Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma
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UNC Lineberger Comprehensive Cancer Center
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| 追踪信息 | |||
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| 首次提交日期 ICMJE | October 3, 2018 | ||
| 首次发布日期e ICMJE | October 5, 2018 | ||
| 最后更新发布日期 | October 5, 2018 | ||
| 预计研究开始日期 ICMJE | October 30, 2018 | ||
| 预计主要完成日期 | October 30, 2019 (主要结果测量的最终数据收集日期) | ||
| 目前主要观察指标 ICMJE |
Number of participants with adverse events as a measure of safety and tolerability of iC9-CAR19 T cells[ Time Frame: 4 weeks ] Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE. CAR-T-cell-related encephalopathy (CRES) symptoms will be graded according to the criteria outline in Section 12.6 CRES Grading in the protocol and CRS symptoms will be graded according to criteria outlined in Section 12.2 CRS Grading of the protocol. |
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| 原始主要观察测量 ICMJE | 与当前相同 | ||
| 目前的二级观察 ICMJE |
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| 描述性信息 | |||
| 简略标题 ICMJE | Anti-CD19 CAR-T Cells With Inducible Caspase 9 Safety Switch for B-cell Lymphoma | ||
| 正式标题 ICMJE | A Phase I Study of Autologous Activated T-cells Targeting the CD19 Antigen and Containing the Inducible Caspase 9 Safety Switch in Subjects With Relapsed/Refractory B-cell Lymphoma | ||
| 简要概况 | This research study combines 2 different ways of fighting disease: antibodies and T cells. Both antibodies and T cells have been used to treat patients with cancers, and both have shown promise, but neither alone has been sufficient to cure most patients. This study combines both T cells and antibodies to create a more effective treatment. The treatment being researched is called autologous T lymphocyte chimeric antigen receptor cells targeted against the CD19 antigen (ATLCAR.CD19) administration. Prior studies have shown that a new gene can be put into T cells and will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes a piece of an antibody called anti-CD19. This antibody sticks to leukemia cells because they have a substance on the outside of the cells called CD19. For this study, the anti-CD19 antibody has been changed so that instead of floating free in the blood part of it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD19 chimeric (combination) receptor-activated T cells seem to kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Preliminary results have shown that subjects receiving this treatment have experienced unwanted side effects including cytokine release syndrome and neurotoxocity. In this study, to help reduce cytokine release syndrome and/or neurotoxicity symptoms, the ATLCAR.CD19 cells have a safety switch that, when active, can cause the cells to become dormant. These modified ATLCAR.CD19 cells with the safety switch are referred to as iC9-CAR19 cells. If the subject experiences moderate to severe cytokine release syndrome and or neurotoxicity as a result of being given iC9-CAR19 cells, the subject can be given a dose of a second study drug, AP1903, if standard interventions fail to alleviate the symptoms of cytokine release syndrome and/or neurotoxicity. AP1903 activates the iC9-CAR19 safety switch, reducing the number of the iC9-CAR19 cells in the blood. The ultimate goal is to determine what dose of AP1903 can be given that reduces the severity of the cytokine release syndrome and/or neurotoxicity, but still allows the remaining iC9-CAR19 cells to effectively fight the lymphoma. The primary purpose of this study is to determine whether receiving iC9-CAR19 cells is safe and tolerable in patients with relapsed/refractory B-cell lymphoma. |
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| 详细说明 | This study is a phase I dose finding trial to determine if chimeric antigen receptor T (CAR-T) cells targeting the CD19 antigen and containing the inducible caspase 9 safety switch can be safely administered to adult subjects with relapsed or refractory B-cell Lymphoma. The safety of iC9-CAR19 cells will be investigated using the 3+3 design. The starting dose of 1 x 106 transduced cells/kg (dose level 1) will enroll at least 3 subjects in the initial cohort. If there are no dose limiting toxicities (DLTs) within 4 weeks of the cell infusion in these 3 subjects, then the next cohort will evaluate 2 x 106 transduced cells/kg. If there is toxicity in 1/3 subjects in the initial cohort, the cohort will be expanded to enroll up to 6 subjects. During iC9-CAR19 T cell dose exploration, AP1903 (0.4 mg/kg), a dimerizing agent that is designed to engage and activate the caspase 9 safety switch to trigger iC9-CAR19 T cell death by apoptosis will be given to subjects who develop grade 4 cytokine release syndrome (CRS) or grade ≥3 CRS that is unresponsive to standard of care interventions, and to subjects who develop grade ≥3 CAR-T-cell-related encephalopathy syndrome (CRES) or grade 2 CRES that does not improve to grade ≤1 within 72 hours with standard of care interventions. Cell Procurement Peripheral blood, up to 300 mL (in up to 3 collections) will