HER2-CAR T Cells in Treating Participants With Brain or Leptomeningeal Metastases
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City of Hope Medical Center
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| 追踪信息 | |||
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| 首次提交日期 ICMJE | June 27, 2018 | ||
| 首次发布日期e ICMJE | October 4, 2018 | ||
| 最后更新发布日期 | October 4, 2018 | ||
| 预计研究开始日期 ICMJE | December 6, 2018 | ||
| 预计主要完成日期 | December 6, 2021 (主要结果测量的最终数据收集日期) | ||
| 目前主要观察指标 ICMJE |
Incidence of dose limiting toxicities (DLTs)[ Time Frame: 21 days post T cell infusion ] Rate and associated 90% Clopper and Pearson binomial confidence limits (90% CI) will be estimated for participants experiencing DLTs at the recommended phase 2 dose schedule. Number of participants with treatment related adverse events as assessed by CTCAE v5.0.[ Time Frame: Up to 15 years ] Tables will be created to summarize all toxicities and side effects by dose, time post treatment, organ, severity and arm. |
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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 | HER2-CAR T Cells in Treating Participants With Brain or Leptomeningeal Metastases | ||
| 正式标题 ICMJE | A Phase 1 Cellular Immunotherapy Study of Intraventricularly Administered Autologous HER2-Targeted Chimeric Antigen Receptor (HER2-CAR) T Cells in Patients With Brain and/or Leptomeningeal Metastases From HER2 Positive Cancers | ||
| 简要概况 | This phase I trial studies the side effects and best dose of HER2-CAR T cells in treating participants with cancer that has spread to the brain or leptomeninges. HER2-CAR T cells delivered into the ventricles of the brain may recognize and kill tumor cells. |
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| 详细说明 | PRIMARY OBJECTIVES: I. Determine the safety and recommended phase 2 dosing (RP2D) of intraventricularly administered memory-enriched autologous HER2(EQ)BBzeta/CD19t+ T cells (HER2-chimeric antigen receptor [CAR] T cells) in participants with brain and/or leptomeningeal metastases from HER2 positive cancers. SECONDARY OBJECTIVES: I. Assess cerebrospinal fluid (CSF) and peripheral blood for HER2-CAR T cell persistence and endogenous immune system activation. II. Describe changes in cytokine levels in the CSF and peripheral blood. III. Describe changes in circulating tumor cells in the CSF. IV. In study participants who complete at least the first three cycles of HER2-CAR T cell infusions: describe the CNS clinical benefit defined as disease response rate based on Response Assessment in Neuro-Oncology Criteria (RANO) criteria (stable disease [SD], partial response [PR], or complete response [CR] in the brain). V. In study participants who complete at least the first three cycles of HER2-CAR T cell infusions: describe the systemic clinical benefit based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. VI. In study participants who complete at least the first three cycles of HER2-CAR T cell infusions: estimate the median central nervous system (CNS) progression-free and overall survival rates (mPFS and mOS), (newly diagnosed versus recurrent metastases). VII. In study participants who undergo tumor resection or biopsy during or after study treatment or upon autopsy, evaluate the tumor micro-environment for: HER2-CAR T cell persistence, immune cell subsets, cytokine levels, HER2 antigen expression levels. VIII. Use biomathematical modeling of tumor growth to evaluate benefit of treatment. OUTLINE: This is a dose-escalation study. Participants receive HER2-CAR T cells via intraventricular administration over 5 minutes once weekly for 3 doses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, participants are followed up at 4 weeks, 3, 6, 8, 10, and 12 months, and then for up to 15 years. | ||
| 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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| 研究工具 |
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| 招募信息 | |||
| 招募状态 ICMJE | Not yet recruiting | ||
| 预计入组 ICMJE |
21 | ||
| 原始预计入组 ICMJE | 与当前相同 | ||
| 预计研究完成日期 | December 6, 2021 | ||
| 预计主要完成日期 | December 6, 2021 (主要结果测量的最终数据收集日期) | ||
| 合格标准 ICMJE | Inclusion Criteria: - SCREENING: Participant has newly diagnosed (not previously treated with radiation) or recurrent brain and/or leptomeningeal metastases after radiation - Note: Participants with leptomeningeal metastasis (diagnosed by positive CSF cytology or characteristic findings on brain or spine magnetic resonance imaging [MRI]) may have concomitant brain metastases, but having both is not required - SCREENING: Participant must have a Karnofsky performance status (KPS) >= 70 - SCREENING: Participant must have a life expectancy of >= 8 weeks - SCREENING: The effects of HER2-CAR T cells on a developing fetus are unknown. For this reason, women of child-bearing potential must have negative serum pregnancy test and agree to use a reliable form of birth control prior to study entry and for at least two months following duration of study participation. Male