肿瘤细胞治疗研究
英文原题：Phase I Study of Umbilical Cord Blood Natural Killer (NK) Cell Therapy for Children With High-risk, R/R Neuroblastoma.
⚠ 该试验的登记信息已有 19 个月未更新， 页面上显示的「招募中」可能已经失效。联系研究中心之前，建议先到 ClinicalTrials.gov 核对登记原文的最新状态与联系方式。
这是一项 I 期注册临床试验，评估脐带血 NK 细胞治疗神经母细胞瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 30 例。试验地点：中国 · 广州（共 2 个中心，其中中国 2 个）。登记号：NCT06631391。
不限性别 · ≥ 1 Day 且 ≤ 18 Years
纳入标准：
必须满足以下所有标准才能参加本试验：
1. 同意参加试验并签署书面知情同意书；
2. 年龄≤18岁，性别不限；
3. Karnofsky（≥16岁）或Lansky（<16岁）体力状况评分（附录II）至少为50分；
4. 根据临床诊断标准诊断为儿童高危、复发/难治性神经母细胞瘤，且已接受综合治疗（手术、化疗、放疗±干细胞移植±GD2单克隆抗体治疗）的患者；
5. 预期生存期至少12周；
6. 患者必须从既往所有抗癌化疗的急性毒性反应中完全恢复，如骨髓抑制恢复至I级；
7. 骨髓抑制性化疗：末次骨髓抑制性化疗后至少21天（若既往使用过亚硝基脲类药物，则为42天）；
8. 除化疗外的研究性药物或抗癌治疗：计划开始NK细胞免疫治疗前28天内不得使用。必须确认已从该治疗的临床显著毒性中完全恢复；
9. 造血生长因子：末次长效生长因子给药后至少14天，或末次短效生长因子给药后至少3天；
10. X线放疗（XRT）：局部姑息性XRT（小野照射）后至少14天；若涉及其他大面积骨髓（BM）照射，包括既往放射性碘标记间碘苄胍（131I-MIBG）治疗，则须至少42天前结束；
11. 未接受全身照射（TBI）的干细胞输注：无活动性移植物抗宿主病，须在移植或干细胞输注后至少56天结束；
12. 筛选期实验室检查必须符合以下条件：
1. 中性粒细胞绝对计数（ANC）≥1.0×10^9/L（若骨髓受累，则ANC ≥0.5×10^9/L）
2. 血小板计数（PLT）≥75×10^9/L（若骨髓受累，则PLT ≥20×10^9/L）
3. 胆红素≤1.5倍正常值上限（ULN）
4. 肌酐≤1.5倍ULN（采用标准Cockcroft-Gault公式计算）
5. ALT/AST ≤3倍ULN（若有肝转移，可放宽至5倍ULN）
13. 研究期间，能够配合门诊治疗、实验室监测及必要的临床访视；儿童或青少年受试者的父母/监护人能够在启动任何方案相关程序前理解、同意并签署知情同意书（ICF）及适用的儿童知情同意书；经父母/监护人同意，受试者能够表达其同意（如适用）。
排除标准：
符合以下任一标准的患者不能参加本试验：
1. 有症状的脑转移（脑转移经过治疗且入组前症状稳定2个月以上的患者可以入组，但必须经头颅MRI、CT或静脉造影证实无脑出血症状）；
2. 患有以下心血管疾病：II级或以上心肌缺血或心肌梗死，控制不佳的心律失常（包括男性QTc间期≥450 ms、女性≥470 ms）；按照NYHA标准（附录三），III-IV级心力衰竭，或超声心动图提示左心室射血分数（LVEF）<50%；
3. 有间质性肺疾病病史或同时患有间质性肺疾病；
4. 凝血功能异常（INR>1.5或凝血酶原时间（PT）>ULN+4秒或APTT>1.5 ULN），具有出血倾向或目前正在接受溶栓或抗凝治疗；
5. 入组前12个月内发生动脉/静脉血栓栓塞事件，如脑血管意外（包括短暂性脑缺血发作、脑出血、脑梗死）、深静脉血栓和肺栓塞；
6. 已知的遗传性或获得性出血及血栓形成倾向（如血友病患者、凝血功能障碍、血小板减少、脾肿大等）；
7. 长期未愈合的伤口或骨折（肿瘤所致病理性骨折除外）；
8. 入组前4周内接受过大手术或遭受严重创伤、骨折或溃疡；
9. 显著影响口服药物吸收的因素，如无法吞咽、慢性腹泻和肠梗阻；
10. 入组前6个月内发生腹部瘘、胃肠道穿孔或腹腔脓肿；
11. 尿常规检查提示尿蛋白≥+，且经证实24小时尿蛋白定量≥1.0 g；
12. 需要对症治疗的有症状浆膜腔积液（包括胸腔积液、腹水、心包积液）；注：无症状浆膜腔积液可以入组，有症状浆膜腔积液经积极对症治疗（不得使用抗肿瘤药物处理浆膜腔积液）后，由研究者判断符合入组标准者可以入组；
13. 需要抗微生物治疗的活动性感染（如需要抗菌药物、抗病毒药物，不包括慢性乙型肝炎抗病毒治疗、抗真菌药物治疗）；
14. 有无法戒除的精神活性物质滥用史或患有精神障碍；
15. 入组前4周内参加过其他抗肿瘤药物临床试验；
16. 首次给药前2周内接受全身激素治疗或接受任何形式的免疫抑制治疗；
17. 过去2年内，患有需要全身性治疗的活动性自身免疫性疾病（如使用疾病调节药物、皮质类固醇或免疫抑制剂）；注：替代治疗（如甲状腺素、胰岛素，或针对肾上腺或垂体功能不全的生理性皮质类固醇替代治疗）不算作全身性治疗；
18. IL-2使用禁忌；
19. 患有需要静脉全身性治疗的活动性感染；
20. 首次使用研究药物前一个月内接种过活疫苗，允许接种灭活病毒的季节性流感疫苗，但不允许接种鼻内减毒活流感疫苗；
21. 既往或同时患有其他未治愈的恶性肿瘤，已治愈的皮肤基底细胞癌、宫颈原位癌和浅表性膀胱癌除外；
22. 研究者判断可能影响临床研究的进行和研究结果确定的其他情况；
23. 筛选期间的病毒学检测显示以下任何一项：
1. HBsAg阳性且HBV DNA超过正常上限
2. 抗-HCV阳性且HCV RNA阳性
3. HIV阳性
24. 接受过同种异体组织/器官移植；
25. 依从性差，无法配合临床研究。
Inclusion Criteria:
All of the following criteria must be met in order to be eligible for this trial:
1. Agree to participate in the trial and sign a written informed consent form;