be obtained from subjects for cell procurement. In subjects with low T-cell count (CD3 count as assayed by flow cytometry less than 200/μL) in the peripheral blood, a leukopheresis may be performed to isolate sufficient T cells. The parameters for pheresis will be up to 2 blood volumes Lymphodepleting Regimen Subjects will receive a "pre-conditioning" cytoreductive regimen of bendamustine 70 mg/m2/day administered IV followed by an IV dose of fludarabine 30 mg/m2/day administered over 3 consecutive days. These agents will be administered per institutional guidelines. Prophylaxis (e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine chemotherapy will be provided per institutional guideline Administration of iC9-CAR19 T cells Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9-CAR19 T cells within 2 - 14 days after completing the lymphodepleting chemotherapy regimen. We will administer iC9-CAR19 post lymphodepletion at dose levels specified in the table in section 4.1. A recently published trial in refractory DLBCL established that a dose of 2 x 106 CAR19+ T cells/kg was safe and associated with significant in vivo expansion and we anticipate similar results with iC9-CAR19+ T cells. Duration of Therapy Therapy in this study involves 1 infusion of iC9-CAR19 cells. Duration of Follow-up Subjects who receive a cell infusion will be followed for up to 15 years for replication-competent retrovirus evaluation or until death, whichever occurs first. Subjects who are removed from study and do not receive the cellular therapy product due to unacceptable adverse events will be followed until resolution or stabilization of the adverse event. | ||
| 研究类型 ICMJE | Interventional | ||
| 研究阶段 | Phase 1 | ||
| 研究设计 ICMJE | 分配: 干预模型: Single Group Assignment 干预模型描述: 盲法: Interventional 盲法描述: 主要目的: Treatment |
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| 适用条件 ICMJE | |||
| 干预项目 ICMJE |
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| 招募信息 | |||
| 招募状态 ICMJE | Not yet recruiting | ||
| 预计入组 ICMJE |
12 | ||
| 原始预计入组 ICMJE | 与当前相同 | ||
| 预计研究完成日期 | October 30, 2033 | ||
| 预计主要完成日期 | October 30, 2019 (主要结果测量的最终数据收集日期) | ||
| 合格标准 ICMJE | Inclusion Criteria for the Study: Unless otherwise noted, subjects must meet all of the following criteria to participate in all stages of this study: - Written informed consent and HIPAA authorization for release of personal health information. - Adults ≥18 years of age. - Histologically confirmed B-cell NHL, including the following types defined by WHO 2016: Aggressive Lymphomas: - DLBCL not otherwise specified (NOS) - T cell/histiocyte rich large B cell lymphoma; primary cutaneous DLBCL, leg type; EBV-positive DLBCL NOS; DLBCL associated with chronic inflammation; Lymphomatoid granulomatosis; Large B-cell lymphoma with IRF4 rearrangement; Intravascular large B-cell lymphoma; ALK-positive large B-cell lymphoma - Primary mediastinal (thymic) large B-cell lymphoma - High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement; high grade B-cell lymphoma, NOS - B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma - Transformation of indolent lymphoma or CLL to DLBCL will also be included Indolent Lymphomas: - Follicular lymphoma - Splenic marginal zone lymphoma - Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue - Nodal marginal zone lymphoma - Mantle cell lymphoma - Subjects with CNS disease will not be excluded as long it has been stable for 3 months --For aggressive lymphomas, relapsed or refractory disease, defined as one of the following: - Residual disease after primary therapy and not eligible for autologous stem cell transplant (ASCT) - Relapsed or persistent disease after prior ASCT - Beyond 1st complete remission with relapsed or persistent disease and not eligible or appropriate for conventional allogeneic or ASCT - For indolent lymphomas, subjects must have received at least 2 prior lines of therapy for their lymphoma - Subjects relapsed after allogeneic stem cell transplant will be eligible if they meet other inclusion criteria and have no active graft vs host disease (GVHD) - Measurable or assessable disease by Lugano criteria - Karnofsky score of > 60% - Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study, and for 6 months after the study is concluded. WOCBP are those who have not been surgically sterilized or have not been free from menses for > 1 year. The two birth control methods can be composed of: two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. WOCBP subjects will also be instructed to tell their male partners to use a condom. Exclusion Criteria for the Study: Subjects meeting any of the following exclusion criteria will not be able to participate in this study (procurement, lymphodepletion and cell infusion): - Subject is pregnant or lactating. - Tumor in a location where enlargement could cause airway obstruction. - Current use of systemic corticosteroids at doses ≥10mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at discretion of investigator. - Active infection with HIV, HTLV, HBV, HCV (can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells) defined as not