肿瘤细胞治疗研究
英文原题：B7H3/IL13Ra2 Bispecific Armored Chimeric Antigen Receptor T-Cell Therapy Study for Recurrent/Refractory Glioblastoma
这是一项 I 期注册临床试验，评估人源细胞治疗用于胶质母细胞瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 14 例。试验地点：中国 · 杭州（共 1 个中心，其中中国 1 个）。登记号：NCT07193628。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： • 同意遵守研究治疗计划和访视安排，自愿参加并签署书面知情同意书。 • 签署知情同意书时年龄18–75岁（含），性别不限。 • Karnofsky体能状态（KPS）评分≥60%。 • 组织病理学和/或细胞学确诊B7H3和/或IL13Ra2阳性复发/难治性胶质母细胞瘤，且B7H3阳性表达率>30%、IL13Ra2阳性表达率>30%；接受术后放疗及同步、辅助替莫唑胺化疗后疾病进展或复发；至少有1个可测量病灶（按RANO标准，两个相互垂直径线均≥10 mm）。 • 预期生存期≥12周。 • 器官功能符合实验室指标：ANC≥1.5×10⁹/L、血小板≥100×10⁹/L、ALC≥0.3×10⁹/L、血红蛋白≥8.0 g/dL；总胆红素≤1.5×ULN；无肝受累者AST/ALT≤3×ULN，有肝受累者AST/ALT≤5×ULN；血清肌酐≤1.6×ULN，或按Cockcroft-Gault公式计算肌酐清除率≥50 mL/min；INR及APTT均≤1.5×ULN；LVEF>50%。 • 有生育能力男性及育龄女性同意自签署知情同意书起至末次研究药物给药后1年采取有效避孕措施。育龄女性须在研究药物给药前≤7天内妊娠试验阴性。 排除标准： • 病灶位于小脑、脑桥或延髓等后颅窝结构。 • 合并脑膜转移或脑脊液中检出恶性肿瘤细胞。 • 癫痫和/或颅内压升高，药物无法控制或稳定。 • 合并其他中枢神经系统疾病，或筛选前6个月内有CNS疾病史，如未控制的脑血管意外、短暂性脑缺血发作、中风或累及中枢神经系统的其他自身免疫病。 • 筛选前5年内诊断其他恶性肿瘤；充分治疗的宫颈原位癌、皮肤基底细胞癌或鳞状细胞癌、根治治疗后的局限性前列腺癌及根治治疗后的乳腺导管原位癌除外。 • 既往接受B7H3/IL13Ra2靶向治疗、基因治疗或细胞治疗。 • 有长期使用免疫抑制剂或大剂量激素史；用于慢性支气管炎或哮喘的吸入激素不受此限。 • 既往接受异基因造血干细胞移植；或符合自体造血干细胞移植条件并同意接受移植。 • 未控制的活动性细菌、病毒或真菌感染。 • 任何不稳定全身性疾病，包括但不限于心血管疾病（如不稳定型心绞痛、筛选前6个月内心肌梗死、NYHA≥Ⅲ级心衰、需药物治疗的严重心律失常）以及肺、肝、肾、消化系统或代谢性疾病。 • CAR-T输注前1周内接受口服抗凝治疗。 • 细胞输注前4周内或药物5个半衰期内（取较短者）接受抗肿瘤治疗（包括化疗、靶向、免疫、肿瘤电场治疗、研究药物等），和/或毒性尚未恢复至CTCAE 5.0≤1级；脱发除外，≤2级周围神经毒性可接受。 • 细胞输注前12周内接受放疗；照射野外疾病进展，或可排除放疗/化疗后假性进展者可入组。 • 签署知情同意前4周内接受重大手术或发生严重创伤，手术副作用尚未恢复，或研究期间计划接受重大手术。 • HBsAg阳性；HBcAb阳性且外周血HBV DNA定量高于检测下限；HCV抗体阳性且外周血HCV RNA定量高于检测下限；HIV抗体阳性；活动性梅毒感染。 • 妊娠或哺乳期女性。 • 研究者认为会影响依从性或不适合参加本试验的其他情况。
Inclusion Criteria: * 1: Agree to comply with the trial treatment plan and visit schedule, voluntarily enroll in the trial, and sign the informed consent form in writing. 2: On the day of signing the informed consent form, the subject shall be aged between 18 and 75 years inclusive, with no restriction on gender. 3: Karnofsky Performance Status (KPS) score ≥ 60% 4: Patients with B7H3- and/or IL13Ra2-positive recurrent or refractory glioblastoma confirmed by histopathology and/or cytology, meeting the following criteria: The positive expression rate of B7H3 \> 30%; The positive expression rate of IL13RA2 \> 30%; Disease progression or recurrence after standard treatment (postoperative radiotherapy combined with concurrent and adjuvant chemotherapy with temozolomide); The subject has at least one measurable lesion (based on RANO criteria, with mutually perpendicular diameters both ≥ 10mm). 5: Expected survival time ≥ 12 weeks; 6: Subjects must have adequate organ function, meeting the following laboratory test criteria: Bone Marrow Function: Absolute Neutrophil Count (ANC) ≥ 1.5×10⁹/L; Platelet Count (PLT) ≥ 100×10⁹/L; Absolute Lymphocyte Count ≥ 0.3×10⁹/L; Hemoglobin (HGB) ≥ 8.0 g/dL. Liver function: Serum total bilirubin (T-Bil) ≤ 1.5 × upper limit of normal (ULN); for patients without liver involvement, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN; for patients with liver involvement, ALT and AST ≤ 5 × ULN; Renal function: Serum creatinine ≤ 1.6 × ULN, or creatinine clearance (Ccr) ≥ 50 mL/min (calculated according to the Cockcroft-Gault formula); Coagulation function: International normalized ratio (INR) ≤ 1.5 × ULN; activated partial thromboplastin time (APTT) ≤ 1.5 × ULN; Left ventricular ejection fraction \> 50%. 