肿瘤细胞治疗研究
英文原题：Odronextamab for Relapsed and Refractory Large B-cell Lymphomas Before CAR-T
这是一项 II 期注册临床试验，评估 CAR-T 细胞治疗弥漫大 B 细胞淋巴瘤、滤泡性淋巴瘤、B 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 27 例。试验地点：美国 · 西雅图（共 1 个中心）。登记号：NCT06784726。
不限性别 · ≥ 18 Years
纳入标准： * 组织学确诊的大B细胞淋巴瘤，包括非特指型弥漫性大B细胞淋巴瘤（DLBCL）、原发性纵隔大B细胞淋巴瘤、高级别B细胞淋巴瘤、由惰性淋巴瘤转化而来的DLBCL、3B级滤泡性淋巴瘤（FL） * 可测量病灶，定义为筛选前一个月内PET、CT或磁共振成像（MRI）显示至少一个可测量病灶≥ 15 mm，依据国际工作组淋巴瘤疗效评价共识标准 * 大B细胞淋巴瘤既往一线治疗必须失败，且须符合接受商业化axicabtagene ciloleucel（axi-cel）、lisocabtagene maraleucel（liso-cel）或tisagenlecleucel（tisa-cel）的FDA标签标准 * 年龄≥ 18岁 * 能够理解并提供书面知情同意 * 既往接受过抗CD20抗体治疗 * 东部肿瘤协作组体能状态评分为0-1；若体能状态评分为2归因于淋巴瘤，经治疗医师或主要研究者（PI）判断，允许入组 * 采用Cockcroft-Gault公式计算的肌酐清除率≥ 45 mL/min * 总胆红素≤ 1.5倍正常值上限（ULN），Gilbert综合征患者除外 * 天冬氨酸氨基转移酶和丙氨酸氨基转移酶≤ 2.5倍ULN * 肺功能充分，定义为呼吸困难≤ 1级且室内空气下血氧饱和度（SpO2）≥ 92% * 心功能充分，定义为左心室射血分数≥ 50%且无心包积液证据 * 血小板计数≥ 75 x 10^9 /L * 血红蛋白（Hg）水平≥ 9 g/dL * 中性粒细胞绝对计数（ANC）≥ 1 x 10^9 /L * 骨髓受累或脾脏隔离的患者：血小板计数≥ 25 x 10^9 /L * 骨髓受累或脾脏隔离的患者：Hg ≥ 7.0 g/dL * 骨髓受累或脾脏隔离的患者：ANC ≥ 0.5 x 10^9 /L * 有生育能力的女性（WOCBP，定义为未接受手术绝育或至少1年无月经者）在开始odronextamab前2天内血清妊娠试验阴性 * 有生育能力的男性和WOCBP患者必须愿意从研究招募至CAR T细胞输注后至少6个月内使用高效避孕方法 * 患者不得在Odron末次给药完成后至少6个月内捐献卵子或精子 排除标准： * 可检测到脑脊液恶性细胞，或脑转移，或有脑脊液恶性细胞或脑转移病史。有继发性中枢神经系统（CNS）淋巴瘤病史的患者，若筛选时至少3个月内无淋巴瘤CNS疾病证据，可能符合条件 * 有癫痫发作性疾病、脑血管缺血/出血、痴呆、小脑疾病或任何累及中枢神经系统（CNS）的自身免疫性疾病史 * 在首次给予研究药物前，接受过标准抗肿瘤化疗（非生物制剂），且距末次给药时间在5个半衰期内或2周内，以较短者为准 * 在首次给予研究药物前2周内接受过标准放疗 * 既往接受过抗CD20 x 抗CD3双特异性治疗，除非满足以下所有条件：疾病对既往双特异性治疗有应答（根据Lugano标准为CR或PR），且末次既往双特异性治疗给药后12个月内未出现疾病进展，并且肿瘤必须仍表达CD20（按标准治疗[SOC]进行CD20检测） * 异基因干细胞移植 * 任何CAR-T细胞治疗 * 患者不得正在接受其他研究性药物 * 在首次给予研究药物前2周内接受过利妥昔单抗、阿仑单抗或其他研究性或商业化生物制剂治疗 * 在首次给予研究药物前2周内接受过免疫抑制治疗（生物制剂除外） * 在首次给予研究药物前2周内接受过研究性非生物制剂治疗 * 有归因于与研究药物化学或生物学组成相似的化合物的过敏反应史 * 对四环素类抗生素组中任何化合物有超敏反应史 * 并发活动性恶性肿瘤且患者正在接受全身治疗，除非经PI批准 * 已知活动性且未控制的细菌、病毒、真菌、分枝杆菌或其他感染 * 存在可能干扰研究实施或使患者面临重大风险的重度并发疾病或医学状况的证据，包括但不限于重度心血管疾病（例如纽约心脏协会III级或IV级心脏病、过去6个月内的心肌梗死、不稳定性心律失常或不稳定性心绞痛）和/或重度肺部疾病（例如阻塞性肺病和有症状性支气管痉挛史） * 正在进行的全身性皮质类固醇治疗，但用于其他（非肿瘤和非免疫抑制）适应症的皮质类固醇使用除外，最多相当于泼尼松10 mg/天或等效剂量。允许在筛选期间为控制淋巴瘤疾病而短期使用皮质类固醇 * 感染人类免疫缺陷病毒（除非病毒载量检测不到且CD4计数≥ 400）或慢性感染乙型肝炎病毒或丙型肝炎病毒。乙型肝炎（乙型肝炎表面抗原阳性[HepBsAg+]）且感染得到控制的患者，在咨询管理该感染的医生后允许入组 * 已知对别嘌醇和拉布立酶均超敏 * 妊娠或哺乳期女性 * 在首次给予研究药物前28天内接种过活疫苗
Inclusion Criteria: * Histologically confirmed large B cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, DLBCL arising from indolent lymphoma, follicular lymphoma (FL) grade 3B * Measurable disease, defined as at least one measurable lesion ≥ 15 mm on PET, CT, or magnetic resonance imaging (MRI) within one month of screening, according to the International Working Group consensus response evaluation criteria in lymphoma * Prior frontline therapy for large B cell lymphoma must have failed the patient, and criteria must be met for receiving commercial axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), or tisagenlecleucel (tisa-cel) per Food and Drug Administration (FDA) label * Age ≥ 18 years * Capable of understanding and providing a written informed consent * Prior treatment with an anti-CD20 antibody therapy * Eastern Cooperative Oncology Group performance status of 0-1; we allow enrollment of patients with a performance status of 2 if it is attributed to lymphoma per discretion of the treating physician or principal investigator (PI) * Creatinine clearance ≥ 45 mL/min calculated by Cockcroft-Gault equation * Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), except in patients with Gilbert's syndrome * Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x