肿瘤细胞治疗研究
英文原题：Autologous B7-H3 Chimeric Antigen Receptor T Cells in Previously Treated Extensive-Stage Small Cell Lung Cancer With Recurrent or Refractory Disease
这是一项 I 期注册临床试验，评估自体 CAR-T 细胞治疗小细胞肺癌、实体瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 40 例。试验地点：美国 · 贝塞斯达（共 1 个中心）。登记号：NCT07509034。
不限性别 · ≥ 18 Years 且 ≤ 120 Years
* 纳入标准：
* 年龄 >=18 岁。
* 组织学确诊的小细胞肺癌（SCLC）或肺外神经内分泌癌（EP-NEC），且在一线治疗后复发或难治。注：非肺原发部位的小细胞癌也符合条件。
* 东部肿瘤协作组体能状态评分（ECOG PS）0-2。
* 室内空气下脉搏血氧饱和度 >= 90%。
* 天冬氨酸转移酶（AST）< 3 倍机构正常值上限（ULN）。注：如有肝转移，<= 5 倍 ULN 可接受。
* 丙氨酸氨基转移酶（ALT）< 3 倍机构 ULN。注：如有肝转移，<= 5 倍 ULN 可接受。
* 总胆红素 <=2 倍机构 ULN。
* 肌酐 <=1.5 倍机构 ULN 或肌酐清除率（CrCl）>= 50 mL/min/1.73m^2（按慢性肾脏病流行病学协作组 [CKD-EPI] 公式计算，或采用实验室提供的 eGFR 计算值）。
* 绝对中性粒细胞计数（ANC）>= 750/mcL。
* 血小板计数 >= 75,000/mcL。
* 绝对淋巴细胞计数（ALC）>=300/mcL 且 CD3+ 细胞计数 >=150/mcL。
* 筛选时超声心动图（ECHO）显示心脏射血分数正常，定义为 >= 45%。
* 根据实体瘤疗效评价标准（RECIST）1.1 版，至少有 1 个可测量病灶，且既往未接受过放疗。
* 在单采前至少一周，所有既往抗肿瘤治疗的急性毒性作用已恢复至常见不良事件评价标准（CTCAE）v.6.0 的 <2 级，上述 ANC 和 ALC 参数除外。
* 单采前必须满足以下标准：
* 化疗和生物/靶向药物：
* 距末次标准骨髓抑制性化疗给药 >=14 天。
* 距生物制剂、靶向药物或酪氨酸激酶抑制剂治疗结束 >= 7 天。
* 距既往单克隆抗体治疗 >= 3 周或 5 个半衰期（以较短者为准）。
* 放疗：
* 距末次放疗 >= 1 周。
* 针对非靶病灶的姑息性放疗无需洗脱期。
* 距肝脏放疗、化疗栓塞和/或射频消融 >= 3 周。
* 类固醇和免疫抑制治疗：
* 皮质类固醇：距治疗剂量（> 0.5 mg/kg/天泼尼松或等效剂量）>= 2 周。注：吸入或局部用类固醇不构成排除。
* 允许生理替代剂量（最高 5 mg/天泼尼松等效剂量），如有必要可根据受试者 BMI 调整。
* 距其他免疫抑制药物（如钙调神经磷酸酶抑制剂、甲氨蝶呤、雷帕霉素、沙利度胺等）>= 2 周。
* 抗 PD-1 及任何研究性治疗：
* 距抗 PD-1 单克隆抗体治疗 >= 2 周。
* 距任何研究性治疗或临床试验参与 >= 2 周或研究产品 5 个半衰期（以较短者为准）。
* 其他标准：
* 自小分子酪氨酸激酶抑制剂（如EGFR抑制剂）、PARP抑制剂或KRAS G12C抑制剂用药后72小时。
* 有生育能力的个体（IOCBP）必须同意在研究入组时及联合化疗末次给药后长达12个月内采用高效避孕措施（激素避孕、宫内节育器[IUD]、禁欲、手术绝育）。
注：IOCBP定义为已经历月经初潮且未接受成功手术绝育或未绝经的任何个体。
* 有生育能力的个体必须同意在研究入组时及研究药物末次给药后长达7个月内采用有效避孕方法（屏障避孕、手术绝育、禁欲）。我们还建议有生育能力的个体若其伴侣有生育潜力，应要求伴侣采用高效节育措施（激素避孕、IUD、手术绝育）。有生育能力的个体在同一时期内不得冷冻或捐献精子。
* 哺乳期参与者必须愿意从研究治疗开始至研究药物末次给药后6个月内停止哺乳。
* 参与者能够理解并愿意签署书面知情同意书。
排除标准：
* 有归因于抗B7-H3抗体或与自体B7-H3 CAR T细胞化学或生物学组成相似的化合物、环磷酰胺、氟达拉滨或本研究中使用的其他药物的过敏反应史。
* 人类免疫缺陷病毒（HIV）、乙型肝炎病毒（HBV）或丙型肝炎病毒（HCV）感染暴露，定义如下：
* HIV血清学阳性。
* 通过乙型肝炎表面抗原（HBsAg）检测证实的活动性HBV感染。
* HCV血清学阳性。
* 既往使用整合载体的基因治疗（自体B7-H3 CAR T细胞再治疗除外）。
* 既往任何异基因造血干细胞移植史。
* 存在真菌、细菌、病毒或其他感染，若对积极治疗有应答则允许。
* 中枢神经系统（CNS）疾病，如脑血管缺血/出血、痴呆、小脑疾病或累及CNS的自身免疫性疾病，可能损害神经毒性评估能力。
* 筛选时IOCBP经β-人绒毛膜促性腺激素（β-HCG）血清或尿液妊娠试验确认妊娠。
* 通过病史、体格检查、心电图（ECG）评估的未控制合并疾病或医学状况，或会不可接受地增加参与者风险或损害研究终点评估能力的情况。
* INCLUSION CRITERIA:
* Age \>=18 years old.
