肿瘤细胞治疗研究
英文原题：Phase I Study of TX103 CAR-T Cells in Participants With Advanced Solid Tumors
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗实体瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 85 例。试验地点：中国 · 北京（共 2 个中心，其中中国 2 个）。登记号：NCT07231081。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准：
* 1. 自愿参加：受试者必须自愿参加本临床试验，充分理解并签署知情同意书（ICF），愿意且能够遵守所有研究程序。
2. 年龄：签署ICF时年龄≥18岁且<75岁的男性或女性患者。
3. 诊断：受试者必须经病理学确诊为B7-H3/CD276阳性晚期实体瘤，且标准治疗失败或对标准治疗不耐受。
* 腹腔灌注队列：限于复发或转移性卵巢癌、输卵管癌、原发性腹膜癌，或其他局限于腹腔内伴腹膜转移的晚期实体瘤受试者。
* 静脉输注队列：伴或不伴腹膜转移的晚期实体瘤受试者，最好包括头颈部鳞状细胞癌、食管癌、肺部恶性肿瘤、三阴性乳腺癌、结直肠癌及间叶组织来源恶性肿瘤。
4. B7-H3/CD276表达：肿瘤组织免疫组化（IHC）结果显示B7-H3/CD276阳性≥20%，定义为非坏死肿瘤组织中B7-H3/CD276膜表达阳性的存活肿瘤细胞百分比。
5. 可测量/可评估病灶：
* 腹腔灌注队列Ia期：至少有一个符合RECIST 1.1的可评估病灶；
* 静脉输注队列（Ia和Ib）及腹腔灌注队列（Ib）：至少有一个符合RECIST 1.1的可测量病灶。
6. 体能状态：美国东部肿瘤协作组（ECOG）体能状态评分为0-1。
7. 预期生存期：预期生存期>6个月。 8. 单采能力：有足够的静脉通路进行白细胞单采，且无操作禁忌症。
9. 筛选期内器官功能充分（依据NCI CTCAE v5.0）：
1. 血液学：WBC ≥ 3.0×10⁹/L；血红蛋白 ≥ 8.0 g/dL；中性粒细胞绝对计数 ≥ 1.5×10⁹/L；血小板计数 ≥ 75.0×10⁹/L。检测前14天内未接受输血或支持治疗（如G-CSF、促红细胞生成素、TPO激动剂、IL-11）。
2. 肾功能：血清肌酐 ≤ 1.5×正常值上限（ULN），且估算肾小球滤过率（eGFR）或肌酐清除率（CrCl，按Cockcroft-Gault公式计算）> 50 mL/min。
3. 肝功能：ALT和AST ≤ 2.5× ULN（肝转移患者 ≤ 5.0× ULN）。
4. 胆红素：总胆红素 ≤ 2.0× ULN（Gilbert综合征患者除外）。
5. 凝血功能：PT、APTT或INR ≤ 1.5× ULN（未接受抗凝治疗）。
6. 心功能：入组前1个月内左心室射血分数（LVEF）≥ 50%。
7. 妊娠试验：有生育潜力的女性血清妊娠试验阴性。
8. 避孕：有生育潜力的受试者必须同意自签署知情同意书之日起至末次输注后365天采取有效避孕措施。
排除标准：
* 1. 妊娠或哺乳期女性。 2. 病毒感染：
1. HIV抗体或梅毒血清学检测阳性；
2. HBsAg或HBcAb阳性且HBV DNA ≥ 2000 IU/mL；
3. HCV抗体阳性且HCV RNA可检测到；
4. 存在其他活动性病毒血症。 3. 已知对TX103 CAR-T或研究药物的任何成分（包括氟达拉滨、环磷酰胺或托珠单抗）有超敏反应、过敏、不耐受或禁忌，或曾有严重过敏反应史。
4. 活动性自身免疫性疾病，包括但不限于自身免疫性肝炎、间质性肺炎、葡萄膜炎、肠炎、肝炎、垂体炎、血管炎、肾炎、甲状腺功能亢进或甲状腺功能减退。
* 患有白癜风或已缓解且无需干预的儿童期哮喘的受试者可纳入。
* 需要药物干预（如支气管扩张剂）治疗哮喘的受试者排除。
5. 正在接受全身性免疫抑制治疗，或研究者判断在研究期间需要长期使用免疫抑制剂。允许使用局部、吸入或鼻用皮质类固醇。
6. 既往接受过任何基因工程T细胞治疗（包括CAR-T或TCR-T）或任何其他基因治疗。
7. 有器官移植史。 8. 未经治疗或有症状的中枢神经系统（CNS）转移或软脑膜转移。
* 既往接受过脑/软脑膜转移治疗且神经系统稳定≥1个月（MRI）且停用全身性皮质类固醇>2周的受试者可能符合条件。
9. 影像学（CT/MRI）显示肿瘤侵犯大血管（如主动脉、肺动脉/静脉、腔静脉）或血管边缘不清晰。
10. 输注前1年内有癫痫或诱发癫痫发作的疾病史。
