肿瘤细胞治疗研究
英文原题：CAR T Cells After Lymphodepletion for the Treatment of IL13Rα2 Positive Recurrent or Refractory Brain Tumors in Children
这是一项 I 期注册临床试验，评估自体 CAR-T 细胞治疗肿瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 18 例。试验地点：美国 · 杜阿尔特、洛杉矶、安娜堡（共 3 个中心）。登记号：NCT04510051。
不限性别 · ≥ 4 Years 且 ≤ 25 Years
纳入标准： * 受试者和/或合法授权代表签署知情同意书。 * 在适当情况下，将根据机构指南获取同意 * 同意使用来自诊断性肿瘤活检的存档组织 * Karnofsky体能状态（KPS）>= 60%，但因疾病累及导致活动能力丧失者除外；例如，因脊髓压迫而局限于轮椅 * 预期寿命 > 4周 * 受试者既往有组织学确诊的恶性脑肿瘤，且在接受既往常规治疗后出现进展 * 影像学证据显示，在初始常规治疗（包括初始放疗）结束后超过12周，可测量病灶出现进展/复发 * City of Hope（COH）临床病理学通过免疫组织化学（IHC）确认初始肿瘤表现或复发疾病中IL13Ralpha2+肿瘤表达（H-score >= 50） * 如果受试者带有分流管，该分流管必须是可编程的，且受试者必须能够耐受分流管关闭至少连续2天 * 血小板 >= 50,000/mm^3（在签署主知情同意书后6周内进行） * 总胆红素 =< 2 x 正常上限（ULN）（除非患有Gilbert病）（在签署主知情同意书后6周内进行） * 天冬氨酸转氨酶（AST）=< 2 x ULN（在签署主知情同意书后6周内进行） * 丙氨酸转移酶（ALT）=< 2 x ULN（在签署主知情同意书后6周内进行） * 肌酐清除率 >= 75mL/min/1.73m^2（在签署主知情同意书后6周内进行） * 人类免疫缺陷病毒（HIV）抗原（Ag）/抗体（Ab）联合检测、丙型肝炎病毒（HCV）*和活动性HBV（表面抗原阴性）血清学阴性（在签署主知情同意书后6周内进行） * 如果阳性，必须进行丙型肝炎核糖核酸（RNA）定量检测 * 有生育潜力的女性（WOCBP）：尿或血清妊娠试验阴性。如果尿妊娠试验阳性或无法确认为阴性，则需要进行血清妊娠试验（在签署主知情同意书后6周内进行） * 有生育潜力的女性和男性*同意在研究期间至方案治疗末次给药后至少6个月内使用有效避孕方法或避免异性性行为。 * 有生育潜力定义为未接受手术绝育（男性和女性），或未在月经开始后连续无月经 > 1年（仅女性） * 具备进行外周血单核细胞采集（PBMC）的资格 * 研究受试者在进行外周血单核细胞（PBMC）采集当天，地塞米松总剂量不得超过0.1mg/kg/天（0.03mg/kg/次，每日三次，最大6mg/天） * 研究受试者必须具有适当的静脉通路 * 研究参与者自接受既往靶向药物、化疗或放疗末次给药以来，必须已至少过去2周 * 注：如果研究参与者体重低于50公斤，研究团队应向供者单采中心（DAC）提供参与者当前体重，以便遵循机构指南 * 符合继续进行留置中枢神经系统（CNS）导管置入的条件 * 血清肌酐 < 1.6 mg/dL * 白细胞（WBC）>= 2,000/dL * 中性粒细胞绝对计数（ANC）>= 1,000 * 血小板 > 50,000/dL * 国际标准化比值 =< 1.3 * 胆红素 < 1.5 mg/dL * 丙氨酸转移酶（ALT）和天冬氨酸转氨酶（AST）< 2 x 正常上限 * KPS >= 60%，但因疾病累及导致活动能力丧失者除外；例如，因脊髓压迫而局限于轮椅 * 二线放疗（白细胞单采后）在手术切除或活检/导管置入前至少4周已完成 * 符合继续进行淋巴细胞清除的条件 * 肺：研究参与者不需要补充氧气即可维持血氧饱和度大于95%，和/或不具有胸部x线片上任何进行性放射学异常 * 心脏：研究参与者不需要升压药支持，和/或不具有症状性心律失常 * 活动性感染：研究参与者没有超过38.5摄氏度的发热；在CAR T细胞输注前48小时内没有细菌、真菌或病毒血培养阳性，和/或没有任何脑膜炎迹象 * 肝：研究参与者血清总胆红素或转氨酶不超过2 x 正常上限 * 肾：研究参与者血清肌酐 < 1.8 mg/dL * 神经：研究参与者开始淋巴细胞清除前，术后没有未控制的癫痫发作 * 符合继续进行每次CAR T细胞输注的条件 * 研究参与者有已放行的冷冻保存T细胞产品 * 研究参与者不需要补充氧气即可维持血氧饱和度大于95%，和/或不具有胸部x线片上任何进行性放射学异常 * 研究参与者不需要升压药支持，和/或不具有症状性心律失常 * 研究参与者没有超过38.5摄氏度的发热；在T细胞输注前48小时内没有细菌、真菌或病毒血培养阳性，和/或没有任何脑膜炎迹象 * 研究参与者血清总胆红素或转氨酶不超过2 x 正常上限 * 研究参与者血清肌酐 < 1.8 mg/dL * 研究参与者没有未控制的癫痫发作 * 研究参与者的血小板计数必须 >= 50,000。然而，如果血小板水平在 25,000-49,000 之间，则在给予血小板输注且输注后血小板计数 >= 50,000 后，可进行 T 细胞输注 * 研究参与者在 CAR T 细胞治疗期间所需的 dexamethasone 总剂量不得超过 0.1mg/kg/天（0.03mg/kg/次，每日三次，最大 6mg/天） * 洗脱期要求： * 含亚硝基脲的化疗方案完成后至少 6 周； * temozolomide 完成后至少 23 天，和/或任何其他不含亚硝基脲的细胞毒性化疗方案完成后 4 周。如果患者最近一次治疗仅使用了靶向药物，且其已从该靶向药物的任何毒性中恢复，则仅需从末次给药后等待 2 周 * 对于 bevacizumab，在开始研究治疗前需要至少 4 周的洗脱期 排除标准： * 肺部：研究参与者需要补充氧气以维持血氧饱和度大于 95%，且预计该情况在 2 周内不会缓解 * 心脏：研究参与者需要升压药支持，和/或有症状性心律失常 * 肾脏：研究参与者需要透析 * 神经系统：研究参与者有未控制的癫痫发作活动，和/或临床明显的进行性脑病 * 研究参与者未能理解方案的基要内容，和/或参与本 I 期研究的风险/获益。法定监护人可代替研究参与者 * 研究参与者患有任何非恶性并发疾病，且该疾病经当前可用治疗控制不佳，或其严重程度使研究团队认为将研究参与者纳入方案是不明智的，则不符合资格 * 研究参与者患有任何其他活动性恶性肿瘤 * 正在接受严重感染治疗或处于大手术后恢复期的研究参与者不符合资格，直至研究团队认为其恢复完全 * 研究参与者患有任何未控制的疾病，包括持续或活动性感染。研究参与者有已知的活动性乙型或丙型肝炎感染；研究参与者有任何活动性感染的体征或症状、血培养阳性或感染的放射学证据 * 研究参与者在入组后 4 周内确认 HIV 阳性 * 仅限女性：妊娠或哺乳期 * 研究者认为可能无法遵守所有研究程序（包括与可行性/后勤相关的依从性问题）的潜在参与者
