肿瘤细胞治疗研究
英文原题：T Cells Expressing HER2-specific Chimeric Antigen Receptors(CAR) for Patients With HER2-Positive CNS Tumors
这是一项 I 期注册临床试验，评估 HER2T 细胞治疗脑肿瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 10 例。试验地点：美国 · 休斯顿（共 2 个中心）。登记号：NCT02442297。
不限性别 · ≥ 3 Years
细胞采集时纳入标准： • 复发/难治性HER2阳性原发中枢神经系统（CNS）肿瘤，或转移至CNS的HER2阳性肿瘤。若医学上可行，可在采集细胞后、治疗前进行肿瘤切除（全切或次全切）。 • Karnofsky/Lansky评分≥60。 • 已向受试者/监护人说明知情同意内容，其理解并签署同意书，且已获得副本。 细胞采集时排除标准： • 弥漫性内生性脑桥胶质瘤（DIPG）。 • 肿瘤体积较大导致中线移位，和/或有脑疝迫近的症状/体征。 • 已知HIV阳性。 治疗阶段纳入标准： • 复发/难治性HER2阳性原发CNS肿瘤，或转移至CNS的HER2阳性实体瘤。HER2阳性通过免疫组化（IHC）或RT-PCR判定，并与标准对照比较；IHC须≥1级且染色强度≥1+。染色比例分级：0级无染色，1级1%–25%，2级26%–50%，3级51%–75%，4级76%–100%；强度分为阴性、1+、2+和3+，以乳腺癌标准芯片作参照。 • 已置入颅内导管（如Rickham或Ommaya导管）。 • 年龄≥3岁。 • 预期生存期≥6周。 • Karnofsky/Lansky评分≥60。 • 总胆红素≤ULN的3倍，AST和ALT≤ULN的5倍，血清肌酐≤年龄对应ULN的2倍，血红蛋白≥7.0 g/dL；室内空气下脉搏血氧饱和度≥90%。 • 有性生活者同意在T细胞输注后6个月内采用高效避孕方法；男性伴侣须使用安全套。 • 有可用的自体转导T淋巴细胞：流式细胞术检测HER2-CAR表达≥15%，细胞毒性试验中对HER2阳性靶细胞的杀伤率≥20%。 • 肿瘤切除术后患者已从手术中恢复；有神经功能缺损者，缺损至少稳定1周后方可治疗。 • CAR-T输注前已停用其他试验性抗肿瘤治疗至少2周。允许在输注前48小时内使用替莫唑胺；医学需要时允许地塞米松总剂量最高2 mg/日。 • 已向受试者/监护人说明知情同意内容，其理解并签署同意书，且已获得副本。 治疗阶段排除标准： • 严重并发感染。 • 已知HIV阳性。 • 妊娠或哺乳期。 • 有对含鼠源蛋白产品发生超敏反应的病史。 • 弥漫性内生性脑桥胶质瘤（DIPG）。 • 地塞米松剂量>2 mg/日或等效剂量。
Inclusion criteria at the time of procurement. * Recurrent or refractory HER2 positive primary central nervous system (CNS) tumor or HER2 positive tumor metastatic to the CNS. Patients in whom tumor resection (gross total or subtotal resection) is medically feasible can undergo surgery after procurement and prior to treatment. * Karnofsky/Lansky score of greater than or equal to 60 * Informed consent explained to, understood by and signed by subject/guardian. Subject/guardian given copy of informed consent Exclusion Criteria at the time of procurement: * Diagnosis of DIPG * Bulky tumors causing midline shift and/or symptoms/signs due to impending herniation * Known HIV positivity Treatment Inclusion criteria: * Recurrent or refractory HER2-positive\* primary CNS tumor or HER2-positive solid tumor metastatic to the CNS \* Immunohistochemistry (IHC) or RT-PCR will be used to determine HER2 positivity. Results will be compared to standard controls. HER2 expression in tumors on IHC should be greater than or equal to grade 1 and greater than or equal to 1+ intensity score. Wherein grades are defined as: Grade 0: no staining; Grade 1: 1-25%; Grade 2: 26-50% and Grade 3: 51-75% and Grade 4: 76-100% of cell staining for HER2 and intensity scores are: negative; 1+; 2+ and 3+ using breast cancer standard arrays as a guide for intensity. * Intracranial catheter (such as Rickham or Ommaya) in place * Age ≥ 3 years * Life expectancy ≥ 6 weeks * Karnofsky/Lansky score ≥ 60 * Bilirubin less than or equal to 3x upper limit of normal, AST less than or equal to 5x upper limit of normal, ALT less than or equal to 5x upper limit of normal, serum creatinine less than or equal to 2x upper limit of normal for age, and Hgb greater than or equal to 7.0 g/dL * Pulse oximetry of greater than or equal to 90% on room air * Sexually active subjects must be willing to utilize one of the more effective birth control methods for 6 months after the T cell infusion. The male partner should use a condom * Available autologous transduced T lymphocytes with greater than or equal to 15% expression of HER2 CAR determined by flow-cytometry and killing of HER2-positive targets greater than or equal to 20% in cytotoxicity assay * Patients who have undergone tumor resection should have recovered from the surgery. Patients with neurological