肿瘤细胞治疗研究
英文原题：Umbilical Cord Blood NK Cell Therapy for High-Risk Pediatric Soft Tissue Sarcoma: Efficacy and Safety Study
⚠ 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。
这是一项分期未标注的注册临床试验，评估脐带血 NK 细胞治疗软组织肉瘤的安全性、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：中国 · 广州、东莞（共 2 个中心，其中中国 2 个）。登记号：NCT06848582。
不限性别 · ≤ 18 Years
纳入标准：
要符合研究资格，参与者必须满足以下所有标准：
1. 给予知情同意并签署书面知情同意书。
2. 年龄 ≤ 18岁，无性别限制。
3. Karnofsky（≥16岁）或Lansky（<16岁）（附录2）体能状态评分至少为50（附录2）。
4. 诊断为高危和复发/难治性儿童软组织肉瘤，经临床标准确认，并且既往接受过综合治疗（手术、化疗、放疗和/或干细胞移植）。
5. 预计生存时间至少12周。
6. 从既往抗癌化疗的所有急性毒性中完全恢复，例如骨髓抑制恢复至I级。
7. 骨髓抑制性化疗：末次骨髓抑制性化疗后至少21天（若既往使用亚硝基脲则为42天）。
8. 除化疗外的试验药物或抗癌治疗：在计划开始NK细胞免疫治疗前28天内未使用。必须从该治疗的临床显著毒性中完全恢复。
9. 造血生长因子：末次给予长效生长因子后至少14天，或末次给予短效生长因子后3天。
10. X线治疗（XRT）：局部姑息性XRT（小野照射）后至少14天，或其他实质性骨髓（BM）照射后至少42天，包括既往放射性碘-131间碘苄胍（131I-MIBG）治疗。
11. 未接受全身照射（TBI）的干细胞移植：无活动性移植物抗宿主病（GvHD）证据，且移植或干细胞移植后至少56天。
12. 筛选期实验室检查必须满足以下条件：
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）。
血小板计数（PLT）≥ 75 × 10^9/L（若骨髓受累则PLT ≥ 20 × 10^9/L）。
胆红素 ≤ 正常上限（ULN）的1.5倍。肌酐 ≤ ULN的1.5倍（按标准Cockcroft-Gault公式计算）。
ALT/AST ≤ ULN的3倍（若存在肝转移可放宽至ULN的5倍）。
13. 能够遵守研究期间的门诊治疗、实验室监测和必要的临床访视。对于儿童或青少年参与者，父母/监护人必须能够在启动任何方案相关程序之前理解、同意并签署研究知情同意书（ICF）和适用的儿童同意书。参与者将能够在父母/监护人同意下表达其同意（如适用）。
排除标准：
符合以下任一标准的参与者不符合研究资格：
1. 存在有症状的脑转移（入组前脑转移经治疗且症状稳定至少2个月的患者可入选，但须经颅脑MRI、CT或静脉造影确认无脑出血症状）。
2. 有或当前患有心血管疾病，包括≥II级心肌缺血或心肌梗死、未控制的心律失常（包括男性QTc间期≥450 ms，女性≥470 ms），或根据NYHA标准（附录3）≥III-IV级心力衰竭，或根据超声心动图左心室射血分数（LVEF）< 50%。
3. 有或当前患有间质性肺病。
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），伴有出血倾向或正在接受抗凝或溶栓治疗。
5. 入组前12个月内任何静脉或动脉血栓栓塞事件，包括脑血管意外（包括短暂性脑缺血发作、脑出血、脑梗死）、深静脉血栓形成和肺栓塞。
6. 已知的遗传性或获得性出血和血栓形成倾向（如血友病患者、凝血功能障碍、血小板减少、脾肿大）。
7. 长期未愈合的伤口或骨折（不包括肿瘤引起的病理性骨折）。
8. 入组前4周内进行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，如吞咽困难、慢性腹泻和肠梗阻。
10. 过去6个月内有腹部瘘、胃肠道穿孔或腹膜炎病史。
11. 尿常规显示蛋白尿≥ ++，且确认24小时尿蛋白≥ 1.0 g。
12. 存在需要治疗的有症状浆膜腔积液（包括胸腔积液、腹水、心包积液）；注意：无症状浆膜腔积液可入组，有症状浆膜腔积液经积极对症治疗（不使用抗肿瘤药物进行浆膜腔积液治疗）后可入组，并根据研究者判断符合入组条件。
13. 需要抗微生物治疗的主动感染（如需要使用抗菌药物、抗病毒药物，但不包括慢性乙型肝炎抗乙肝治疗、抗真菌药物治疗）。
14. 有精神药物滥用史且无法戒除或有精神障碍。
15. 过去4周内参加过其他抗肿瘤药物临床试验。
16. 首次给予研究药物前2周内接受过全身激素治疗或其他形式的免疫抑制治疗。
17. 过去2年内有需要全身治疗的活跃性自身免疫性疾病史（例如，使用疾病修饰药物、皮质类固醇或免疫抑制剂）；注意：替代治疗（例如，针对肾上腺或垂体功能障碍的甲状腺激素、胰岛素或生理性皮质类固醇替代治疗）不被视为全身治疗。
18. 有IL-2使用禁忌症。
19. 需要全身静脉治疗的活跃性感染。
20. 首次使用研究药物前1个月内接种过活疫苗；允许接种针对季节性流感的活疫苗、注射用灭活病毒疫苗，但不允许经鼻接种减毒活流感疫苗。
21. 既往或同时患有其他未经治疗的恶性肿瘤，不包括已治愈的浅表性基底细胞癌、宫颈原位癌和浅表性膀胱癌。
22. 研究者判断可能影响临床研究进行和研究结果判定的其他情况。
23. 筛选期病毒筛查显示以下任何一项：
HBsAg阳性且HBV DNA高于正常上限。抗-HCV阳性且HCV RNA阳性。HIV阳性。
24. 既往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:
To be eligible for the study, participants must meet all of the following criteria:
1. Give informed consent and sign a written informed consent form.
2. Age ≤ 18 years, no gender limitation.
3. Karnofsky (≥16 years) or Lansky (\<16 years) (Appendix 2) performance status score of at least 50 (Appendix 2).
4. Diagnosis of high-risk and relapsed/refractory pediatric soft tissue sarcoma, confirmed by clinical criteria, and who have undergone prior comprehensive treatment (surgery, chemotherapy, radiation, and/or stem cell transplantation).
