肿瘤细胞治疗研究
英文原题：Exploratory Study on the Efficacy and Safety of Nebulized hUC-MSC-Derived Exosomes for Non-Acute CIP
这是一项 I/II 期注册临床试验，评估细胞治疗用于多发性骨髓瘤的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 40 例。登记号：NCT07599111。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准： * 已签署书面知情同意书； * 年龄18–75岁，组织学确诊恶性肿瘤； * 至少接受过一个周期免疫检查点抑制剂治疗，并发生免疫检查点抑制剂相关肺炎； * 临床评估确诊为3–4级免疫检查点抑制剂相关肺炎（CIP），诊断及分级符合NCCN《免疫治疗相关毒性管理指南》V1.2025；已接受标准糖皮质激素治疗≥4周，且已停用糖皮质激素或已减量至<20 mg/日泼尼松等效剂量； * 近期HRCT显示双肺仍有CIP残余病灶，包括磨玻璃影、实变、网状影、牵拉性支气管扩张和/或蜂窝样改变，累及肺野范围较大；过去4周重复HRCT未见残余病灶明显消退或改善； * 一般状况良好，ECOG体能状态0–1，原发肿瘤已稳定控制≥6个月； * 有生育能力的受试者同意研究期间及末次给药后360天内采取有效避孕措施。 排除标准： * 当前使用吡非尼酮、尼达尼布等抗纤维化药物； * 无法配合肺功能检查或雾化吸入； * 存在未缓解的间质性肺病或肺纤维化，病因包括靶向治疗、放疗或其他原因； * 严重合并症，包括严重心、肝、肾功能不全或严重血液学异常； * 有严重神经肌肉疾病、器官移植史、活动性癫痫、原发性或严重获得性/继发性免疫缺陷； * 严重过敏体质、精神障碍、28天内使用其他试验性产品，或研究者认为不适合参加的其他情况。
Inclusion Criteria: * Informed consent: Signed written informed consent. * Age and diagnosis: Aged 18-75 years with histologically confirmed malignant tumor. * Treatment history: Received at least one cycle of immune checkpoint inhibitor therapy and developed immune checkpoint inhibitor-related pneumonitis. * Confirmed Grade 3-4 immune checkpoint inhibitor-related pneumonitis (CIP) by clinical evaluation (diagnosis and grading in accordance with the NCCN Guidelines for Management of Immunotherapy-Related Toxicities Version 1.2025), having received standard glucocorticoid therapy for ≥4 weeks, with glucocorticoids either discontinued or tapered to a prednisone-equivalent dose of \<20 mg/day. * Recent HRCT imaging: Persistent residual CIP-related lesions in both lungs, including ground-glass opacity, consolidation, reticular opacity, traction bronchiectasis, and/or honeycombing, involving a large extent of the lung fields; no significant resolution or improvement of these residual lesions on repeated HRCT within the past 4 weeks. * General condition: ECOG PS score 0-1, with stable control of the primary tumor for ≥6 months. * Contraception: Fertile subjects agree to use effective contraception during the study period and for 360 days after the last dose. Exclusion Criteria: * Concomitant medication: Current use of antifibrotic agents such as pirfenidone and nintedanib. * Operational limitation: Inability to cooperate with pulmonary function testing or nebulized inhalation. * History of other pulmonary diseases: Presence of unresolved interstitial lung disease or pulmonary fibrosis induced by targeted therapy, radiotherapy, or other causes. * Severe comorbidities: Including severe cardiac, hepatic, or renal insufficiency, or severe hematological abnormalities. * Specific medical history: Severe neuromuscular disease, history of organ transplantation, active epilepsy, primary or severe acquired/secondary immunodeficiency. * Other factors: Severe allergic constitution, psychiatric disorders, use of other investigational products within 28 days, or any other condition deemed inappropriate by the investigator.
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：Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events (AEs), and serious adverse events (SAEs). · From the date of initial administration through 7 days following the final administration；Percentage of lesion resolution on high-resolution computed tomography (HRCT) · aseline, Week 4, Week 12, and Week 24
次要终点：Forced Vital Capacity as percentage of predicted value (FVC%)；Total Lung Capacity (TLC)；Residual Volume (RV)；Functional Residual Capacity (FRC)；Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)；6-minute walking distance (6MWD)；modified Medical Research Council dyspnea scale (mMRC) score；total St. George's Respiratory Questionnaire (SGRQ) score