2. Age ≤18 years, gender not limited;
3. Karnofsky (≥16 years old) or Lansky (\<16 years old) physical status score (Appendix II) of at least 50;
4. Patients diagnosed with high-risk, recurrent/refractory neuroblastoma in children according to clinical diagnostic criteria, who have undergone comprehensive treatment (surgery, chemotherapy, radiotherapy ± stem cell transplantation ± GD2 monoclonal antibody therapy);
5. Expected survival period of at least 12 weeks;
6. The patient must have fully recovered from the acute toxic effects of all previous anticancer chemotherapy, such as recovery to grade I after bone marrow suppression;
7. Bone marrow suppressive chemotherapy: At least 21 days after the last bone marrow suppressive chemotherapy (if nitrosoureas were used previously, then 42 days);
8. Investigational drugs or anticancer therapies other than chemotherapy: Must not be used within 28 days before the planned start of NK cell immunotherapy. Full recovery from the clinically significant toxicity of that therapy must be confirmed;
9. Hematopoietic growth factors: At least 14 days after the last dose of long-acting growth factors or 3 days after the last dose of short-acting growth factors;
10. X-ray therapy (XRT): At least 14 days after local palliative XRT (small field port); if other substantial bone marrow (BM) irradiation is involved, including prior radioactive iodine metaiodobenzylguanidine (131I-MIBG) treatment, it must end at least 42 days ago;
11. Stem cell infusion without total body irradiation (TBI): No active graft-versus-host disease, must have ended at least 56 days after transplantation or stem cell infusion;
12. Laboratory tests during the screening period must meet the following conditions:
1. Absolute neutrophil count (ANC) ≥1.0×10\^9/L (if bone marrow involvement, then ANC ≥0.5×10\^9/L)
2. Platelet count (PLT) ≥75×10\^9/L (if bone marrow involvement, then PLT ≥20×10\^9/L)
3. Bilirubin ≤1.5 times the upper limit of normal (ULN)
4. Creatinine ≤1.5 times ULN (calculated using the standard Cockcroft-Gault formula)
5. ALT/AST ≤3 times ULN (if there is liver metastasis, this can be relaxed to 5 times ULN)
13. During the study period, able to comply with outpatient treatment, laboratory monitoring, and necessary clinical visits; parents/guardians of pediatric or adolescent participants are capable of understanding, consenting to, and signing the informed consent form (ICF) and applicable child assent forms before initiating any protocol-related procedures; with parental/guardian consent, the participant is capable of expressing their consent (when applicable).