the ULN * Adequate pulmonary function, defined as ≤ grade 1 dyspnea and oxygen saturation (SpO2) ≥ 92% on room air * Adequate cardiac function, defined as left ventricular ejection fraction ≥ 50% and without evidence for pericardial effusion * Platelet count ≥ 75 x 10\^9 /L * Hemoglobin (Hg) level ≥ 9 g/dL * Absolute neutrophil count (ANC) ≥ 1 x 10\^9 /L * Patients with bone marrow involvement or splenic sequestration: Platelet count ≥ 25 x 10\^9 /L * Patients with bone marrow involvement or splenic sequestration: Hg ≥ 7.0 g/dL * Patients with bone marrow involvement or splenic sequestration: ANC ≥ 0.5 x 10\^9 /L * Negative serum pregnancy test within 2 days of initiating odronextamab for women of childbearing potential (WOCBP), defined as those who have not been surgically sterilized or who have not been free of menses for at least 1 year * Fertile male and WOCBP patients must be willing to use highly effective contraceptive methods from study recruitment to at least 6 months after the CAR T-cell infusion * Patients must not provide egg or sperm donation until at least 6 months after the completion of the last dose of Odron Exclusion Criteria: * Detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases. Patients with a history of secondary central nervous system (CNS) lymphoma may be eligible provided that there has been no evidence of CNS disease from lymphoma for at least 3 months at the time of screening * History of a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with central nervous system (CNS) involvement * Standard anti-neoplastic chemotherapy (non-biologic) within 5-times the half-life or within 2 weeks, whichever is shorter, prior to first administration of study drug * Standard radiotherapy within 2 weeks of first administration of study drug * Prior treatment with an anti-CD20 x anti-CD3 bispecific therapy, unless all the following are met: disease responded to prior bispecific therapy (CR or PR per Lugano criteria) and did not experience disease progression within 12 months of the last dose of prior bispecific therapy, and the tumor must still express CD20 (CD20 examination per standard of care \[SOC\]) * Allogeneic stem cell transplantation * Any CAR-T cell therapy * Patients may not be receiving other investigational agents * Treatment with rituximab, alemtuzumab, or other investigational or commercial biologic agent within 2 weeks prior to first administration of study drug * Immunosuppressive therapy (other than biologic) within 2 weeks of first administration of study drug * Treatment with an investigational non-biologic agent within 2 weeks of first administration of study drug * History of allergic reactions attributed to compounds of similar chemical or biologic composition of study drug * History of hypersensitivity to any compound in the tetracycline antibiotics group * Concurrent active malignancy for which the patient is receiving systemic treatment, unless approved by PI * Known active and uncontrolled bacterial, viral, fungal, mycobacterial, or other infection * Evidence of significant concurrent disease or medical condition that could interfere with the conduct of the study, or put the patient at significant risk including, but not limited to, significant cardiovascular disease (e.g., New York Heart Association class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) and/or significant pulmonary disease (e.g., obstructive pulmonary disease and history of symptomatic