肿瘤细胞治疗研究
英文原题：Hypofractionated Radiation in Combination With B7-H3-CAR T Cells for Pediatric Patients With Relapsed/Refractory Sarcomas
Hypofractionated Radiation in Combination With B7-H3-CAR T Cells for Pediatric Patients With Relapsed/Refractory Sarcomas
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗肉瘤、骨肉瘤、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 42 例。试验地点：美国 · 孟菲斯（共 1 个中心）。登记号：NCT07222735。
不限性别 · ≤ 21 Years
纳入标准（采集及制备资格）：既往采集的自体白细胞单采产品可用于制备T细胞；年龄≤21岁；B7-H3阳性肉瘤，使用既往活检组织按标准免疫组化评估，H-score≥100判为阳性。组织学类型包括骨肉瘤、尤文肉瘤、横纹肌肉瘤及非横纹肌肉瘤软组织肉瘤。标准一线治疗后复发（初治曾完全应答、标准影像无病后首次或再次复发）或难治（治疗未完全应答，可自始耐药或治疗中获得耐药）；存在可评估疾病且至少一个病灶适合HFRT，剂量扩展队列还须计划照射野外另有可评估病灶；预计生存期>12周；按年龄采用Karnofsky或Lansky评分≥60。因既往手术（如截肢）导致活动受限，但可使用轮椅或辅助器具活动者，可按可行走者计算体能评分。育龄女性入组前7天内血清妊娠试验阴性且未哺乳/计划哺乳；受试者须适合自体单采，或已有可用自体单采产品。 治疗资格：制造时年龄≤21岁；B7-H3阳性肉瘤；标准一线治疗后复发/难治；至少1个适合HFRT的可评估病灶，剂量扩展队列还须计划照射野外另有可评估病灶；预计生存期>8周；Karnofsky或Lansky评分≥60（因既往手术造成活动受限但可用轮椅/辅助器具者视为可活动）。心功能充分：超声心动图LVEF≥50%。肾功能充分：血清肌酐不超过年龄上限，1–<2岁0.6、2–<6岁0.8、6–<10岁1.0、10–<13岁1.2、13–<16岁男性1.5/女性1.4、≥16岁男性1.7/女性1.4（单位mg/dL）。室内空气下脉搏血氧≥92%；总胆红素≤年龄相应ULN的3倍（Gilbert综合征除外）；ALT或AST≤年龄相应ULN的5倍；血红蛋白≥7 g/dL（可输血）；血小板≥50,000/μL（可输注）；ANC≥1,000/μL。既往治疗所致NCI CTCAE III–IV级非血液学急性毒性均已恢复。育龄女性入组前7天内妊娠试验阴性且未哺乳/计划哺乳；如有性生活，同意T细胞输注后3个月内避孕。 排除标准（采集/制备阶段）：已知原发性免疫缺陷；HIV阳性；严重且未控制的细菌、病毒或真菌感染；除本研究治疗的B7-H3阳性肉瘤以外的活动性恶性肿瘤；研究主要研究者评估为快速进展疾病（需考虑病灶与重要结构的距离）；颅内或脊髓病变；研究者认为会损害健康、妨碍或混淆方案评估的基础疾病；对玉米淀粉或羟乙基淀粉严重过敏。 排除标准（治疗阶段）：已知原发性免疫缺陷、HIV阳性、严重未控制感染、其他活动性恶性肿瘤、快速进展疾病、颅内或脊髓病变，或研究者认为不适合参加的基础疾病；CAR-T 输注前<7天接受相当于甲泼尼龙>0.5 mg/kg/日的全身激素治疗；方案治疗开始前<14天接受研究主要研究者认为会干扰CAR产品活性的全身治疗；方案治疗开始前4周内接受放疗；对玉米淀粉或羟乙基淀粉严重过敏。
INCLUSION CRITERIA \*a previously collected, autologous leukapheresis product can be used for T cell production Collection and manufacturing eligibility * Age ≤ 21 years old * B7-H3+ sarcoma; B7-H3 expression will be evaluated by standard immunohistochemistry (IHC) using any previously obtained biopsy; a tumor is considered B7-H3 positive with a H score greater than or equal to 100 * Osteosarcoma * Ewing Sarcoma * Rhabdomyosarcoma Non-rhabdomyosarcoma soft tissue sarcomas * Evidence of relapsed (cancer that has completely responded \[i.e., no evidence of disease using standard imaging modalities\] to first-line therapy but has recurred for the first or subsequent time); or refractory (cancer that does not respond completely to treatment; cancer may be resistant at the beginning or may become resistant during treatment) disease after standard first-line therapy * Evaluable disease with presence of at least one lesion amenable to hypofractionated radiation therapy * For dose expansion cohort: participants must also have additional evaluable disease beyond planned radiation field * Estimated life expectancy of \> 12 weeks * Karnofsky or Lansky (age-dependent) performance score ≥ 60 * Participants with mobility limitations due to prior surgical intervention (i.e., amputation) but who are up in wheelchair or with other assistive devices will be considered ambulatory for the purpose of performance score determination * For females of child-bearing age: * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment * Not lactating with intent to breastfeed * Participants must be eligible to undergo autologous apheresis or have an available previously collected autologous apheresis product Treatment eligibility * Age ≤ 21 years old at the time of manufacturing * B7-H3+ sarcoma * Evidence of relapsed or refractory disease after standard first-line therapy * Evaluable disease with the presence of at least one lesion amenable to hypofractionated radiation therapy • For dose expansion cohort: participants must also have additional evaluable disease beyond the planned radiation field * Estimated life expectancy of \> 8 weeks * Karnofsky or Lansky (age-dependent) performance score ≥ 60 • Participants with mobility limitations due to prior surgical intervention (i.e., amputation) but who are up in wheelchair or with other assistive device will be considered ambulatory for purpose of performance score determination. * Adequate cardiac function defined by echocardiogram with left ventricular ejection fraction ≥ 50% * Adequate renal function as defined by not exceeding the maximum serum creatinine listed below by age: * 1 to \<2 