Exclusion Criteria:
Patients who meet any of the following criteria are not eligible for this trial:
1. Symptomatic brain metastases (patients whose brain metastases have been treated and whose symptoms have been stable for more than two months prior to enrollment may be enrolled, but must be confirmed by cranial MRI, CT, or venography as having no symptoms of cerebral hemorrhage);
2. Suffering from the following cardiovascular diseases: grade II or higher myocardial ischemia or myocardial infarction, poorly controlled arrhythmias (including QTc interval ≥450 ms for males and ≥470 ms for females); according to the NYHA standard (Appendix Three), class III-IV heart failure, or echocardiography indicating left ventricular ejection fraction (LVEF) \<50%;
3. Having a history of interstitial lung disease or suffering from interstitial lung disease at the same time;
4. Coagulation disorders (INR \>1.5 or prothrombin time (PT) \>ULN +4 seconds or APTT \>1.5 ULN), with a tendency to bleed or currently receiving thrombolytic or anticoagulant therapy;
5. Arterial/venous thromboembolic events occurring within 12 months before enrollment, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
6. Known hereditary or acquired bleeding and thrombosis tendencies (such as hemophilia patients, coagulation disorders, thrombocytopenia, splenomegaly, etc.);
7. Long-term unhealed wounds or fractures (except pathological fractures caused by tumors);
8. Receiving major surgery or experiencing severe traumatic injuries, fractures, or ulcers within 4 weeks before enrollment;
9. Factors significantly affecting the absorption of oral medications, such as inability to swallow, chronic diarrhea, and intestinal obstruction;
10. Experiencing abdominal fistula, gastrointestinal perforation, or abdominal abscess within 6 months before enrollment;
11. Routine urine tests showing proteinuria ≥ +, and confirmed 24-hour urine protein quantification ≥1.0 g;
12. Symptomatic serosal effusions requiring symptomatic treatment (including pleural effusion, ascites, pericardial effusion); Note: Asymptomatic serosal effusions can be enrolled, symptomatic serosal effusions after active symptomatic treatment (anticancer drugs cannot be used for treating serosal effusions), judged by the investigator to meet the enrollment criteria can be enrolled;
13. Active infections requiring antimicrobial treatment (e.g., needing antibacterial drugs, antiviral drugs, excluding chronic hepatitis B antiviral treatment, antifungal drug treatment);
14. History of psychoactive substance abuse that cannot be quit or has mental disorders;
15. Participated in other antitumor drug clinical trials within 4 weeks before enrollment;
16. Receiving systemic hormone therapy or undergoing any form of immunosuppressive therapy within 2 weeks before the first administration;
17. In the past 2 years, suffered from active autoimmune diseases requiring systemic treatment (such as using disease-modifying drugs, corticosteroids, or immunosuppressants); Note: Substitutive treatments (such as thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) do not count as systemic treatment;
18. Contraindications for IL-2 use;
19. Suffering from active infections requiring intravenous systemic treatment;
20. Vaccinated with live vaccines within one month before the first use of the study drug, seasonal influenza vaccination with inactivated virus vaccines is allowed, but intranasal attenuated live influenza vaccines are not allowed;