11. 既往抗肿瘤治疗未解决的毒性未恢复至CTCAE v5.0 1级或以下，但研究者判断无安全性风险的毒性除外（如脱发、2级周围神经病变、经替代治疗稳定的甲状腺功能减退）。
12. 白细胞分离术前1个月内接受过大手术或严重创伤。 13. 任何可能增加风险或干扰研究结果的严重、急性或慢性医学或精神状况，或实验室异常，包括但不限于：
1. 淋巴细胞清除前需要全身性治疗的活动性感染；
2. 未控制的心脏疾病：不稳定型心绞痛、1年内心肌梗死、心力衰竭（NYHA分级≥II级）或需要治疗/干预的临床显著心律失常；
3. 控制不佳的高血压（尽管治疗，收缩压≥160 mmHg或舒张压≥100 mmHg）；
4. 首次输注前3个月内有临床显著出血（如消化道出血、出血性溃疡、大便隐血++或以上、血管炎）；
5. 首次输注前6个月内有动脉/静脉血栓事件（如卒中、TIA、脑出血、DVT、肺栓塞）；
6. 具有临床意义的胸腔、心包或腹腔积液，且无法通过引流或其他方式控制；
7. 严重肝硬化、肝萎缩或严重门静脉高压；
8. 完全性肠梗阻。
14. 过去3年内有或并发恶性肿瘤，但已充分治疗的非黑色素瘤皮肤癌或原位癌（如宫颈、膀胱或乳腺）除外。
Inclusion Criteria:
* 1\. Voluntary participation: Subjects must voluntarily participate in this clinical trial, fully understand and sign the informed consent form (ICF), and be willing and able to comply with all study procedures.
2\. Age: Male or female patients aged ≥18 years and \<75 years at the time of signing the ICF.
3\. Diagnosis: Subjects must have B7-H3/CD276-positive advanced solid tumors confirmed by pathology, who have failed standard therapy or are intolerant to standard treatment.
* Intraperitoneal infusion cohort: limited to subjects with recurrent or metastatic ovarian cancer, fallopian tube cancer, primary peritoneal cancer, or other advanced solid tumors with peritoneal metastases confined to the peritoneal cavity.
* Intravenous infusion cohort: subjects with advanced solid tumors regardless of peritoneal metastasis, preferably including head and neck squamous cell carcinoma, esophageal cancer, lung malignancies, triple-negative breast cancer, colorectal cancer, and mesenchymal-derived malignancies.
4\. B7-H3/CD276 expression: Tumor tissue immunohistochemistry (IHC) results show B7-H3/CD276 positivity ≥20%, defined as the percentage of viable tumor cells with positive membrane expression of B7-H3/CD276 in non-necrotic tumor tissue.
5\. Measurable/evaluable disease:
* Intraperitoneal infusion cohort, Phase Ia: at least one evaluable lesion per RECIST 1.1;
* Intravenous infusion cohorts (Ia and Ib) and intraperitoneal infusion cohort (Ib): at least one measurable lesion per RECIST 1.1.
