肿瘤细胞治疗研究
英文原题：Chemoimmunotherapy and Allogeneic Stem Cell Transplant for NK T-cell Leukemia/Lymphoma
这是一项早期 I 期注册临床试验，评估细胞治疗用于淋巴瘤、白血病、外周 T 细胞淋巴瘤的安全性、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：美国 · 伯明翰、奥兰治、旧金山、大急流城（共 6 个中心）。登记号：NCT03719105。
不限性别 · ≥ 1 Year 且 ≤ 31 Years
纳入标准： * 入组时体重至少10 kg。 * 新诊断且经组织学证实的成熟T细胞或NK细胞肿瘤： * 队列1：侵袭性NK细胞白血病（ICD-O代码9948/3）；鼻型结外NK/T细胞淋巴瘤（ICD-O代码9719/3）。 * 队列2：肠病相关T细胞淋巴瘤（ICD-O代码9717/3）；肝脾T细胞淋巴瘤（ICD-O代码9716/3）；外周T细胞淋巴瘤，非特指型（ICD-O代码9702/3）；血管免疫母细胞性T细胞淋巴瘤（ICD-O代码9705/3）。其他成熟T/NK细胞肿瘤组织学类型须经个案讨论后由研究主席和执行副主席决定是否纳入。淋巴瘤患者须为III或IV期（分期见附录III）。 * 器官功能要求：肝功能充分，即总胆红素≤该年龄组ULN的1.5倍，ALT（SGPT）<该年龄组ULN的3倍。心功能充分，即超声心动图缩短分数≥27%，或放射性核素血管造影测得射血分数≥50%。既往有肺功能障碍者，静息时不得呼吸困难、不得因肺功能不足而运动耐量受限，室内空气下脉搏血氧饱和度须>92%；若当前肺功能障碍由淋巴瘤导致，仍可符合条件。 排除标准： * ALK阳性或ALK阴性间变性大细胞淋巴瘤（ALCL）。 * 活动性CNS疾病。 * I期或II期疾病（分期见附录III）。 * 针对当前非霍奇金淋巴瘤（NHL）诊断既往接受过细胞毒性化疗。 * 不允许既往接受类固醇或放疗，紧急处理除外。因紧急情况接受放疗和/或类固醇者，须在开始放疗/类固醇后不超过1周启动方案治疗，方可入组。 * 妊娠女性；已初潮女孩须进行妊娠检测。 * 哺乳期女性，除非同意停止哺乳。 * 唐氏综合征。 * 正在使用治疗窗较窄的CYP3A4底物药物。仅队列2：入组前长期使用由CYP3A4代谢且治疗窗较窄的药物者（见附录V）；如适用，允许局部使用。 * 正在使用CYP3A4抑制剂。仅队列2：入组前7天内长期使用已知强效CYP3A4抑制剂者（见附录V）；如适用，允许局部使用。 * 正在使用CYP3A4诱导剂。仅队列2：入组前12天内长期使用已知强效CYP3A4诱导剂者（见附录V）。
Inclusion Criteria: * Patients must weigh at least 10 kilograms at the time of the study enrollment. * Diagnosis Newly diagnosed patients with histologically proven mature T- and NK- cell neoplasms: COHORT 1 * Aggressive NK cell leukemia (ICD-O code 9948/3) * Extranodal NK/T-cell lymphoma, nasal type (ICD-O code 9719/3) COHORT 2 * Enteropathy-associated T-cell lymphoma (ICD-O code 9717/3) * Hepatosplenic T-cell lymphoma (ICD-O code 9716/3) * Peripheral T-cell lymphoma, non-otherwise specified (ICD-O code 9702/3) * Angioimmunoblastic T-cell lymphoma (ICD-O code 9705/3) * Other mature T- and NK-cell neoplasm histologies will considered after case-by-case discussion with Study Chairs and executive Vice-Chair Patients with lymphoma must have stage III or IV disease (See Appendix III for Staging). * Organ Function Requirements Adequate liver function defined as: * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. * ALT (SGPT) \< 3 x ULN for age. Adequate cardiac function defined as: * Shortening fraction of ≥ 27% by echocardiogram, or * Ejection fraction of ≥ 50% by radionuclide angiogram. Adequate pulmonary function defined as: • Patients with a history of pulmonary dysfunction must have no evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry \> 92% while breathing room air unless current dysfunction is due to the lymphoma, in which case the patient is eligible. Exclusion Criteria: * Alk+ or Alk- Anaplastic Large Cell Lymphoma (ALCL) * Patients with active CNS disease. * Patients with stage I or stage II disease (See Appendix III for Staging). * Patients who have received any prior cytotoxic