5. Estimated survival time of at least 12 weeks.
6. Complete recovery from all acute toxicities of prior anti-cancer chemotherapy, such as bone marrow suppression with recovery to grade I.
7. Myelosuppressive chemotherapy: at least 21 days after the last myelosuppressive chemotherapy (42 days if prior use of nitrosourea).
8. Experimental drugs or anti-cancer therapies other than chemotherapy: not used within 28 days prior to the planned start of NK cell immunotherapy. Must be fully recovered from the clinical significant toxicity of the therapy.
9. Hematopoietic growth factors: at least 14 days after the last administration of long-acting growth factor or 3 days after the last administration of short-acting growth factor.
10. X-ray therapy (XRT): at least 14 days after local palliative XRT (small field mouth) or at least 42 days after other substantive bone marrow (BM) irradiation, including prior radioactive iodine-131 meta-iodobenzylguanidine (131I-MIBG) treatment.
11. Stem cell transplantation without whole-body irradiation (TBI): no evidence of active graft versus host disease (GvHD), and at least 56 days after transplantation or stem cell transplantation.
12. Laboratory tests during the screening period must meet the following conditions:
Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L (ANC ≥ 0.5 × 10\^9/L if bone marrow involvement).
Platelet count (PLT) ≥ 75 × 10\^9/L (PLT ≥ 20 × 10\^9/L if bone marrow involvement).
Bilirubin ≤ 1.5 times the upper limit of normal (ULN). Creatinine ≤ 1.5 times the ULN (calculated according to the standard Cockcroft-Gault formula).
ALT/AST ≤ 3 times the ULN (can be relaxed to 5 times the ULN if liver metastasis is present).
13. Ability to comply with outpatient treatment, laboratory monitoring, and necessary clinical visits during the study. For pediatric or adolescent participants, the parent/guardian must be able to understand, consent, and sign the study informed consent form (ICF) and applicable child consent form before initiating any protocol-related procedures. The participant will be able to express their consent (where applicable) under the consent of the parent/guardian.
Exclusion Criteria:
Participants who meet any of the following criteria are not eligible for the study:
1. Presence of symptomatic brain metastasis (patients with brain metastasis treated and symptomatically stable for at least 2 months before enrollment are eligible, but must be confirmed to have no cerebral hemorrhage symptoms by cranial brain MRI, CT, or venous contrast).
2. History of or current cardiovascular disease, including ≥ II-grade myocardial ischemia or myocardial infarction, uncontrolled arrhythmia (including QTc interval ≥ 450 ms in men and ≥ 470 ms in women), or ≥ III-IV-grade heart failure according to the NYHA standard (Appendix 3) or left ventricular ejection fraction (LVEF) \< 50% according to echocardiography.