research participants must agree to use a reliable form of birth control and not donate sperm during the study and for at least six months afterwards - SCREENING: Participant has a histologically confirmed cancer which is HER2+, defined as 3+ by immunohistochemistry (IHC) or gene amplification by fluorescence in situ hybridization (FISH) - SCREENING: Participant must have the ability to understand and the willingness to sign a written informed consent - ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: At least 2 weeks must have elapsed since the participant received his/her last dose of prior chemotherapy or radiation - ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: Research participant must not require more than 6 mg/day of dexamethasone (or the equivalent dose of another corticosteroid) on the day of leukapheresis - ELIGIBILITY TO PROCEED WITH LEUKAPHERESIS: Participant must be willing to undergo placement of a temporary catheter for central venous access if s/he does not have adequate peripheral venous access for collection of T cells - ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Creatinine < 1.6 mg/dL - ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: White blood cell (WBC) > 2,000/uL (or absolute neutrophil count [ANC] > 1,000) - ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Platelets >= 100,000/uL - ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: International normalized ratio (INR) must be < 1.3 - ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Bilirubin < 1.5 mg/dL - ELIGIBILITY TO PROCEED WITH RICKHAM RESERVOIR PLACEMENT: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X upper limits of normal - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Research participants will enroll onto the study once they meet eligibility to proceed with CAR T cell infusion prior to cycle 1. Once enrolled, subjects will be considered on ?active? treatment until they complete the dose limiting toxicity (DLT) evaluation period (~21 days) - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Participant must be taking =< 6 mg/ day of dexamethasone (or the equivalent dose of another corticosteroid) during CAR T cell therapy - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Participant does not have evidence of active infection and does not have a fever exceeding 38.5 degrees C; there is an absence of positive blood culture for bacteria, fungus, or virus within 48-hours prior to HER2-CAR T cell infusion and/or there aren?t any indications of meningitis - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: WBC > 2,000/uL (or ANC > 1,000) - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Platelets > 100,000/uL. However, if platelet level is between 75,000-99,000/uL then HER2-CAR T-cell administration may proceed after platelet transfusion is given, and the post transfusion platelet count is >= 100,000/uL - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Serum creatinine < 1.8 mg/dL - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Serum total bilirubin or transaminases does not exceed 2 X upper limits of normal - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Research participant does not require supplemental oxygen to keep saturation greater than 95% and/or does not have presence of any radiographic abnormalities on chest x-ray that are positive - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Research participant does NOT have any known history of congestive heart failure (CHF) or cardiac symptoms consistent with New York Heart Association (NYHA) classification III-IV within 6 months prior to day 1 of protocol treatment, cardiomyopathy, myocarditis, Myocardial infarction (MI), exposure to cardiotoxic medications or with clinical history suggestive of the above must have an electrocardiogram (EKG) and echocardiogram (ECHO) performed within 42 days prior to registration and as clinically indicated while on treatment - If the research participant has new symptoms of congestive heart failure (CHF), cardiomyopathy, myocarditis, MI, or exposure to cardiotoxic medications, they already had a cardiac consultation, creatinine phosphokinase (CPK), and troponin testing at pre study deeming them fit for study participation - ELIGIBILITY FOR ENROLLMENT AND TO PROCEED WITH INTRAVENTRICULAR ADMINISTRATION OF HER2-CAR T CELLS: Participant has a released cryopreserved HER2-CAR T cell product - ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participant must have at least 1 metastatic brain lesion (measurable disease per RANO-Brain Metastases [BM] is not required?i.e., participant does not need to have at least 1 metastatic lesion >= 1 cm in longest dimension) that is new or increasing in size, or CSF cytology and/or radiographic findings consistent with leptomeningeal metastases - ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participants whose brain metastases have been treated with whole brain radiation (WBRT) or stereotactic radiosurgery (SRS): previously radiated metastases must have >= 