years: 0.6 * 2 to \<6 years: 0.8 * 6 to \<10 years: 1 * 10 to \<13 years: 1.2 * 13 to \<16 years: male 1.5, female 1.4 * ≥ 16 years: male 1.7, female 1.4 * Adequate pulmonary function defined as pulse oximetry ≥ 92% on room air * Total Bilirubin ≤3 times the upper limit of normal for age, except in subjects with Gilbert's syndrome * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤5 times the upper limit of normal for age * Hemoglobin ≥ 7g/dL (can be transfused) * Platelet count ≥ 50,000/μL (can be transfused) * Absolute neutrophil count (ANC) ≥ 1000/μL * Has recovered from all NCI CTAE grade III-IV, non-hematologic acute toxicities from prior therapy * For females of child-bearing age: * Not pregnant with negative serum pregnancy test within 7 days prior to enrollment * Not lactating with intent to breastfeed * If sexually active, agreement to use contraception until 3 months after T cell infusion EXCLUSION CRITERIA Collection and manufacturing eligibility * Known primary immunodeficiency * Known HIV positivity * Severe, uncontrolled intercurrent bacterial, viral, or fungal infection * Known active malignancy other than the B7-H3+ sarcoma being treated on study * Rapidly progressive disease (as assessed by the study PIs, with consideration for proximity to critical structures) * Presence of intracranial or spinal cord disease * Known underlying medical condition(s) for which, in the investigator's opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit, or confound protocol assessments * Known severe hypersensitivity to corn starch or hydroxyethyl starch Treatment eligibility * Known primary immunodeficiency * Known HIV positivity * Severe, uncontrolled intercurrent bacterial, viral, or fungal infection * Known active malignancy other than the B7-H3+ sarcoma being treated on study * Receiving systemic steroid therapy exceeding the equivalent of 0.5 mg/kg/day of methylprednisolone, \< 7 days prior to CAR T cell infusion * Receiving systemic therapy \< 14 days prior to start of protocol therapy, which will interfere with the activity of the CAR product (in the opinion of the study PIs) * Received radiation therapy within the 4 weeks prior to start of protocol therapy * Rapidly progressive disease (as assessed by the study PIs, with consideration for proximity to critical structures) * Presence of intracranial or spinal cord disease * Known underlying medical condition(s) for which, in the investigator's opinion, participation in this trial would not be in the best interest of the participant (e.g., compromises the health of the subject) or that could prevent, limit, or confound protocol assessments * Known severe hypersensitivity to corn starch or hydroxyethyl starch
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：Dose limiting toxicity (DLT) rate · Proportion of evaluable participants experiencing DLTs · up to 4 weeks after CAR T cell infusion；Incidence of adverse events (AEs) · AEs will be assessed and graded using CTCAE v5.0, except for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS), which will be graded according to ASTCT consensus guidelines. AEs will be summarized and reported descriptively · up to 4 weeks after CAR T cell infusion
次要终点：Clinical antitumor activity；B7-H3-CAR T cell trafficking to tumor sites
通过自体单采采集外周血单个核细胞（PBMC）。治疗包括至少一个病灶的HFRT，并同步进行一个疗程的淋巴清除化疗（氟达拉滨/环磷酰胺），随后输注CAR-T 细胞。
以上邮箱 / 电话是登记库里的申办方联系方式（+86，中国），通常不直达某家医院。中国中心的联系方式请以医院或登记平台最新公示为准。
RAD3CAR是一项I期研究，评估B7-H3 CAR-T 细胞联合淋巴清除化疗及低分割放疗（HFRT）的安全性。主要目标是评估HFRT预处理及淋巴清除化疗后，B7-H3 CAR-T 用于≤21岁复发/难治性B7-H3阳性肉瘤患者的安全性。次要目标包括描述联合HFRT的抗肿瘤活性，并确定联合治疗后CAR-T 是否能到达肿瘤部位。
RAD3CAR is a phase I study designed to evaluatethe safety of B7-H3-CAR T cells and lymphodepletion in combination with hypofractionated radiation therapy. Primary objective: \- To evaluate the safety of B7-H3-CAR T cell therapy after priming with hypofractionated radiation therapy (HFRT) and lymphodepleting chemotherapy in patients ≤ 21 years of age with relapsed/refractory B7-H3+ sarcomas. Secondary objectives: * To describe the antitumor activity of B7-H3-CAR T cells in combination with HFRT * To determine if B7-H3-CAR T cells traffic to tumor sites after combination treatment with HFRT
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