6\. Performance status: Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
7\. Life expectancy: Expected survival of \>6 months. 8. Apheresis capability: Adequate venous access for leukapheresis and no contraindications to the procedure.
9\. Adequate organ function (per NCI CTCAE v5.0) within screening period:
1. Hematologic: WBC ≥ 3.0×10⁹/L; hemoglobin ≥ 8.0 g/dL; absolute neutrophil count ≥ 1.5×10⁹/L; platelet count ≥ 75.0×10⁹/L. No transfusions or supportive treatments (e.g., G-CSF, erythropoietin, TPO agonists, IL-11) within 14 days before testing.
2. Renal: Serum creatinine ≤ 1.5× upper limit of normal (ULN) and estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl, per Cockcroft-Gault formula) \> 50 mL/min.
3. Hepatic: ALT and AST ≤ 2.5× ULN (≤ 5.0× ULN for patients with liver metastases).
4. Bilirubin: Total bilirubin ≤ 2.0× ULN (except for patients with Gilbert's syndrome).
5. Coagulation: PT, APTT, or INR ≤ 1.5× ULN (without anticoagulant therapy).
6. Cardiac function: Left ventricular ejection fraction (LVEF) ≥ 50% within 1 month before enrollment.
7. Pregnancy test: Negative serum pregnancy test for women of childbearing potential.
8. Contraception: Subjects with reproductive potential must agree to use effective contraception from the date of informed consent signing until 365 days after the last infusion.
Exclusion Criteria:
* 1\. Pregnant or lactating women. 2. Viral infections:
1. Positive for HIV antibody or syphilis serologic test;
2. Positive for HBsAg or HBcAb with HBV DNA ≥ 2000 IU/mL;
3. Positive for HCV antibody with detectable HCV RNA;
4. Presence of other active viremia. 3. Known hypersensitivity, allergy, intolerance, or contraindication to TX103 CAR-T or any component of the study drugs (including fludarabine, cyclophosphamide, or tocilizumab), or history of severe allergic reactions.
4\. Active autoimmune diseases, including but not limited to autoimmune hepatitis, interstitial pneumonitis, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, or hypothyroidism.
* Subjects with vitiligo or childhood asthma that has resolved and requires no intervention may be included.
* Subjects requiring medical intervention for asthma (e.g., bronchodilators) are excluded.
5\. Receiving systemic immunosuppressive therapy, or judged by the investigator to require long-term immunosuppressants during the study. Topical, inhaled, or intranasal corticosteroids are permitted.
6\. Prior exposure to any gene-engineered T-cell therapy (including CAR-T or TCR-T) or any other gene therapy.
7\. History of organ transplantation. 8. Untreated or symptomatic central nervous system (CNS) metastases or leptomeningeal metastases.
* Subjects previously treated for brain/leptomeningeal metastases may be eligible if neurologically stable for ≥1 month (MRI) and off systemic corticosteroids for \>2 weeks.
9\. Imaging (CT/MRI) showing tumor invasion of major blood vessels (e.g., aorta, pulmonary arteries/veins, vena cava) or indistinct vascular margins.
10\. History of epilepsy or seizure-provoking disorders within 1 year prior to infusion.
11\. Unresolved toxicities from prior anticancer therapy not recovered to CTCAE v5.0 Grade ≤1, except for investigator-judged non-safety-risk toxicities (e.g., alopecia, Grade 2 peripheral neuropathy, stable hypothyroidism with replacement therapy).