chemotherapy for the current diagnosis of NHL. * Previous steroid treatment and/or radiation treatment are not allowed unless they are used for emergency management. Patients who have received emergency irradiation and/or steroid therapy will be eligible only if started on protocol therapy not more than one week from the start of radiotherapy or steroids. * Female patients who are pregnant. Pregnancy tests must be obtained in girls who are post menarchal. * Lactating females, unless they have agreed not to breastfeed their infants. * Patients with Down syndrome. * Patients taking CYP3A4 substrates with narrow therapeutic indices. Patients (COHORT 2 ONLY) chronically receiving medications known to be metabolized by CYP3A4 and with narrow therapeutic indices (See Appendix V). The topical use of these medications (if applicable) is allowed. * Patients taking CYP3A4 inhibitors. Patients (COHORT 2 ONLY) chronically receiving drugs that are known potent CYP3A4 inhibitors within 7 days prior to study enrollment (See Appendix V). The topical use of these medications (if applicable) is allowed. * Patients taking CYP3A4 inducers. Patients (COHORT 2 ONLY) chronically receiving drugs that are known potent CYP3A4 inducers within 12 days prior to study enrollment (See Appendix V).
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 · to assess overall response rate following chemoimmunotherapy induction therapy · 1 year
次要终点：event free survival
适用于侵袭性NK细胞白血病或III/IV期鼻型结外NK/T细胞淋巴瘤患者。化疗方案：改良SMILE：第1天甲氨蝶呤，第2–4天异环磷酰胺、地塞米松和依托泊苷，第8天卡培拉加酶聚乙二醇。如果患者达到完全缓解（CR）且无可用异基因造血干细胞移植，可再接受最多2个改良SMILE周期。帕博利珠单抗：改良SMILE治疗2个周期后达到部分缓解、轻微缓解、无缓解或疾病进展（PR/MR/NR/PD）的患者可使用。若有供者且疾病未进展，则进行异基因干细胞移植。
适用于III/IV期外周T细胞淋巴瘤非特指型、血管免疫母细胞性T细胞淋巴瘤、肝脾T细胞淋巴瘤或肠病相关T细胞淋巴瘤患者；其他组织学类型须经研究主席和执行副主席个案讨论。化疗方案：第1、2、4、6周期使用普拉曲沙（第1、8、15天），并在第1天给予环磷酰胺和多柔比星，第1–5天给予泼尼松；第3、5周期第1天给予维布妥昔单抗、环磷酰胺和多柔比星，第1–5天给予泼尼松。若有供者且疾病未进展，则进行异基因干细胞移植。
研究分为两个队列。队列1：儿童、青少年和青年晚期NK细胞淋巴瘤/白血病患者接受地塞米松、甲氨蝶呤、异环磷酰胺、培门冬酶和依托泊苷组成的改良SMILE化疗，并在方案规定情况下使用帕博利珠单抗。队列2：儿童、青少年和青年晚期外周T细胞淋巴瘤患者接受联合化疗；第1、2、4、6周期使用普拉曲沙，第3、5周期使用维布妥昔单抗，并联合环磷酰胺、多柔比星和泼尼松。两组患者在疾病有应答时均继续接受异基因干细胞移植。
Patients are in 2 cohorts: Cohort 1: dexamethasone, methotrexate, ifosfamide, pegaspargase, and etoposide (modified SMILE) chemotherapy regimen alone and pembrolizumab in children, adolescents, and young adults with advanced stage NK lymphoma and leukemia Cohort 2: combining pralatrexate (PRX) (Cycles 1, 2, 4, 6) and brentuximab vedotin (BV) (Cycles 3, 5) to cyclophosphamide, doxorubicin, and prednisone in children, adolescent, and young adults with advanced peripheral T-cell lymphoma (non-anaplastic large cell lymphoma or non-NK lymphoma/leukemia) . Both groups proceed to allogeneic stem cell transplant with disease response.
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