Inclusion Criteria: * Documented informed consent of the participant and/or legally authorized representative. * Assent, when appropriate, will be obtained per institutional guidelines * Agreement to allow the use of archival tissue from diagnostic tumor biopsies * Karnofsky Performance Status (KPS) \>= 60% except for loss of mobility due to disease involvement; e.g., confinement to a wheelchair due to spinal cord compression * Life expectancy \> 4 weeks * Participant has a prior histologically-confirmed malignant brain neoplasm and has progressed after prior conventional therapy * Radiographic evidence of progression/recurrence of the measurable disease more than 12 weeks after the end of the initial conventional therapy (including initial radiation therapy) * City of Hope (COH) clinical pathology confirms IL13Ralpha2+ tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H-score \>= 50) * If the participant has a shunt, it must be programmable and the participant must be able to tolerate the shunt being switched off for at least 2 consecutive days * Platelets \>= 50,000/mm\^3 (performed within 6 weeks of signing the main informed consent) * Total bilirubin =\< 2 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 6 weeks of signing the main informed consent) * Aspartate transaminase (AST) =\< 2 x ULN (performed within 6 weeks of signing the main informed consent) * Alanine transferase (ALT) =\< 2 x ULN (performed within 6 weeks of signing the main informed consent) * Creatinine clearance of \>= 75mL/min/1.73m\^2 (performed within 6 weeks of signing the main informed consent) * Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV)\* and active HBV (surface antigen negative) (performed within 6 weeks of signing the main informed consent) * If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed * Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (to be performed within 6 weeks of signing the main informed consent) * Agreement by females and males of childbearing potential\* to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy. * Childbearing potential defined as not being surgically sterilized (males and females) or have not been free, once initiated, from menses for \> 1 year (females only) * ELIGIBILITY TO PROCEED WITH PERIPHERAL BLOOD MONONUCLEAR COLLECTION (PBMC) COLLECTION * Research participant must not require more than 0.1mg/kg/day total dose (0.03mg/kg/dose three times per day, max of 6mg/day) of Dexamethasone on the day of peripheral blood mononuclear cell (PBMC) collection * Research participant must have appropriate venous access * At least 2 weeks must have elapsed since the research participant received his/her last dose of prior targeted agents, chemotherapy or radiation * Note: If a research participant weighs less than 50kgs, the study team should provide the Donor Apheresis Center (DAC) with the participant's current weight so that institutional guidelines can be followed * ELIGIBILITY TO PROCEED WITH INDWELLING CENTRAL NERVOUS SYSTEM (CNS) CATHETER PLACEMENT * Serum creatinine \< 1.6 mg/dL * White blood cell (WBC) \>= 2,000/dL * Absolute neutrophil count (ANC) \>= 1,000 * Platelets \> 50,000/dL * International normalized ratio =\< 1.3 * Bilirubin \< 1.5 mg/dL * Alanine transferase (ALT) and aspartate transaminase (AST) \< 2 x upper limits of normal * KPS \>= 60% except for loss of mobility due to disease involvement; e.g., confinement to a wheelchair due to spinal cord