21. Previous or concomitant other uncured malignancies, cured skin basal cell carcinoma, cervical carcinoma in situ, and superficial bladder cancer are excluded;
22. Other conditions judged by the investigator that may affect the conduct of the clinical study and the determination of study results;
23. Virological tests during the screening period show any of the following:
1. HBsAg positive and HBV DNA exceeds the upper limit of normal
2. Anti-HCV positive and HCV RNA positive
3. HIV positive
24. Undergone allogeneic tissue/organ transplantation;
25. Poor compliance, unable to cooperate with the clinical 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：To evaluate the safety and tolerability of umbilical cord blood natural killer cell injection in combination with other treatments of high-risk, recurrent/refractory neuroblastoma in children · According to the '3+3' design principle, the Maximum Tolerated Dose (MTD) is determined. Adverse events observed during the trial are graded according to the NCI CTCAE 5.0 criteria. Adverse events related to the drug (definitely related, probably related, or possibly related) occurring within 36 days after the first infusion of umbilical cord blood NK cells (during the first cycle) are considered as Dose-Limiting Toxicity (DLT). The definitions of DLT include:
(1) Hematological toxicity:
Grade 4 neutropenia lasting ≥7 days; Grade 4 thrombocytopenia lasting ≥7 days; (2) Grade 3/4 non-hematological toxicities (excluding nausea, vomiting, and alopecia); (3) Any toxicity leading to a delay in chemotherapy for more than 2 weeks. · One weeks after the first cycle (each cycle is 28 days)
次要终点：overall response rate (ORR) after 2 courses of umbilical cord blood natural killer cell infusion
所有受试者将接受体外扩增和激活的脐带血NK细胞输注。
神经母细胞瘤是最常见的颅外实体瘤，超过一半的患者在诊断时已处于转移阶段，被归类为高危。高危神经母细胞瘤预后差，生存率低。尽管接受了诱导、巩固和维持治疗（包括GD2单克隆抗体），生存率仍仅为约60%，许多患者仍然会复发、进展和死亡。 NK细胞疗法是一种新兴的免疫疗法，能够有效抑制和杀伤肿瘤细胞，且无明显不良反应，降低肿瘤复发和转移的风险，提高患者的免疫力和生活质量。其安全性已得到广泛认可。目前，针对神经母细胞瘤患者的NK细胞输注治疗临床试验正在进行中，基于NK细胞的免疫疗法对神经母细胞瘤具有巨大的临床前景。我们计划开展一项关于脐带血NK细胞疗法联合其他治疗（GD2抗体、化疗等）用于儿童高危、复发/难治性神经母细胞瘤的I期临床试验，以确定脐带血NK细胞疗法在这些患者中的最大耐受剂量，从而为未来的联合治疗及II期和III期临床研究奠定基础。
Neuroblastoma is the most common extracranial solid tumor, with more than half of the patients diagnosed at the metastatic stage, classified as high-risk. High-risk neuroblastoma has a poor prognosis and low survival rate. Despite treatment with induction, consolidation, and maintenance therapy including GD2 monoclonal antibody, the survival rate is only about 60%, and many patients still relapse, progress, and die. NK cell therapy is an emerging immunotherapy that can effectively inhibit and kill tumor cells without significant adverse reactions, reducing the risk of tumor recurrence and metastasis, and improving patients' immunity and quality of life. Its safety has been widely recognized. Currently, clinical trials of NK cell infusion therapy for neuroblastoma patients are ongoing, and NK cell-based immunotherapy holds great clinical promise for neuroblastoma. We plan to conduct a phase I clinical trial on umbilical cord blood NK cell therapy in combination with other treatments (GD2 antibody, chemotherpay, etc) for high-risk, recurrent/refractory neuroblastoma in children to determine the maximum tolerated dose of umbilical cord blood NK cell therapy in these patients, thereby laying the foundation for future combination therapies and phase II and III clinical studies.
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