A Clinical Study to Evaluate the Safety and Efficacy of BCMA-GPRC5D CAR-T in Patients With R/R MM Who Received Three or More Lines of Therapy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-related Adverse Events
研究概览
简要总结
This is a single-center, open-label, single-arm study to evaluate the safety and efficacy of bispecific BCMA-GPRC5D Chimeric antigen receptor (CAR) T-cells in patients with relapsed or refractory multiple myeloma who received three or more lines of therapy.
详细描述
B-cell maturation antigen (BCMA)-targeted Chimeric antigen receptor (CAR) T-cell therapy has yielded satisfactory clinical outcomes in patients with relapsed or refractory (R/R) multiple myeloma (MM). However, BCMA-targeted CAR-T cells cannot achieve a favorable response in patients with dim or negative BCMA expression on the tumor surface at baseline or relapse. G protein-coupled receptor, class C, group 5, member D (GPRC5D) is highly distributed on MM cells and proves to be a promising target for MM. In normal tissues, it is restrictedly expressed in hair follicle, rendering it a safe target for CAR-T cell therapy as well. To construct a bispecific BCMA-GPRC5D CAR structure would help mitigate the antigen escape and elevates the clinical efficacy.
This is an investigational study. The objectives are to evaluate the safety and efficacy of BCMA-GPRC5D CAR-T cells in adult patients with relapsed or refractory MM disease.
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient or his or her legal guardian voluntarily participates in and signs an informed consent form;
- •Aged ≥ 18 years and ≤ 75 years;
- •Diagnosed as Multiple Myeloma (MM) according to the international standard for multiple myeloma (IMWG);
- •The presence of measurable disease at screening meets one of the following criteria:Serum M-protein ≥ 1.0 g/dL or Urine M-protein ≥ 200 mg/24h or diagnosed as Light-chain MM without measurable disease in serum and urine; Serum free light chain ≥ 10 mg/dL with an abnormal κ/λ ratio;
- •Patients must relapse or be refractory after three or more lines of therapy, which at least include: one Proteasome Inhibitor (PI), one Immunomodulatory Drug (IMiD), and one anti-CD38 monoclonal antibody;
- •diagnosed as relapsed/refractory disease or primary refractory disease;
- •The last treatment is ineffective, or the disease progresses within 60 days after the end of the last therapy;
- •Patients must recover from the toxicity of the last therapy (< grade 2 by CTCAE criteria);
- •ECOG score 1-2 points and the expected survival period ≥ 3 months;
- •Liver, kidney and cardiopulmonary functions meet the following requirements:
- •Total bilirubin ≤ 1.5×ULN, alanine aminotransferase (ALT) ≤ 3 × ULN and aspartate aminotransferase (AST) ≤ 3 × ULN;
- •Serum creatinine ≤ 1.5×ULN, or creatinine clearance ≥ 60 mL/min;
- •Hemoglobin (Hb) ≥ 50 g/L without prior blood transfusion within 7 days;
- •Baseline peripheral oxygen saturation > 92%;
- •Corrected serum calcium ≤ 12.5 mg/dL (≤ 3.1 mmol/L) or free (ionized, ionic) calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L);
- •Left ventricular ejection fraction (LVEF) > 45%, without confirmed pericardiac effusion and abnormal electrocardiography with clinical significance;
- •Without clinically significant pleural effusion;
- •Venous access could be established; without contraindications of apheresis.
排除标准
- •Previous diagnosis and treatment of other malignancies within 3 years;
- •Patients received previous anti-tumor therapies before apheresis including following therapies: targeted therapies, epigenetics modulation drugs, other drugs or medical devices (invasive) of clinical trials, monoclonal antibodies, cytotoxic agents, PIs, IMiDs, radiotherapy;
- •Central Nervous System (CNS) involvement;
- •Patients with Fahrenheit macroglobulinemia, POEMS syndrome, or primary AL, amyloidosis;
- •Subjects with positive HBsAg or HBcAb positive and peripheral blood HBV DNA titer is higher than the lower limit of detection of the research institution; HCV antibody positive; HIV antibody positive; CMV DNA titer is higher than the lower limit of detection of the research institution; EBV DNA titer is higher than the lower limit of detection of the research institution;
- •Patients have a severe allergic history;
- •Patiens have severe systemic diseases or poor cardiovascular, liver, kidney functions;
- •Acute or chronic graft versus host disease (GvHD) occurs within 6 months before the screening or needs be treated with immunosuppressive agents;
- •Active autoimmune or inflammatory diseases of the nervous system;
- •Patients develop oncology emergencies and need to be treated before screening or infusion;
- •Uncontrolled infections that need antibiotics treatment;
- •Exposure to hematopoietic growth factor of cells within 1-2 weeks before apheresis;
- •Exposure to Corticosteriods or immunosuppressive agents within 2 weeks before apheresis;
- •Patients receive a major surgical operation within 4 weeks before lymphodepletion or do not recover completely before the enrollment; or plan to receive a major surgical operation during the study period;
- •Live attenuated vaccine within 4 weeks before screening;
- •Patients with severe mental illness;
- •Patients are addcited to alcohol or drugs;
- •Pregnant or Lactating Women; Patients and his or her spouse have a fertility plan within two years after CAR-T cell infusion;
- •Other conditions considered inappropriate by the researcher.
研究组 & 干预措施
Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells
Patients will receive lymphodepletion chemotherapy with fludarabine (30 mg/m2 body surface area) plus cyclophosphamide (300 mg/m2 body surface area) for 3 consecutive days during D-7 to D-3, followed by the infusion of BCMA-GPRC5D CAR-T cells at a single dose of 4.0×10^6/kg ± 50%/kg for one day.
干预措施: Fludarabine + Cyclophosphamide + BCMA-GPRC5D CAR-T Cells (Drug)
结局指标
主要结局
Incidence of Treatment-related Adverse Events
时间窗: within 2 years after infusion
Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome are graded by American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0)
次要结局
- Pharmacokinetics and pharmacodynamics - Cmax(within 2 years after infusion)
- Pharmacokinetics and pharmacodynamics - Tmax(within 2 years after infusion)
- Pharmacokinetics and pharmacodynamics - AUC 0-28d(within 2 years after infusion)
- Pharmacokinetics and pharmacodynamics - AUC 0-90d(within 2 years after infusion)
- Pharmacokinetics and pharmacodynamics - AUC 0-inf(within 2 years after infusion)
- Pharmacokinetics and pharmacodynamics - AUC 0-t1/2(within 2 years after infusion)
- Clinical efficacy of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma(within 2 years after infusion)
- Overall response rate (ORR) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma.(within 2 years after infusion)
- Clinical benefit rate(within 2 years after infusion)
- Duration of Response (DoR) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma.(within 2 years after infusion)
- Progress-free survival (PFS) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma.(within 2 years after infusion)
- Overall survival (OS) of administering BCMA-GPRC5D CAR-T cells in Relapsed/Refractory multiple myeloma.(within 2 years after infusion)
- Antigen expression in tumor cells at different time points(within 2 years after infusion)
- Minimal Residual Disease (MRD)(within 2 years after infusion)
研究者
MEI HENG
Proferssor, Cheif Doctor
Wuhan Union Hospital, China