bronchospasm) * Ongoing systemic corticosteroid treatment, with the exception of corticosteroid use for other (non-tumor and non-immunosuppressive) indications up to a maximum of 10 mg/day of prednisone or equivalent. A short course of corticosteroid for lymphoma disease control during screening is allowed * Infection with human immunodeficiency virus (unless viral load is undetectable and CD4 count ≥ 400) or chronic infection with hepatitis B virus or hepatitis C virus. Patients with hepatitis B (hepatitis B surface antigen positive \[HepBsAg+\]) with controlled infection were permitted upon consultation with the physician managing the infection * Known hypersensitivity to both allopurinol and rasburicase * Pregnant or breast-feeding women * Administration of live vaccination within 28 days of first administration of study drug
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：Failure to undergo leukapheresis · Will include failures due to disease progression or adverse events (AEs) due to odronextamab (Odron), or requirement of other lymphoma-directed therapy for bridging before leukapheresis due to lack of response. Will report the total number and percentage with 95% confidence interval (CI). · Up to 5 years
次要终点：Receipt of chimeric antigen receptor T-cell therapy (CAR-T)；Overall response rate (ORR) following bridging prior to CAR-T infusion；Progression free survival (PFS) following CAR-T infusion；CR rate；PFS in patients who achieve CR after 2 cycles of Odron, choose to opt out of CAR-T, and receive up to a total of 12 months of Odron；Incidence of AEs
患者根据以下方案接受 odronextamab IV 治疗： * 第1周期剂量递增：C1D1 给予 0.2 mg，C1D2 给予 0.5 mg，C1D8 和 C1D9 分别给予 2 mg，C1D15 和 C1D16 分别给予 10 mg（0.7/4/20 方案）。 * 第2-4周期给药：Odron 每周给予 160 mg。 * 剩余周期每两周一次给予 320 mg。 请参见详细说明以获取更多信息。
这项II期试验测试odronextamab在嵌合抗原受体T（CAR-T）细胞治疗前给药（桥接治疗）对经过一段时间改善后复发（relapsed）或对先前治疗无反应（refractory）的大B细胞淋巴瘤患者的有效性。Odronextamab是一种双特异性抗体，可同时结合两种不同的抗原。Odronextamab结合CD3（一种T细胞表面抗原）和CD20（一种肿瘤相关抗原，在B细胞发育的大多数阶段表达于B细胞，在B细胞癌症中常过表达），并可能干扰癌细胞的生长和扩散能力。桥接治疗已被用于维持疾病控制并提高成功接受CAR-T细胞治疗的机会。然而，桥接治疗通常在白细胞分离术后给予，这无助于防止在决定进行CAR-T细胞治疗与白细胞分离术之间的疾病进展。在白细胞分离术前给予odronextamab作为桥接治疗可能延缓疾病进展，以便进行白细胞分离术，并增加复发或难治性大B细胞淋巴瘤患者成功接受CAR-T细胞治疗的可能性。
This phase II trial tests the effectiveness of odronextamab given before chimeric antigen receptor T (CAR-T) cell therapy (bridging therapy) in patients with large B-cell lymphomas that have come back after a period of improvement (relapsed) or that have not responded to previous treatment (refractory). Odronextamab is a bispecific antibody that can bind to two different antigens at the same time. Odronextamab binds to CD3, a T-cell surface antigen, and CD20 (a tumor-associated antigen that is expressed on B-cells during most stages of B-cell development and is often overexpressed in B-cell cancers) and may interfere with the ability of cancer cells to grow and spread. Bridging therapy has been used to maintain disease control and to increase the chance of successful receipt of CAR-T cell therapy. However, bridging therapy is typically given after leukapheresis, which does not help prevent disease progression between the decision for CAR-T cell therapy and leukapheresis. Giving odronextamab as bridging therapy before leukapheresis may delay disease progression to allow leukapheresis and increase the likelihood of successful CAR-T cell therapy in patients with relapsed or refractory large B-cell lymphomas.
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