20% increase in longest diameter that is also >= 5 mm absolute increase from prior brain MRI or histopathologically proven recurrent tumor. Otherwise, new or not previously radiated lesions must be present - Note: Participants who have undergone local therapy (surgical resection or biopsy, or SRS), must have recovered from all acute side effects before starting treatment with HER2-CAR T cells - ADDITIONAL ELIGIBILITY TO START CYCLE 1: If a participant with brain metastases does not meet the above criteria, but there is still concern by the study team that changes in an enhancing brain lesion seen on brain MRI could be due to tumor progression, then the participant can undergo resection or biopsy of the lesion(s) to distinguish between tumor progression versus radiation necrosis. If there is histopathological evidence of tumor progression, then the participant can proceed with study treatment - ADDITIONAL ELIGIBILITY TO START CYCLE 1: Research participant does not have uncontrolled seizure following surgery prior to starting the first CAR T cell dose - ADDITIONAL ELIGIBILITY TO START CYCLE 1: Participants must have recovered from toxicity (=< grade 1) of prior therapy (excluding alopecia and peripheral neuropathy) - ADDITIONAL ELIGIBILITY TO START CYCLE 1: Wash-out requirements (standard or investigational). The required waiting period between the last dose of the most recent chemotherapy agent(s) and first dose of HER2-CAR T cells is: - Four weeks for a cytotoxic chemotherapy, except for capecitabine, which will only require a 1 week waiting period from the last dose (on a dosing schedule of bid x 14 days, then off x 7 days); - At least 6 weeks must have passed since the completion of a nitrosourea-containing chemotherapy regimen; - At least four half-lives for a targeted agent Exclusion Criteria: - EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks - EXCLUSION CRITERIA FOR STUDY SCREENING: Research participants with a known history of congestive heart failure (CHF) or cardiac symptoms consistent with NYHA classification III-IV within 6 months prior to day 1 of protocol treatment, cardiomyopathy, myocarditis, myocardial infarction (MI), exposure to cardiotoxic medications or with clinical history suggestive of the above must have an EKG and echocardiogram (ECHO) performed within 42 days prior to registration and as clinically indicated while on treatment. - Research participants with new symptoms of CHF, cardiomyopathy, myocarditis, MI, or exposure to cardiotoxic medications must have a cardiac consultation, creatinine phosphokinase (CPK), and troponin testing at pre study and as clinically indicated - EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant requires dialysis - EXCLUSION CRITERIA FOR STUDY SCREENING: Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy - EXCLUSION CRITERIA FOR STUDY SCREENING: Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase 1 study. A legal guardian may substitute for the research participant - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is unwilling to stop treatment with chemotherapy or endocrine therapy during the first 3 cycles of the HER2-CAR T cell study - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has a coagulopathy or bleeding disorder or cannot safely discontinue anticoagulation prior to placement of a Rickham reservoir - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has a chronic or active viral infection of the CNS - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has any uncontrolled illness, including ongoing or active infection; participant has known active hepatitis B or C infection; participants with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is human immunodeficiency virus (HIV) seropositive based on testing performed within 4 weeks of screening - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has an autoimmune disease - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant has another active malignancy - EXCLUSION CRITERIA FOR STUDY SCREENING: Participants with lung metastases (exception may be allowed per principal investigator [PI] discretion for participants that are not symptomatic from their lung metastases) - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is unable to undergo a brain MRI - EXCLUSION CRITERIA FOR STUDY SCREENING: Participant is breast feeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with HER2-CAR T cells, breastfeeding should be discontinued if the mother wants to participate in this study - EXCLUSION CRITERIA FOR STUDY SCREENING: Patient has a serious medical or psychiatric illness that could, in the investigator?s opinion, potentially interfere with the safety monitoring requirements and completion of treatment according to this protocol | ||
| 性别 |
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| 年龄 | 最小年龄：18 Years ，最大年龄：75 Years | ||
| 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 | City of Hope Medical 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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