3. History of or current interstitial lung disease.
4. Coagulation function abnormality (INR \> 1.5 or prothrombin time (PT) \> ULN + 4 seconds or APTT \> 1.5 ULN), with bleeding tendency or receiving anticoagulation or thrombolytic therapy.
5. Any venous or arterial thromboembolic event within 12 months prior to enrollment, including cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism.
6. Known hereditary or acquired bleeding and thrombotic tendency (e.g., hemophiliacs, coagulation dysfunction, thrombocytopenia, splenomegaly).
7. Long-term, untreated wounds or fractures (excluding pathologic fractures caused by tumor).
8. Major surgery or severe traumatic injury, fracture, or ulcer within 4 weeks prior to enrollment.
9. Factors that significantly affect the absorption of oral drugs, such as difficulty swallowing, chronic diarrhea, and intestinal obstruction.
10. History of abdominal fistula, gastrointestinal perforation, or peritonitis within the past 6 months.
11. Urinary routine showing ≥ ++ proteinuria, and confirmed 24-hour urine protein ≥ 1.0 g.
12. Presence of symptomatic serous cavity effusion requiring treatment (including pleural effusion, ascites, pericardial effusion); note: asymptomatic serous cavity effusion can be enrolled, symptomatic serous cavity effusion can be enrolled after active symptomatic treatment (not using anti-cancer drugs for serous cavity effusion treatment), and eligible for enrollment according to the judgment of the researcher.
13. Active infection requiring anti-microbial therapy (e.g., requiring the use of antibacterial drugs, antiviral drugs, but not including chronic hepatitis B anti-hepatitis B treatment, anti-fungal drug treatment).
14. History of substance abuse of psychiatric drugs and inability to quit or with psychiatric disorders.
15. Participation in other anti-tumor drug clinical trials within the past 4 weeks.
16. Receiving systemic hormone treatment or other forms of immunosuppressive treatment within 2 weeks prior to the first dose of the study drug.
17. History of active autoimmune disease requiring systemic treatment (e.g., using disease-modifying drugs, corticosteroids, or immunosuppressive agents) within the past 2 years; note: alternative treatment (e.g., thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary dysfunction) is not considered systemic treatment.
18. Contraindications for IL-2 use.
19. Active infection requiring systemic venous treatment.
20. Administration of live vaccines within 1 month prior to the first use of the study drug; live vaccines against seasonal influenza, injectable inactivated virus vaccines are allowed, but nasal administration of live attenuated influenza vaccines is not allowed.
21. Prior or concurrent other untreated malignant tumors, excluding cured superficial basal cell carcinoma, cervical in situ carcinoma, and superficial bladder carcinoma.
22. Other conditions judged by the researcher to potentially affect the conduct of the clinical research and the determination of research results.
23. Viral screening during the screening period showing any of the following:
HBsAg positive and HBV DNA above the normal upper limit. Anti-HCV positive and HCV RNA positive. HIV positive.
24. Prior allogeneic tissue/organe transplantation.
25. Poor compliance, unable to cooperate with clinical research.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：overall response rate (ORR) · ORR was evaluated according to the International Neuroblastoma Response Criteria (INRC) · Two weeks after the second cycle (a total of 16 weeks after the strart of first umbilical cord blood natural killer cell infusion)
治疗方案包括在3个月内特定时间点注射8剂NK细胞，随后进行为期3年的随访期。
这是一项单臂、开放标签、非盲、I/II期临床试验，评估脐带血自然杀伤（NK）细胞在高危和复发/难治性软组织肉瘤（STS）儿童中的安全性和有效性。 目的： 评估NK细胞在高危和复发/难治性STS患者中的安全性和有效性。 观察NK细胞在这些患者中的药代动力学和药效学。 研究设计： 单臂、开放标签、非盲设计。40例高危和复发/难治性STS患者将接受NK细胞联合其他治疗。 治疗方案包括在3个月内的特定时间点注射8剂NK细胞，随后进行3年随访期。
This is a single-arm, open-label, non-blind, phase I/II clinical trial evaluating the safety and efficacy of umbilical cord blood natural killer (NK) cell in children with high-risk and relapsed/refractory soft tissue sarcoma (STS). Objective: Assess the safety and efficacy of NK cell in high-risk and relapsed/refractory STS patients. Observe the pharmacokinetics and pharmacodynamics of NK cells in these patients. Study Design: Single-arm, open-label, non-blind design. 40 patients with high-risk and relapsed/refractory STS will receive the NK cell combined with other treatment . The treatment regimen involves 8 doses of NK cells injected at specific time points over 3 months, followed by a 3-year follow-up period.
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