研究目的：Ⅱ期主要目的为评估高分辨率计算机断层扫描（HRCT）病灶消退比例，由独立盲态评审者进行评估。次要目的包括评估肺功能、运动能力、呼吸困难、生活质量、氧合及全面评估安全性和耐受性。Ⅰ期重点确定安全性、剂量限制性毒性（DLT）及Ⅱ期推荐剂量。 研究人群：18–75岁、组织学确诊恶性肿瘤的非急性免疫检查点抑制剂相关肺炎（CIP）患者。关键条件包括：至少接受一个周期免疫检查点抑制剂（ICI）治疗并发生3–4级CIP（依据NCCN V1.2025指南）；接受标准糖皮质激素治疗≥4周，当前剂量<20 mg/日泼尼松等效剂量或已停药；HRCT仍有CIP残余病灶且过去4周无明显改善；ECOG 0–1，原发肿瘤稳定≥6个月；研究期间及末次给药后360天内采取有效避孕。 主要排除条件包括：合并使用吡非尼酮、尼达尼布或其他抗纤维化药物；不能完成肺功能检查或耐受雾化；放疗或靶向治疗所致间质性肺病未缓解；严重心、肝、肾或血液系统功能障碍；器官移植、严重免疫缺陷、活动性癫痫或严重过敏体质；28天内使用其他试验药物。 研究设计与样本量：Ⅰ期采用开放标签剂量递增，纳入9–18人，评估DLT和安全性；Ⅱ期计划纳入40人，采用随机、双盲、安慰剂对照设计。 研究终点：Ⅰ期主要终点为DLT发生率、AE和SAE发生率。Ⅱ期主要终点为第4、12、24周HRCT病灶消退比例，由独立盲态评审者评估。次要终点包括肺功能（FVC%、TLC、RV、FRC、DLCO）、功能和症状指标（6分钟步行距离、mMRC呼吸困难评分、SGRQ、LCQ）及氧合指标（PaO₂、肺泡-动脉氧分压差A-aDO₂、氧合指数）。探索性终点包括血清生物标志物动态变化（KL-6、IL-1β、IL-6、IL-10等细胞因子及Treg、Th1/Th17等免疫细胞亚群）。 安全性监测：按CTCAE v5.0评估AE/SAE并判断因果关系；进行体格检查、生命体征、SpO₂、12导联心电图及血常规、生化、凝血、尿液、CRP和ESR检查。 研究终止规则：所有40名受试者完成24周随访并锁定数据库后可成功结束；出现意外严重或不可接受的安全风险、证实疗效突出或无效、因入组缓慢/经费/重大方案偏离而由申办方终止，或监管机构/伦理委员会要求终止时，可提前终止。个体出现DLT或严重超敏反应、CIP迅速进展（如影像学恶化>50%）、肿瘤进展或临床恶化、撤回知情同意、依从性差且干预无效、失访或死亡，或研究者认为不适宜继续参与时，可停止其研究治疗。 研究时间：筹备及启动为2026年1月至5月；Ⅰ/Ⅱ期入组为2026年6月至2027年5月；治疗和随访与入组阶段重叠，持续至2028年6月；数据库锁定及统计分析为2028年7月至8月；研究结束为2028年8月至12月。
Study Objectives The primary objective of Phase II is to evaluate the percentage of lesion resolution on high-resolution computed tomography (HRCT) as assessed by independent blinded reviewers. Secondary objectives include evaluating effects on pulmonary function, exercise capacity, dyspnea, quality of life, and oxygenation, as well as comprehensively assessing safety and tolerability. Phase I focuses on determining safety, dose-limiting toxicities (DLT), and recommended Phase II dose. Study Population The target population is patients with non-acute CIP aged 18-75 years with histologically confirmed malignancy. Key inclusion criteria include: At least one cycle of immune checkpoint inhibitor (ICI) therapy and development of Grade 3-4 CIP per NCCN Guidelines V1.2025 Standard glucocorticoid treatment for ≥4 weeks, with current dose \<20 mg/day prednisone equivalent or discontinued Persistent residual CIP lesions on HRCT without significant improvement in the past 4 weeks ECOG PS 0-1 and stable primary tumor for ≥6 months Effective contraception during the study and for 360 days after last dosing Key exclusion criteria include: Concomitant use of pirfenidone, nintedanib, or other antifibrotic agents Inability to perform pulmonary function tests or tolerate nebulization Unresolved interstitial lung disease from radiotherapy or targeted therapy Severe cardiac, hepatic, renal, or hematological dysfunction Organ transplantation, severe immunodeficiency, active epilepsy, or severe allergic status Other investigational drug use within 28 days Study Design and Sample Size Phase I: 9-18 subjects, open-label, dose-escalation design to evaluate DLT and safety Phase II: 40 subjects, randomized, double-blind, placebo-controlled design Study Endpoints Phase I Primary Endpoints Incidence of DLT Incidence of adverse events (AE) and serious adverse events (SAE) Phase II Primary Endpoint Percentage of HRCT lesion resolution at Weeks 4, 12, and 24, assessed by independent blinded reviewers Secondary Endpoints Pulmonary function: FVC%, TLC, RV, FRC, DLCO Functional and symptomatic measures: 6MWD, mMRC dyspnea score, SGRQ, LCQ Oxygenation: PaO₂, A-aDO₂, oxygenation index Exploratory Endpoints Dynamic changes in serum biomarkers: KL-6, cytokines (IL-1β, IL-6, IL-10), immune cell subsets (Tregs, Th1/Th17) Safety Assessments Monitoring of AEs/SAEs graded by CTCAE v5.0 and causality assessment Physical examination, vital signs, SpO₂, 12-lead ECG Laboratory tests: CBC, biochemistry, coagulation, urinalysis, CRP, ESR Study Termination Rules Overall Study Termination Successful completion after all 40 subjects finish 24-week follow-up and database lock Occurrence of unexpected serious or unacceptable safety risks Demonstration of overwhelming efficacy or futility Sponsor termination due to slow enrollment, funding, or major protocol deviations Regulatory or ethics committee requirements Individual Subject Discontinuation Development of DLT or severe hypersensitivity Rapid CIP progression (e.g., \>50% radiological worsening) Tumor progression or clinical deterioration Withdrawal of informed consent Poor compliance unresponsive to intervention Loss to follow-up or death Investigator judgment of inappropriateness for continued participation Study Timeline Preparation and initiation: January 2026 - May 2026 Phase I/II enrollment: June 2026 - May 2027 Treatment and follow-up (overlapping with enrollment): through June 2028 Database lock and statistical analysis: July 2028 - August 2028 Study closeout: August 2028 - December 2028
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