12\. Major surgery or significant trauma within 1 month prior to leukapheresis. 13. Any severe, acute, or chronic medical or psychiatric condition, or laboratory abnormality that may increase risk or interfere with study results, including but not limited to:
<!-- -->
1. Active infection requiring systemic therapy prior to lymphodepletion;
2. Uncontrolled cardiac disease: unstable angina, myocardial infarction within 1 year, heart failure (NYHA class ≥ II), or clinically significant arrhythmia requiring treatment/intervention;
3. Poorly controlled hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg despite therapy);
4. Clinically significant bleeding (e.g., GI bleeding, bleeding ulcers, stool occult blood ++ or above, vasculitis) within 3 months before first infusion;
5. Arterial/venous thrombotic events (e.g., stroke, TIA, intracerebral hemorrhage, DVT, pulmonary embolism) within 6 months before first infusion;
6. Clinically significant pleural, pericardial, or peritoneal effusions not controllable by drainage or other means;
7. Severe cirrhosis, hepatic atrophy, or severe portal hypertension;
8. Complete intestinal obstruction. 14. History of or concurrent malignancy within the past 3 years, except for adequately treated non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, or breast).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：Safety#Incidence and severity of adverse events (AEs) · To evaluate the possible adverse events after TX103 infusion, including the incidence, and severity of AEs. · 1 year post CAR-T cells infusion；Safety#Incidence of Dose Limiting Toxicity (DLT) · Type, incidence, and severity of dose limiting toxicities (DLTs) within 28 days after the first TX103 infusion. · 28 days after the first TX103 infusion；The maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of TX103 · From first dose of TX103 until the end of Dose Limiting Toxicity (DLT) observation period (typically 28 days post-infusion for each dose).
次要终点：Progression Free Survival (PFS)；Disease Control Rate (DCR)；Overall survival (OS)；Objective response rate (ORR)；Time to Remission (TTR)；Duration of Response (DOR)；Duration of disease control (DDC)
该组受试者将通过静脉输注接受 TX103 CAR-T 细胞。将采用标准 3+3 剂量递增设计评估安全性、耐受性和初步抗肿瘤活性。计划剂量水平如下：剂量水平 1：1.0 × 10⁸ CAR-T 细胞；剂量水平 2：3.0 × 10⁸ CAR-T 细胞；剂量水平 3：9.0 × 10⁸ CAR-T 细胞；剂量水平 4：2.0 × 10⁹ CAR-T 细胞。
该组受试者将通过腹腔内（IP）输注接受 TX103 CAR-T 细胞。该队列将在 IV 剂量递增队列之后依次启动。IP 队列的起始剂量将基于 IV 队列中确定的安全且可能有效的剂量。进一步的剂量递增将由安全科学委员会根据累积的安全性和有效性数据确定。计划剂量水平如下：剂量水平 1：1.0 × 10⁸ CAR-T 细胞；剂量水平 2：3.0 × 10⁸ CAR-T 细胞；剂量水平 3：9.0 × 10⁸ CAR-T 细胞；剂量水平 4：2.0 × 10⁹ CAR-T 细胞；剂量水平 5：4.0 × 10⁹ CAR-T 细胞。 剂量递增将依次进行，在每个剂量水平进行安全性评估后再递增。
该组受试者将接受在 Ia 期剂量递增队列中确定的安全且可能有效的剂量的 TX103 CAR-T 细胞。扩展队列将聚焦于在 Ia 期中显示出初步抗肿瘤活性迹象的肿瘤类型，选择时还将考虑临床需求和其他相关因素。该队列的目的是进一步评估 TX103 CAR-T 疗法在这些选定肿瘤类型中的安全性、耐受性和初步疗效。
这是一项单臂、开放标签的I期研究，旨在评估TX103 CAR-T细胞在TX103阳性晚期实体瘤受试者中的安全性、耐受性和抗肿瘤活性。该研究还旨在探索TX103 CAR-T细胞疗法的最大耐受剂量（MTD）并确定推荐的II期剂量（RP2D）。
This is a single-arm, open-label, Phase I study to evaluate the safety, tolerability, and antitumor activity of TX103 CAR-T cells in subjects with TX103-positive advanced solid tumors. The study also aims to explore the maximum tolerated dose (MTD) and determine the recommended Phase II dose (RP2D) of TX103 CAR-T cell therapy.
MEMBER ACCOUNT
登录成功会直接打开下一页。