NCT04486872Unknown1 期
A Single-arm, Open-label, Dose Escalation Study to Explore Safety, Efficacy and Pharmacokinetics of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells in Adult Patients With Relapsed or Refractory Diffuse Large B Cell Lymphoma
First Affiliated Hospital of Zhejiang University1 个研究点 分布在 1 个国家目标入组 18 人开始时间: 2020年7月25日最近更新:
适应症
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- The types and Incidence of adverse events
研究概览
简要总结
This is a single-arm, open-label, dose escalation, phase I study, aiming to evaluate the safety and efficacy of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific Chimeric Antigen Receptor (CAR) T-cells in patient with relapsed or refractory diffuse B cell lymphoma.
详细描述
CD19 CAR-T cell therapy has made breakthroughs in the treatment of B cell lymphoma and leukemia, but 30% of patients still have antigen escape, which may be related to variants in tumor cells and the expansion of CD19-negative tumor cells after treatment with CD19 CAR-T cells. CD19/CD20 bispecific CAR-T cell targeting multiple antigens can attack tumor cells while overcoming tumor antigen escape caused by a single target, maximizing efficacy and duration of treatment, and can also solve the problem of uneven distribution or low expression of single target on the tumor surface.
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
- •The subject or her/his legally guardian(s) must sign the informed consent form approved by the Institutional Ethics Committee (IEC) prior to any screening procedures;
- •Subjects aged 18 years or older with relapsed or refractory DLBCL (including primary mediastinal large B-cell lymphoma and transformed follicular lymphoma), of which refractory is defined as:
- •Have no response to the recent treatment including:
- •The best response to the treatment regimen is progressive disease (PD) ,or;
- •stable disease(SD) which maintained less than 6 months after the last treatment, or;
- •not suitable for autologous hematopoietic stem cell transplantation (ASCT), or ASCT refractory, including:
- •progressive disease after ASCT or relapse within 12 months (relapse must be confirmed by biopsy), or;
- •If remedial treatment is given after ASCT, the subject must have no response or relapse after the last treatment.
- •Subjects who have previously received ≥2 lines treatment, and at least including:
- •Anti-CD20 monoclonal antibody(rituximab), unless the CD20 negative;
- •A chemotherapy regimen containing anthracyclines;
- •The DLBCL patients who transformed from follicular lymphoma must have previously received chemotherapy for follicular lymphoma and have developed chemotherapy-refractory diseases after transform to DLBCL.
- •Confirmation for either CD19 or CD20 positivity using immunohistochemistry or flow cytometry(accepting the previous results from the a third-level grade A hospitals before the collection of peripheral blood mononuclear cells or peripheral blood. For CD20 positive only, the investigator needs to determine whether the treatment benefit);
- •According to the preliminary assessment of Hodgkin's lymphoma and non-Hodgkin's lymphoma, staging and response assessment recommendations (2014 version), there is at least one measurable lesion at baseline;
- •If the subject has received a single target in the past, such as CD19-CAR cell therapy, it must be confirmed that the disease has progressed or relapsed after treatment and is at least 1 month from the planned single collection period
- •Life expectancy ≥12 weeks;
- •Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening;
- •Adequate organ function:
- •Renal function defined as:
- •A serum creatinine of ≤1.5 × Upper Limit of Normal(ULN), or;
- •Estimated Glomerular Filtration Rate (eGFR) ≥60 ml/min/1.73m2；[eGFR=186×（age）-0.203×SCr-1.154（mg/dl）， female ×0.742 on the basis of the calculation results]；
- •Liver function defined as:
- •Alanine aminotransferase (ALT)≤ 5 × Upper Limit of Normal(ULN) for age, and;
- •Total bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN.
- •Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and blood oxygen saturation > 91% on room air;
- •Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA);
- •Adequate bone marrow reserve without transfusions defined as:
- •Absolute neutrophil count (ANC) >1×10^9 /L；
- •Absolute lymphocyte count (ALC) ≥0.3×10^9 /L；
- •Platelets ≥50×10^9 /L;
- •Hemoglobin > 8.0 g/dl;
- •Subjects who use the following drugs should meet the following criteria:
- •Steroids: Therapeutic doses of steroids must be stopped 2 weeks prior to A-02 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 - 12 mg/m2/day hydrocortisone or equivalent;
- •Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks prior to sign the informed consent form;
- •Anti-proliferative therapy other than pretreatment chemotherapy within 2 weeks of A-02 infusion;
- •CD20 antibody-related treatment must be discontinued within 4 weeks of A-02 infusion or 5 half-lives (whichever is longer);
- •CNS disease prophylaxis must be stopped > 1 week prior to A-02 infusion (e.g. intrathecal methotrexate);
- •The investigator judged that the subject recovered from the toxicity of the previous anti-tumor treatment to grade 1 or below (except for special grade 2 or below toxicity that cannot be recovered in a short period of time, such as hair loss), suitable for pretreatment. Chemotherapy and treatment of CAR-T cells;
- •Women of child-bearing potential and all male subjects must agree to use highly effective methods of contraception for at least 12 months following A-02 infusion and until CAR-T cells are no longer present by Polymerase chain reaction(PCR) on two consecutive tests.
排除标准
- •Subjects who meet any of the following criteria will not be enrolled:
- •Subjects who have received any CD19/CD20 dual-target cell therapy products before signing the informed consent form;
- •Subjects with detectable cerebrospinal fluid malignant cells or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma;
- •Subjects with current or previous history of central nervous system disease, such as seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the central nervous system;
- •Subjects who have previously received allogeneic hematopoietic stem cell transplantation (HSCT); or suitable and consenting to Autologous hematopoietic stem cell transplantation (ASCT);
- •Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of A-02 infusion;
- •Investigational medicinal product within the last 30 days prior to sign the informed consent form;
- •Subjects with active hepatitis B（defined as hepatitis B surface antigen positive, or hepatitis B core antibody positive with hepatitis B virus DNA detection value > 1000 copies/ml）or hepatitis C(HCV RNA positive);
- •Subjects positive for HIV antibody or treponema pallidum antibody;
- •Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to A-02 infusion);
- •Unstable angina and/or myocardial infarction within 6 months prior to sign the informed consent form;
- •Previous or concurrent malignancy with the following exceptions:
- •Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to sign the informed consent form);
- •In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to sign the informed consent form;
- •A primary malignancy which has been completely resected and in complete remission for ≥ 5 years;
- •Pregnant or nursing women (women of childbearing age were tested positive for pregnancy during screening period);
- •Subjects with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis);
- •Other conditions that the investigator thinks he/she should not be included in this clinical trial, such as poor compliance.
结局指标
主要结局
The types and Incidence of adverse events
时间窗: Up to 12 months
Adverse events at each visit with the NCI CTCAE v5.0 used as a guide for the grading of severity.
次要结局
- Duration of overall response(Up to 12 months)
- Objective response rate(Up to 12 months)
- Duration of response(Up to 12 months)
- Overall survival(Up to 12 months)
- Progression-free survival(Up to 12 months)
研究者
shentu jianzhong
Prof
First Affiliated Hospital of Zhejiang University
研究点 (1)
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