NCT04844086终止1 期
Infusion of CD19-Specific Chimeric Antigen Receptor T-cells Produced by Rapid Personalized Manufacture for Patients With Advanced Lymphoid Malignancies
适应症
干预措施
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Maximun Tolerated Dose (MTD) of the RPM CD19- mbIL15-CAR-T
研究概览
简要总结
This is an open-label Phase 1 study to determine the feasibility, safety, and the recommended maximum tolerated Dose (MTD) of a single infusion of RPM CD19 mbIL15 CAR-T cells for adult patients. Approximately 24 subjects will be enrolled and it is anticipated approximately 16 subjects will be infused at the varied doses of T cells.
详细描述
This is an open-label Phase 1 study to determine the feasibility, safety, and the recommended maximum tolerated Dose (MTD) of a single infusion of RPM CD19 mbIL15 CAR-T cells for adult patients. Approximately 24 subjects will be enrolled and it is anticipated approximately 16 subjects will be infused at the varied doses of T cells.
This study will very rapidly administer T cells that are genetically modified by electroporation using DNA plasmids from the SB system to co-express CD19RCD8CD28 (the CAR), mbIL15, and HER1t. The presence of mbIL15 may allow for reduced doses of CAR-T cells to be infused to reduce the risk for adverse events, such as cytokine release syndrome (CRS).
The key features of study design are listed below.
- Uncontrolled
- Blinding: open-label
- Randomized: no
- Duration of treatment: single infusion within day
- Titration: none
- Single center, Taiwan
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
- 20 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •for Enrollment:
- •A subject may participate in the study if all the following criteria is met:
- •Patients with CD19+ malignancies that are refractory to or relapsed after current standard treatment (including allogeneic or autologous HSCT) and not suitable for other treatment options, such as second-time HSCT. CD19+ malignancies include:
- •Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia (ALL):
- •Refractory ALL is defined as failure to achieve CR at the end of induction.
- •Relapsed ALL is defined as reappearance of blasts in the blood or bone marrow (≥ 5%) or in any extramedullary site after a CR.
- •Relapsed/Refractory B-cell originated Non-Hodgkin Lymphoma (NHL) including 1) de-novo diffuse large B-cell lymphoma or primary mediastinal large B-cell lymphoma, 2) large-B cell lymphoma transformed from indolent lymphomas, 3) follicular lymphoma of all grades, 4) mantle cell lymphoma, and 5) CD20(+) high-grade B-cell lymphomas. Refractory disease for lymphoma is defined as:
- •Progressive disease or stable disease lasting < 6 months, as best response to most recent chemotherapy regimen; or disease progression or recurrence < 12 months after prior autologous HSCT.
- •Prior therapy must have included an anti-CD20 monoclonal antibody-containing regimen and an anthracycline-containing chemotherapy regimen
- •For patients with transformed follicular lymphoma (TFL), prior chemotherapy for follicular lymphoma and subsequent refractory disease after transformation to DLBCL.
- •At least one measurable lesion, demonstrating that the nodal lesion is ≥ 1.5 cm in the longest diameter or the extranodal lesion is ≥ 1.0 cm in the longest diameter, according to the Lugano Classification (2014).
- •Patients must have received at least 2 prior lines of therapy. HSCT (allogeneic or autologous) can be accounted as one of the prior line therapy, and the subjects must have been at least 3 months from prior HSCT.
- •Karnofsky Performance Scale ≥ 60
- •Patient able to provide written informed consent for participating in the study
- •Age ≥ 20 years and ≤ 75 years old at the time of providing informed consent
- •Patients shall be at least 3 weeks from the last cytotoxic chemotherapy before apheresis. Short-acting targeted therapies (e.g., tyrosine kinase inhibitors) must be stopped > 72 hours before apheresis.
- •Monoclonal antibody use including Anti-CD20 therapy has been discontinued at least 4 weeks before leukapheresis and CAR-T cells infusion except for systemic inhibitory/stimulatory immune checkpoint therapy. Immune checkpoint therapy has been discontinued at least 3 half-lives before leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4-1BB agonists, etc.).
- •Absolute lymphocyte count (ALC) ≥ 1.0x109/L and absolute number of CD3+ T cells (ATC) ≥ 0.3x109/L, absolute neutrophil count (ANC) ≥ 1.0 x109/L for lymphoma and ANC ≥ 0.5 x109/L for ALL, platelets ≥ 50.0 x109/L, hemoglobin ≥ 80.0 g/L within 7 days before apheresis.
- •Adequate organ function demonstrated by the following:
- •Renal: serum creatinine <2 x upper limit of normal (ULN)
- •Hepatic: ALT/AST ≤ 2.5 x ULN or ≤ 5 x ULN if documented liver metastases, total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert's Syndrome in whom total bilirubin must be ≤ 3.0 mg/dL.
