclusion criteria will undergo leukapheresis following trial enrollment.
CAR T-cell products will then be manufactured according to the antigen expression on the patient's biopsied tumor cells. These cells will then undergo stringent testing before the patient undergoes lymphodepletion followed by CART infusion. These patients will be admitted for the infusion and closely monitored for any CRS or ICANS.
This study will have a Phase 1 safety run in for the first 3-6 patients who receive the Epo-R-CD19 CAR T (with or without epoetin (erythropoietin)) to determine the tolerability and safety of this product. For the first 3-6 patients, if there are any DLT seen by Day 28, a data safety monitoring committee will be convened to assess the trial. Staggered dosing will be implemented for the first 2 participants in every dose level (DL1, DL2 and DL-1).
For Phase 2, the RP2D will depend on DLT. If there is no DLT at DL+1 and DL+2, then the investigators will proceed with DL+2 as the RP2D dose. On the other hand, if there is DLT despite DL-1, then the study will be redesigned. Phase 2 will continue until a total of 20 patients received their CAR T-cell infusions.
CAR-T monitoring will be performed at Day 0, 7, 14, 21, 28, month 2, 3, 4, 5, 6, 12 and yearly thereafter. The total duration of the study is 15 years from CAR T infusion.
详细描述
2.1 Hypothesis
- The infusion of CD19 with or without CD 22 targeted CAR T-cells in patients with high risk or R/R BCL will improve the overall response rates and survival outcomes. The choice of antigen target is determined by detailed flow cytometric profiling of biopsied lymphoma cells if possible.
- The co-expression of Epo-R in our CD19 CAR T-cells will allow endogenous or exogenous Epo levels to support survival and expansion of infused T cells, thus overcoming the issue of suboptimal T-cell expansion and persistence due to prior chemotherapies in patients with high risk or R/R DLBCL.
2.2 Objectives for Phase 1:
Primary objective of Phase 1 lead in is to determine safety, as defined by incidence of dose limiting toxicities (DLT) associated to the Epo-R-CD19 CAR and CD22 pooled products, as well as determination of the RP2D of the Epo-R-CD19
The secondary objective is to assess efficacy of the Epo-R-CD19 CAR as defined by:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 10 Years 至 80 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 10 to 80 years at screening
- •PET-CT measurable disease by Lugano classification (Deauville score of ≥4) and
- •Tissue biopsy of any tumour site and flow cytometry study of CD19 and CD22 expression.
- •Relapsed B-cell lymphoma after one line of systemic therapy or autologous bone marrow transplant. This includes DLBCL, PMBCL, HGBCL, DLBCL arising from indolent lymphoma, Burkitt's lymphoma/leukemia, Mantle cell lymphoma.
- •High risk B-cell lymphoma (BCL). High risk BCL is defined by any of the criteria below:
- •High-risk genetics - double/triple hit or p53mut or deletion.
- •IPI score ≥ 3
- •Richter's transformation from chronic lymphocytic leukaemia.
- •Disease refractory to treatment - PET-CT positive disease after 2 courses of rituximab-containing chemoimmunotherapy.
- •PBMC product available
- •Karnofsky or Lansky score >
- •Or ECOG 0-2
- •Patient expected survival is more than 3 months to allow for manufacture and release of CAR T-cells.
排除标准
- •Patients who test positive on urine or blood pregnancy testing and are pregnant or are lactating.
- •Participant of reproducible age who refuse the use of the following birth control methods if engaging in sexual activity that could lead to pregnancy. The methods include condoms, diaphragm, intrauterine device, hormonal based contraception.
- •Concomitant genetic syndromes associated with BM failure states, such as Fanconi anaemia, Kostmann syndrome, Schwachman syndrome, or any other BM failure syndrome with the exception of Down syndrome.
- •Active hepatitis B or hepatitis C within 3 months of screening.
- •Active HIV infection within 3 months of screening.
- •Grade 2 to 4 graft-vs-host disease (GVHD).
- •Received an investigational medicinal product within 1 month of screening.
- •If the total sum of CD19 and CD22 antigens expressed is less than 95.0%, patients will not be eligible. If subsequent immunophenotying of the patient's sample confirms that total sum of CD19 and CD22 antigens ≥ 95%, the patient may be rescreened.
- •Central nervous system: Uncontrolled seizures or status epilepticus; decreased conscious state (any cause)
- •Foreign patients who cannot commit to agreeable to stay in Singapore for at least 3 months post CAR T infusion and are committed to the long term monitoring post CAR T at home and in Singapore.
- •Prior treatment with any CAR T cell therapy (approved or investigational)
研究组 & 干预措施
CAR T-cells
The CAR T-cells used in this clinical trial are autologous T cells that have been cultured ex vivo and transduced with a retroviral vector delivering a gene encoding a CAR, as described in the accompanying Chemistry, Manufacturing and Controls (CMC) document.
Each infusion bag will have affixed to it a label containing the following: product identifier, product name and volume. In addition, the label will also have at least 2 unique identifiers such as name of patient, patient's alphanumeric identifier and birth date, according to applicable regulations. Prior to infusion, 2 individuals will verify all information and confirm the identity to ensure that the information is correctly matched to the patient and that the patient receives only their autologous product. This is done according to local institutional guidelines.
干预措施: CART infusion (Other)
结局指标
主要结局
Best objective response post CAR-T infusion
时间窗: 6 months
Best objective response will be assessed using standardised lymphoma response criteria at regular intervals up to 6 months post CAR-T infusion.
次要结局
未报告次要终点