* Histologically confirmed small cell lung cancer (SCLC) or extrapulmonary neuroendocrine cancers (EP-NEC) that has recurred following or is refractory to first-line therapy. Note: small cell cancers of non-lung primary sites are also eligible.
* Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2.
* Pulse oximetry \>= 90% on room air.
* Aspartate Transferase (AST) \< 3 X institutional upper limit of normal (ULN). Note: in case of liver metastases \<= 5 X ULN is acceptable.
* Alanine Aminotransferase (ALT) \< 3 X institutional ULN. Note: in case of liver metastases \<= 5 X ULN is acceptable.
* Total bilirubin \<=2 X institutional ULN.
* Creatinine \<=1.5 X institutional ULN OR creatinine clearance (CrCl) \>= 50 mL/min/1.73m\^2 (calculated by the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] formula or calculated eGFR provided by a laboratory).
* Absolute Neutrophil Count (ANC) \>= 750/mcL.
* Platelet count \>= 75,000/mcL.
* An absolute lymphocyte count (ALC) \>=300/mcL and CD3+ cell count \>=150/mcL.
* Normal cardiac ejection fraction as defined by \>= 45% by echocardiogram (ECHO) at screening.
* At least 1 measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 that has not been previously irradiated.
* Recovered from acute toxic effects of all prior cancer therapy to Grade \<2 per Common Terminology Criteria for Adverse Events (CTCAE) v.6.0 at least one week before apheresis excluding the parameters for ANC and ALC mentioned above.
* The following criteria must be met prior to apheresis:
* Chemotherapy and biologic/targeted agents:
* \>=14 days since the last dose of standard myelosuppressive chemotherapy.
* \>= 7 days since the completion of biologic agent, targeted agent, or tyrosine kinase inhibitor therapy.
* \>= 3 weeks or 5 half-lives (whichever is shorter) since prior therapy with a monoclonal antibody.
* Radiotherapy:
* \>= 1 week since the last radiotherapy session.
* No washout period required for palliative radiation to non-target lesions.
* \>= 3 weeks since hepatic radiation, chemoembolization, and/or radiofrequency ablation.
* Steroids and immunosuppressive therapy:
* Corticosteroids: \>= 2 weeks since the therapeutic doses (\> 0.5 mg/kg/day prednisone or equivalent). Note: Inhaled or topical steroids are not exclusionary.
* Physiologic replacement doses (up to 5 mg/day prednisone equivalent) are allowed and can be adjusted based on participant's BMI if warranted.
* \>= 2 weeks since the other immunosuppressive medication (e.g., calcineurin inhibitors, methotrexate, rapamycin, thalidomide, etc.).
* Anti-PD-1 and any investigational therapies:
* \>= 2 weeks since Anti-PD-1 monoclonal antibody therapy.
* \>= 2 weeks or 5 half-lives of the investigational product (whichever is shorter) since any investigational treatment or clinical trial participation.
* Other criteria:
* 72 hours since small molecule tyrosine kinase inhibitors (e.g., EGFR inhibitors), PARP inhibitors, or KRAS G12C inhibitors.
* Individuals of childbearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device \[IUD\], abstinence, surgical sterilization) at the study entry and up to 12 months after the last dose of combined chemotherapy.
Note: IOCBP is defined as any individual who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.
* Individuals able to father a child must agree to use an effective method of contraception (barrier, surgical sterilization, abstinence) at the study entry and up to 7 months after the last dose of study drugs. We also will recommend individuals able to father a child with partners of childbearing potential ask partners to be on highly effective birth control (hormonal, IUD, surgical sterilization). Individuals able to father a child must not freeze or donate sperm within the same period.
* Nursing participants must be willing to discontinue nursing from study treatment initiation through 6 months after the last dose of the study drug(s).