- •Cardiac: no clinically significant ECG findings, hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram
- •Pulmonary: baseline oxygen saturation > 90% on room air
- •Not receiving anti-thymocyte globulin (ATG), alemtuzumab, or other T-cell immunosuppressive antibodies, donor-lymphocyte infusion or T-cell infusion for the past 3 weeks before apheresis;
- •Negative serology for Anti-HTLV-I / HTLV-II (DHTLV I/II)
排除标准
- •for Enrollment
- •A subject who met any of the following criteria is not eligible to enter the study:
- •Received previous treatment with anti-CD19 therapy;
- •Is with a history of CNS malignancy and/or active CNS diseases;
- •Has previous or concurrent malignancies other than CD19+ malignancies;
- •Has active neurological, autoimmune, or inflammatory disorders;
- •Has clinically significant cardiac diseases, or cardiac arrhythmia not controlled with medical treatment;
- •Has cardiac involvement with lymphoma;
- •Has any active infections, conditions, and diseases that may interfere with the assessment of safety and efficacy of the study deemed by the investigator or designee;
- •Received live vaccine within 6 weeks of the screening
- •Received radiation therapy within 2 weeks of the planned CAR-T cells infusion;
- •Is with positive serology for HIV;
- •Is with positive hepatitis B or hepatitis C infection, defined as positive HBs Ag or positive Anti-HCV Ab;
- •Active graft versus host disease (GVHD) ≥ grade 2 using the CIBMTR Acute GVHD Grading System or requiring systemic steroid therapy greater than physiologic dosing; Note: Overall grading of GVHD is based on the criteria published by Przepiorka et al., Bone Marrow Transplant 1995; 15(6):825-8, see the GVHD Grading and Staging table at CIBMTR Forms Instruction Manual (Last updated: 2020/03/10), page 301-303 (Available at https://www.cibmtr.org/manuals/fim, accessed on 08 Apr 2020).
- •Use of investigational medicinal product within 30 days before the screening;
- •Positive beta HCG in female of child-bearing potential (defined as not post-menopausal for 12 months) or history of previous surgical sterilization or lactating females.
- •Patients with known allergy to mouse products or cetuximab.
- •Inclusion Criteria for Lymphodepletion and T-Cell Infusion:
- •Prior to Lymphodepletion (LD):
- •Patients must have no evidence of clinically significant infection;
- •No acute neurological toxicity >grade 1 (with the exception of peripheral sensory neuropathy) prior to conditioning chemotherapy;
- •No clinically significant cardiac dysfunction;
- •Serum creatinine < 2x ULN;
- •No evidence of grade ≥2 acute GVHD;
- •Pulmonary: oxygen saturation > 90% on room air;
- •Adequacy of T cells apheresis products to manufacture CAR-T product.
- •Prior to CAR-T cells infusion:
- •Patients shall be at least 4 weeks from the last cytotoxic chemotherapy (excluding the study mandated lymphodepleting chemotherapy) before infusion. Short-acting targeted therapies (e.g., tyrosine kinase inhibitors) must be stopped > 72 hours before infusion.
- •At least 4 weeks from anti-thymocyte globulin (ATG), alemtuzumab, or other T-cell immunosuppressive antibodies, donor-lymphocyte infusion or T-cell infusion;
- •Steroids, if given as GVHD therapy, must be stopped >72 hours prior to infusion. However, the following physiological replacement doses of steroids are allowed: < 6-12 mg/m2/day hydrocortisone or equivalent.
- •Non-hematologic toxicity grade ≥2 (CTCAE version 5) related to the lymphodepleting chemotherapy until the toxicity has resolved to grade ≤1 and the subject is afebrile;
- •No grade >2 neurologic, pulmonary, cardiac, gastrointestinal, renal, or hepatic (excluding albumin) toxicity;
- •Adequacy of the CAR-T cells for infusion.
- •Exclusion Criteria For Lymphodepletion and T-Cell Infusion:
- •A subject who meets any of the following criteria should not undergo LD or infusion of CAR-T cells.
- •New onset of cardiac arrhythmia not uncontrolled with medications;
- •Hypotension warrants the use of vasopressor;
- •Active infections within 1 week prior to CAR-T infusion that necessitate the use of oral or intravenous anti-infective treatments; subjects with ongoing use of prophylactic antibiotics, antifungals, or antivirals are eligible as long as there is no evidence of active infection.
- •Presence of CNS or neurological abnormalities;
- •Received HSCT after screening or planned to receive HSCT during the study period;
- •Any conditions not suitable for the CAR-T cells infusion in the PI or designee's judgement.
研究组 & 干预措施
Infusion RPM CD19-mbIL15-CAR-T cell
Experimental
In this study, anti-CD19 autologous chimeric antigen receptor T-cells infusion produced by rapid personalized manufacture are used to treat patients with relapsed/refractory Advanced Lymphoid Malignancies.
Route of administration: Intravenous injection.
Lymphodepletion conditioning:
Lymphodepletion will be conducted several days prior to RPM CD19-mbIL15-CAR-T cell infusion.
A combination of fludarabine and cyclophosphamide will be used for lymphodepletion.
干预措施: RPM CD19-mbIL15-CAR-T cells (Biological)
结局指标
主要结局
Maximun Tolerated Dose (MTD) of the RPM CD19- mbIL15-CAR-T
时间窗: within 4 weeks after infusion
MTD is the highest dose at which no more than 1 of 6 patients experiences a dose limiting toxicity.
次要结局
- Feasibility of the product manufacturing process(day 0 to month 12)
- Adverse events related to treatment(day 0 to month 12)
- Persistence of infused T cells(day 0 to month 12)
- Safety Switch Function(day 0 to month 12)
- Immunogenicity(day 0 to month 12)
- Cytokine Profile(day 0 to month 12)
- Homing ability of the infused T-cells(day 0 to month 12)
- Disease response after T cell infusion(day 0 to month 12)
- Progression-Free Survival(day 0 to month 12)
- Overall Survival(day 0 to month 12)
- Emergence of CD19neg malignant B cells(day 0 to month 12)
研究者
研究点 (1)
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