7: Male subjects with reproductive potential and female subjects of childbearing age must agree to use effective contraceptive measures from the time of signing the informed consent form until 1 year after the last administration of the trial drug. For female subjects of childbearing age, the pregnancy test result within ≤7 days before the administration of the trial drug must be negative. Exclusion Criteria: * 1: The lesion is located in the posterior fossa structures such as the cerebellum, pons, and medulla oblongata. 2: Complicated with meningeal metastasis or detectable malignant tumor cells in cerebrospinal fluid. 3: Presence of epilepsy and/or high intracranial pressure that cannot be controlled or stabilized with medication. 4: Subjects with current comorbid other central nervous system (CNS) diseases or a history of CNS diseases within 6 months prior to screening, such as uncontrolled cerebrovascular accident, transient ischemic attack, stroke, and any other autoimmune diseases involving the central nervous system. 5: Subjects who have been diagnosed with other malignant tumors within 5 years prior to screening, excluding adequately treated carcinoma in situ of the cervix, basal cell or squamous cell carcinoma of the skin, localized prostate cancer after radical treatment, and ductal carcinoma in situ of the breast after radical treatment. 6: Subjects who have previously received treatment targeting B7H3/IL13Ra2. 7: Subjects who have previously received gene therapy or cell therapy. 8: Subjects who have a history of long-term use of immunosuppressive drugs or high-dose steroid hormones; inhaled hormones used for the treatment of chronic bronchial inflammation or asthma are not affected. 9: Subjects who have previously received allogeneic hematopoietic stem cell transplantation; or those who are eligible for and agree to undergo autologous hematopoietic stem cell transplantation. 10: Uncontrolled active bacterial, viral, or fungal infection. 11: Any unstable systemic disease, including but not limited to cardiovascular diseases such as unstable angina pectoris, myocardial infarction (within 6 months before screening), congestive heart failure (New York Heart Association \[NYHA\] classification ≥ III), severe arrhythmias requiring medication, as well as pulmonary, hepatic, renal, digestive system, or metabolic diseases. 12: Subjects who have received oral anticoagulant therapy within 1 week prior to CAR-T cell infusion. 13: Subjects who have received anti-tumor therapy (including chemotherapy, targeted therapy, immunotherapy, TTfield therapy, investigational trial drugs, and other anti-tumor treatments) within 4 weeks prior to cell infusion or within 5 half-lives of the drug (whichever is shorter), and/or have not recovered from toxic reactions (recovery to CTCAE Version 5.0 grade ≤ 1) (except for alopecia; peripheral neurotoxicity with grade ≤ 2 is acceptable). 