compression * Second-line radiation therapy (post-leukapheresis) completed at least 4 weeks prior to surgical resection or biopsy/catheter placement * ELIGIBILITY TO PROCEED WITH LYMPHODEPLETION * Pulmonary: 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 progressive * Cardiac: Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias * Active infection: Research participant does not have a fever exceeding 38.5 degree celsius; there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to CAR T cell infusion and/or there aren't any indications of meningitis * Hepatic: Research participant serum total bilirubin or transaminases does not exceed 2 x normal limit * Renal: Research participant serum creatinine \< 1.8 mg/dL * Neurologic: Research participant does not have uncontrolled seizure activity following surgery prior to starting lymphodepletion * ELIGIBILITY TO PROCEED WITH EACH CAR T CELL INFUSION * Research participant has a released cryopreserved T cell product * 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 progressive * Research participant does not require pressor support and/or does not have symptomatic cardiac arrhythmias * Research participant does not have a fever exceeding 38.5 degree celsius; there is an absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to T cell infusion and/or there aren't any indications of meningitis * Research participant serum total bilirubin or transaminases does not exceed 2 x normal limit * Research participant serum creatinine \< 1.8 mg/dL * Research participant does not have uncontrolled seizure activity * Research participant platelet count must be \>= 50,000. However, if platelet level is between 25,000-49,000, then T-cell infusion may proceed after platelet transfusion is given and the post transfusion platelet count is \>= 50,000 * Research participants must not require more than 0.1mg/kg/day total dose (0.03mg/kg/dose three times per day, max of 6mg/day) of dexamethasone during CAR T cell therapy * Wash-out requirements: * At least 6 weeks since the completion of a nitrosourea-containing chemotherapy regimen; * At least 23 days since the completion of temozolomide and/or 4 weeks for any other non-nitrosourea-containing cytotoxic chemotherapy regimen. If a patient's most recent treatment was with a targeted agent only, and s/he has recovered from any toxicity of this targeted agent, then a waiting period of only 2 weeks is needed from the last dose * For bevacizumab the wash out period of at least 4 weeks is required before starting study treatment Exclusion Criteria: * Pulmonary: Research participant requires supplemental oxygen to keep saturation greater than 95% and the situation is not expected to resolve within 2 weeks * Cardiac: Research participant requires pressor support and/or has symptomatic cardiac arrhythmias * Renal: Research participant requires dialysis * Neurologic: Research participant has uncontrolled seizure activity and/or clinically evident progressive encephalopathy * Failure of research participant to understand the basic elements of the protocol and/or the risks/benefits of participating in this phase I study. A legal guardian may substitute for the research participant * Research participant with any non-malignant