being well controlled on therapy. Subjects are required to have negative HIV antibody or negative HIV viral load, negative HTLV1 and HTLV2 antibodies, negative Hepatitis B surface antigen, and negative HCV antibody or viral load. In addition, subjects with positive Hepatitis B core antibody, will have Hepatitis B viral load tested and subjects with positive Hepatitis B viral load will also be excluded. - Subject must either have core antibody negative HBV (results can be pending at the time of cell procurement) OR if a subject is hepatitis B core antibody positive they must have their hepatitis B viral load checked. These subjects will be excluded if their viral load is positive at baseline. Subjects who are core antibody positive and viral load negative at baseline will be considered eligible. - Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years. Eligibility criteria to be met prior to procurement: - Subjects must sign a consent to undergo cell procurement. - Life expectancy ≥ 12 weeks. - Evidence of adequate organ function as defined by: The following is required within 7 days prior to procurement: - Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN) - AST ≤ 3 times ULN - Creatinine Clearance (CrCl) >30mL/min per Cockcroft and Gault (See Section 12.3) - Pulse oximetry of >90% on room air - Left ventricular ejection fraction (LVEF) ≥35% as measured by ECHO, with no additional evidence of decompensated heart failure. - Imaging results from within 90 days prior to procurement to assess presence of active disease. - Negative serum pregnancy test within 72 hours prior to procurement or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for >1 year, or documentation of surgical menopause involving bilateral oophorectomy. Eligibility criteria to be met prior to lymphodepletion: - Written informed consent to enroll in the CAR T-cell therapy trial must be obtained prior to lymphodepletion. - Imaging results from within 7 days prior to lymphodepletion. Imaging must occur at least 3 weeks after most recent therapy (used as baseline measure for documentation of progression before the lymphodepletion) to document measurable or assessable disease. Imaging does not need to be repeated if it is within 7 days prior to lymphodepletion. - Evidence of adequate organ function as defined by: The following are required within 72 hours prior to lymphodepletion: - Adequate bone marrow function (ANC ≥1.0 x 109/L and platelets ≥75 x 109/L). Subjects cannot have received platelet transfusion within 7 days of lymphodepletion. - Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated bilirubin is <1.5× ULN) - AST ≤ 3 times ULN - Creatinine Clearance (CrCl) >30mL/min per Cockcroft and Gault - Pulse oximetry of > 90% on room air - Negative serum pregnancy test within 72 hours prior to lymphodepletion or documentation that the subject is post-menopausal. Post-menopausal status must be confirmed with documentation of absence of menses for > 1 year, or documentation of surgical menopause involving bilateral oophorectomy. - Subjects that have received therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion. - Available autologous transduced activated T cells product meets the certificate of analysis. - Has not received any investigational agents or received any tumor vaccines within the previous six weeks prior to lymphodepletion. - Subject is not taking a prohibited or contraindicated medication prior to lymphodepletion. Contraindicated medications should be discontinued at least two weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated medication, whichever is shorter. - Subject is not taking strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) as these may increase plasma concentrations of bendamustine, and decrease plasma concentrations of its metabolites. See http://medicine.iupui.edu/clinpharm/ddis/ for an updated list of strong inhibitors of CYP1A2. (This applies to subjects who receive bendamustine for lymphodepletion (required) up through 72 hours after the last dose of bendamustine). - Subject has not received chemotherapy within the previous 3 weeks prior to lymphodepletion. Eligibility criteria to be met prior to cell infusion after lymphodepletion: - No evidence of uncontrolled infection or sepsis. - Negative serum pregnancy within 7 days of cell infusion (does not need to be repeated if pre-lymphodepletion pregnancy test is within window). | ||
| 性别 |
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| 年龄 | 最小年龄：18 Years ，最大年龄：N/A | ||
| 接受健康的志愿者 | 没有 | ||
| 可入组国家 ICMJE | United States | ||
| 管理信息 | 数据检测委员会 | Yes | |
| 研究涉及美国FDA监管的产品 |
研究美国FDA监管的药品: Yes 研究涉及美国FDA监管的设备产品: No |
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| IPD 共享声明 |
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| 责任方 | ， | ||
| 研究赞助商 ICMJE | UNC Lineberger Comprehensive Cancer Center | ||
| 合作者 ICMJE | |||
| 研究员 ICMJE |
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| PRS 账户 | |||
| 验证日期 | October 2018 | ||
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ICMJE 国际医学期刊编辑委员会和 世界卫生组织 ICTRP 要求的元素 |
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