* Ability of the participant to understand and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
* History of anaphylactic reactions attributed to anti-B7-H3 antibodies or compounds of similar chemical or biologic composition to autologous B7-H3 CAR T cells, cyclophosphamide, fludarabine, or other agents used in this study.
* Infection exposure with the human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) as defined below:
* Positive serology for HIV.
* Active HBV infection as demonstrated by test for hepatitis B surface antigen (HBsAg).
* Positive serology for HCV.
* Prior gene therapy using an integrating vector (except for autologous B7-H3 CAR T cells retreatment).
* History of any previous allogeneic hematopoietic stem cell transplant.
* Presence of fungal, bacterial, viral, or other infection is permitted if responding to active treatment.
* Central Nervous System (CNS) disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or autoimmune disease with CNS involvement that may impair the ability to evaluate neurotoxicity.
* Pregnancy confirmed with beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test in IOCBP at screening.
* Uncontrolled intercurrent illness or medical condition(s) evaluated by medical history, physical exam, electrocardiogram (ECG) or situations that would unacceptably increase risk for the participant or impair the ability to evaluate the endpoints of the study.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：Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of autologous B7-H3 CAR T cells · The MTD/MAD is the dose level at which no more than 1 of up to 6 participants experience DLT during autologous B7-H3 CAR T cell treatment, and the dose below that at which at least 2 (of \<=6) participants have DLT as a result of treatment. · Dose Limiting Toxicity (DLT) period (day 0 through day 28)；Determine disease control rate (DCR) · DCR will be reported as a percentage of participants who achieve a complete response, partial response, or stable disease following autologous B7-H3 CAR T cells treatment. · Until disease progression or 15 years, whichever occurs first
次要终点：Assess safety of autologous B7-H3 CAR T cells infusion；Objective Response Rate (ORR)；Duration of Response (DOR)；Progression Free Survival (PFS)；Overall Survival (OS)；Evaluate safety of re-treatment
自体 B7-H3 CAR T 细胞的递增剂量。
自体 B7-H3 CAR T 细胞的最大耐受剂量（MTD）或最大给药剂量（MAD）。
背景： 小细胞肺癌（SCLC）是致死率最高的肺癌类型。肺外神经内分泌癌（EPNEC）是一种类似的癌症，发生在肺部以外的任何部位。EPNEC同样致命。B7-H3是一种常见于SCLC和EPNEC肿瘤细胞中的蛋白。研究人员可以改造人体自身的T细胞（即免疫细胞），使其靶向B7-H3。当这些改造后的T细胞回输到体内时——这种治疗方法称为B7-H3嵌合抗原受体（CAR）T细胞疗法——它们可能有助于杀死癌细胞。 目的： 在SCLC或EPNEC患者中测试B7-H3 CAR T细胞疗法。 入选条件： 年龄18岁及以上、患有SCLC或EPNEC且治疗后未缓解或复发的患者。 设计： 参与者将接受筛选。他们将进行血液检查和心脏功能检查。他们将接受影像学扫描。 参与者将接受单采术：通过针头从体内采集血液。血液将通过一台机器分离出T细胞。剩余的血液将通过另一根针头回输到体内。采集的T细胞将被改造，使其能够攻击带有B7-H3的细胞。 参与者将住院至少15天。他们将接受化疗药物以做好治疗前的身体准备。这些药物将通过插入静脉的针头所连接的管路给药。 改造后的T细胞将通过静脉输注。参与者将留在医院，直到身体状况足够好可以回家。 随访将持续15年。
Background: Small cell lung cancer (SCLC) is the deadliest form of lung cancer. Extrapulmonary neuroendocrine cancer (EPNEC) is a similar type of cancer that develops anywhere other than the lungs. EPNEC is also deadly. B7-H3 is a protein often found in SCLC and EPNEC tumor cells. Researchers can modify a person s own T cells, or immune cells, to target B7-H3. When these modified T cells are returned to the body-a treatment called B7-H3 chimeric antigen receptor (CAR) T cell therapy-they may help kill cancer cells. Objective: To test B7-H3 CAR T cell therapy in people with SCLC or EPNEC. Eligibility: People aged 18 years and older with SCLC or EPNEC that either did not respond or returned after treatment. Design: Participants will be screened. They will have blood tests and tests of their heart function. They will have imaging scans. Participants will undergo apheresis: Blood will be taken from the body through a needle. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different needle. The collected T cells will be altered to make them attack cells with B7-H3. Participants will be in the hospital for at least 15 days. They will receive chemotherapy drugs to prepare their body for the treatment. These drugs will be given through a tube attached to a needle inserted into a vein. The modified T cells will be infused through a vein. Participants will remain in the hospital until they are well enough to go home. Follow-up visits will continue for 15 years....
MEMBER ACCOUNT
登录成功会直接打开下一页。