deficits should have deficits that are stable for minimum of 1 week prior to treatment. * Subjects should have been off other investigational antineoplastic therapy for two weeks prior to CAR T cell infusion. Temozolomide will be allowed up to 48 hours pre-infusion. Dexamethasone up to a total dose of 2 mg per day will be allowed if medically indicated * Informed consent explained to, understood by and signed by research subjects/guardian. Subject/guardian given copy of informed consent. Treatment Exclusion Criteria: * Severe intercurrent infection * Known HIV positivity * Pregnant or lactating * History of hypersensitivity reactions to murine protein-containing products. * Diagnosis of DIPG * Steroid dose of dexamethasone greater than 2 mg per day (or equivalent)
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：Number of patients with dose limiting toxicity after administration of autologous T cells expressing transgenic chimeric antigen receptors (CAR) targeting the HER2 molecule · To evaluate the safety of autologous T cells expressing transgenic chimeric antigen receptors (CAR) targeting the HER2 molecule administered into the tumor, tumor resection cavity, and/or cerebrospinal fluid (CSF) space of subjects with progressive recurrent or refractory HER2-positive primary central nervous system (CNS) tumor or HER2 positive tumor metastatic to the CNS, excluding diffuse intrapontine glioma (DIPG), after standard of care interventions. · 6 weeks
次要终点：Number of Patients with a tumor response
HER2染色3级（51%–100%细胞染色）且强度3+者进入高风险组。将评估3种细胞给药方案（方案1、2、3），每种方案由A、B、C三种细胞剂量组合构成。
不符合高风险组标准的其他患者进入标准风险组。将评估3种细胞给药方案（方案1、2、3），每种方案由A、B、C三种细胞剂量组合构成。
本研究面向脑肿瘤患者。人体有多种抗感染和抗病机制，但单一方法通常不足以对抗癌症。本研究将抗体与T细胞结合：抗体是可保护机体免受感染并可能对抗癌症的蛋白质；T细胞（T淋巴细胞）是血液中的免疫细胞，可杀伤其他细胞，包括病毒感染细胞和肿瘤细胞。两者都已用于癌症治疗并显示出潜力，但单独使用尚不足以治愈大多数患者。本研究使用的抗体为抗HER2（人表皮生长因子受体2）抗体。该抗体可结合许多脑肿瘤表达的HER2。研究者将HER2抗体连接到T细胞上，形成嵌合抗原受体（CAR）。HER2-CAR T细胞可能杀伤患者的肿瘤，但体内持续时间不长，因此延长T细胞存活可能有助于其抗癌。本研究使用的HER2-CAR T细胞是尚未获美国食品药品监督管理局批准的试验性产品。研究旨在确定HER2-CAR T细胞的最大安全剂量、了解副作用，并评估这种实验性治疗是否可能帮助自愿参加研究的脑肿瘤患者。
This study is for patients that have brain cancer. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: antibodies and T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting immune cells present in the blood that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. They have shown promise, but have not been strong enough to cure most patients. The antibody used in this study is called anti-HER2 (Human Epidermal Growth Factor Receptor 2). This antibody sticks to tumor cells because of a substance on the outside of these cells called HER2. Many types of brain tumors are positive for HER2 . HER2 antibodies have been used to treat people with HER2-positive cancers. For this study, the HER2 antibody has been changed so that instead of floating free in the blood it is now attached to T cells. When an antibody is joined to a T cell in this way it is called a chimeric antigen receptor (CAR). These CAR-T cells seem to be able to kill tumors like the one these patients have, but they don't last very long and so their chances of fighting the cancer are limited. Therefore, developing ways to prolong the life of these T cells should help them fight cancer. These HER2-CAR T cells are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the largest safe dose of HER2-CAR T cells, to learn what the side effects are, and to see whether this experimental intervention might help patients with brain tumors who volunteer to test this new agent.
MEMBER ACCOUNT
登录成功会直接打开下一页。