14: Subjects who have received radiotherapy within 12 weeks prior to cell infusion (those with progressive disease outside the irradiated field or those in whom pseudo-progression after radiotherapy/chemotherapy can be excluded are eligible for enrollment). 15: Subjects who have undergone major surgery or significant traumatic injury within 4 weeks prior to informed consent, or have not recovered from the side effects of surgery, or plan to undergo major surgery during the trial period. 16: Positive for hepatitis B surface antigen (HBsAg); positive for hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA quantitative test result above the lower limit of detection; positive for hepatitis C virus (HCV) antibody with peripheral blood HCV RNA quantitative test result above the lower limit of detection; positive for human immunodeficiency virus (HIV) antibody; subjects with active syphilis infection. 17: Pregnant or lactating women. 18: Investigators consider that the subject has other conditions that may affect compliance or make them unsuitable for participation in this trial.
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：The incidence of grade 3-4 adverse events (AEs) related to B7H3/IL13Ra2 CAR-T therapy. · The incidence of grade 3-4 adverse events (AEs) related to B7H3/IL13Ra2 CAR-T therapy assessed by the NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria . · 28 days after first infusion of CAR-T treatment
次要终点：Objective response rate (ORR) within 12 months of the follow-up period；Duration of response (DOR) within 12 months of the follow-up period；Disease control rate (DCR) within 12 months of the follow-up period；Progression-Free Survival (PFS) within 12 months of the follow-up period；Overall Survival (OS) within 12 months of the follow-up period
经Ommaya储液囊向受试者脑室内注射2.5×10⁶个EPC-003 CAR-T细胞。
经Ommaya储液囊向受试者脑室内注射5×10⁶个EPC-003 CAR-T细胞。
经Ommaya储液囊向受试者脑室内注射10×10⁶个EPC-003 CAR-T细胞。
经Ommaya储液囊向受试者脑室内注射20×10⁶个EPC-003 CAR-T细胞。
本研究者发起、开放标签Ⅰ期临床试验评估全人源抗B7H3/IL13Ra2装甲CAR-T细胞注射液（EPC-003）治疗复发/难治性胶质母细胞瘤的安全性和疗效。计划纳入约14例患者。筛选期为第-28至-15天；符合条件者经Ommaya储液囊于第0、7、14、21、28和35天每周接受一次脑室内注射，共6次。研究分为剂量递增和剂量扩展两个阶段。
This study is an investigator-initiated, open-label Phase I clinical trial designed to evaluate the safety and efficacy of EPC-003 fully human anti-B7H3/IL13Ra2 armored Chimeric Antigen Receptor T-Cell Therapy (CAR-T) cell injection in patients with recurrent or refractory glioblastoma. Approximately 14 patients with relapsed or refractory glioblastoma are planned to be enrolled in this trial. During the screening period (Days -28 to -15), subjects will undergo relevant examinations or observations to confirm the disease status, treatment history, and other related information. Subjects who meet the screening criteria will be enrolled in the clinical trial to receive EPC-003 treatment. Specifically, they will receive intraventricular injection of EPC-003 via Ommaya reservoir on Day 0 (D0), Day 7 (D7), Day 14 (D14), Day 21 (D21), Day 28 (D28), and Day 35 (D35), once a week, totaling 6 administrations. All CAR-T cell infusions will be delivered via intraventricular injection. This trial comprises two phases: the first phase is the dose-escalation phase, and the second phase is the dose-expansion phase.
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