intercurrent illness which is either poorly controlled with currently available treatment, or which is of such severity that the study team deems it unwise to enter the research participant on protocol shall be ineligible * Research participant with any other active malignancies * Research participant being treated for severe infection or recovering from major surgery is ineligible until recovery is deemed complete by the study team * Research participant with any uncontrolled illness including ongoing or active infection. Research participant with known active hepatitis B or C infection; research participant with any signs or symptoms of active infection, positive blood cultures or radiological evidence of infections * Research participant who has confirmed HIV positivity within 4 weeks of enrollment * Females only: Pregnant or breastfeeding * Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
以上为辅助阅读译文。是否适合入组须由主治医生判断，最终以登记平台与研究者确认为准。
主要终点：Incidence of adverse events · Will assess the incidence of grade 3 toxicities, dose limiting toxicities, and all other toxicities. Toxicity and adverse events will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 and the revised cytokine release syndrome (CRS) grading system. Symptoms and toxicities will be evaluated by physical exam and blood chemistry/hematology results and adverse event reporting. Rate and associated 90% Clopper and Pearson binomial confidence limits (90% CI) will be estimated for participants experiencing dose limiting toxicities. Tables will be created to summarize all toxicities and side effects by time post treatment, organ, severity and disease subgroup. · Up to 1 year after the last chimeric antigen response (CAR) T cell infusion
次要终点：Persistence and expansion of CAR T cells；Peripheral blood and CSF cytokine levels；Peripheral blood and CSF immune cell characterization；Progression free survival；Overall survival；Disease response；CAR T cells detected in tumor tissue；IL13Ralpha2 antigen expression levels in tumor tissue
患者在第-5天和第-4天接受环磷酰胺静脉注射，并在第-5天至第-2天接受氟达拉滨静脉注射。随后，患者在第0天接受自体 IL13(EQ)BBzeta/CD19t+ T 细胞，经脑室内给药，持续5分钟，每周一次。在没有疾病进展或不可接受的毒性的情况下，自体 IL13(EQ)BBzeta/CD19t+ T 细胞治疗每7天重复一次，最多4个周期。只要患者继续符合资格标准并且有可输注的剂量，患者可以接受额外的 IL13(EQ)BBzeta/CD19t+ T 细胞周期。
这项I期试验研究化疗和细胞免疫疗法在治疗IL13Ralpha2阳性脑肿瘤儿童中的副作用，这些肿瘤在一段改善期后复发（复发性）或对治疗无反应（难治性）。细胞免疫疗法（IL13(EQ)BBzeta/CD19t+ T细胞）是脑肿瘤特异性细胞，可能诱导机体免疫系统发生变化，并可能干扰肿瘤细胞生长和扩散的能力。化疗药物，如环磷酰胺和氟达拉滨，通过不同方式阻止肿瘤细胞生长，要么杀死细胞，要么阻止其分裂，要么阻止其扩散。许多脑肿瘤患者对治疗有反应，但随后肿瘤又开始生长。将化疗与细胞免疫疗法联合给予可能杀死更多肿瘤细胞并改善治疗结果。
This phase I trial investigates the side effects of chemotherapy and cellular immunotherapy in treating children with IL13Ralpha2 positive brain tumors that have come back after a period of improvement (recurrent) or do not respond to treatment (refractory). Cellular immunotherapy (IL13(EQ)BBzeta/CD19t+ T cells) are brain-tumor specific cells that may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as as cyclophosphamide and fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Many patients with brain tumor respond to treatment, but then the tumor starts to grow again. Giving chemotherapy in combination with cellular immunotherapy may kill more tumor cells and improve the outcome of treatment.
MEMBER ACCOUNT
登录成功会直接打开下一页。
