肿瘤细胞治疗研究
英文原题：Odronextamab for the Treatment of Relapsed and Refractory Diffuse Large B-cell Lymphoma Before and After Chimeric Antigen Receptor T-cell Therapy
这是一项 II 期注册临床试验，评估 CAR-T 细胞治疗弥漫大 B 细胞淋巴瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 34 例。试验地点：美国 · 萨克拉门托（共 1 个中心）。登记号：NCT06854159。
不限性别 · ≥ 18 Years
纳入标准： * 签署知情同意书时年龄≥ 18岁 * 患者必须经组织学或细胞学确诊为复发/难治性（R/R）弥漫性大B细胞淋巴瘤（DLBCL）；转化型滤泡性淋巴瘤患者符合条件 * 患者必须至少接受过2种既往治疗且治疗失败 * 预期寿命≥ 3个月 * 根据机构指南，符合任何美国食品药品监督管理局（FDA）批准的嵌合抗原受体（CAR）T细胞治疗条件的候选者 * 美国东部肿瘤协作组（ECOG）体能状态≤ 2（Karnofsky≥ 50%） * 白细胞≥ 2,500/µL * 中性粒细胞绝对计数≥ 1,000/µL，或有骨髓受累的患者> 500/µL * 为满足中性粒细胞绝对计数（ANC）合格标准，受试者在首次给予odronextamab前2天内不得接受过粒细胞集落刺激因子 * 血小板≥ 50,000/µL，或有骨髓受累的患者≥ 25,000/µL * 为满足血小板合格标准，患者在首次给予odronextamab前2天内不得接受过血小板输注治疗 * 总胆红素≤ 1.5 x 机构正常值上限（ULN） * 注：已知患有Gilbert病且血清胆红素水平≤ 3 x 机构ULN的患者可入组。已知患有Gilbert综合征的患者，若总胆红素值> 4 x ULN，将被排除 * 无论是否存在肝脏淋巴瘤浸润，天冬氨酸氨基转移酶（AST）> 3 x ULN和/或丙氨酸氨基转移酶（ALT）> 3 x ULN且同时总胆红素> 1.5 x ULN的受试者将被排除 * AST（血清谷草转氨酶[SGOT]）/ALT（血清谷丙转氨酶[SGPT]）≤ 3 x 机构ULN（有肝脏受累的患者AST和/或ALT ≤ 5 x ULN） * 无论是否存在肝脏淋巴瘤浸润，AST > 3 x ULN和/或ALT > 3 x ULN且同时总胆红素> 1.5 x ULN的受试者将被排除 * 根据Cockcroft-Gault公式计算的肌酐清除率≥ 30 mL/min/1.73 m^2 * 血红蛋白≥ 8 g/dL，或有骨髓受累的患者≥ 7 g/dL * 注：允许根据治疗医生的判断给予生长因子或输血支持 * 碱性磷酸酶≤ 2.5 x ULN（有记录的肝脏受累或骨转移患者≤ 5 x ULN） * 国际标准化比值（INR）和活化部分凝血活酶时间（aPTT）≤ 1.5 x ULN * 注：此条仅适用于未接受治疗性抗凝的患者；正在接受治疗性抗凝（如低分子量肝素或华法林）的患者应处于稳定剂量 * 超声心动图或门控血池显像（MUGA）扫描显示心脏射血分数> 50% * 血清肌酐≤ 1.5 x ULN，或根据Cockcroft-Gault公式计算的肌酐清除率≥ 50 mL/min * 对于感染HIV的受试者： * 无除淋巴瘤以外的AIDS定义性疾病史，或开始联合抗逆转录病毒治疗（ART）前CD4+ T细胞低于200/mm^3的病史 * 接受有效抗逆转录病毒治疗且6个月内病毒载量检测不到的HIV感染患者符合本试验的入组条件 * 在研究入组时，CD4+ T细胞必须已从既往淋巴瘤治疗中恢复至≥ 250/mm^3 * 在研究入组时，HIV病毒载量必须通过标准实验室检测方法检测不到 * 在既往淋巴瘤治疗期间，患者不得有记录归因于HIV+状态的感染 * 无ART不依从史，且愿意在研究期间坚持ART * 不允许使用与研究药物具有重叠或相似毒性特征的抗逆转录病毒药物 * 接受抑制性治疗且病毒载量阴性、无肝损伤证据的乙型或丙型肝炎患者符合入组条件 * 有生育潜力的人及生殖伴侣必须同意在研究入组前、研究参与期间以及末次研究药物给药后6个月（180天）内使用充分的避孕措施（激素或屏障避孕法；禁欲）。研究期间及末次研究药物给药后6个月内禁止捐献卵子和精子 * 愿意且能够提供知情同意 排除标准： * 任何状况，包括实验室异常的存在，经研究主要研究者（PI）或入组医生判定，若受试者参与研究将使其面临不可接受的风险，或会混淆研究数据的解读能力 * 研究入组时已知原发性中枢神经系统（CNS）淋巴瘤受累或已知非原发性CNS非霍奇金淋巴瘤（NHL）未控制受累 * 已知（过去12个月内）或当前存在相关CNS病理，例如： * 癫痫、惊厥、瘫痪、失语、卒中、严重脑损伤、小脑疾病、器质性脑综合征、精神病、脑血管意外，或 * 脑磁共振成像（MRI）显示存在炎性病灶和/或血管炎的证据 * 过去5年内患有另一种活动性恶性肿瘤（B细胞NHL除外），以下情况例外：已接受潜在治愈性治疗的非黑色素瘤皮肤癌、原位宫颈癌，或经治疗研究者判定已通过确定性局部控制以治愈性目的得到有效治疗的任何其他肿瘤 * 研究入组时或研究入组前2周内存在任何活动性感染（细菌、病毒、真菌、分枝杆菌、寄生虫或其他）的证据，如果需要持续治疗和/或在免疫抑制时有可能导致播散性疾病或严重感染。应有证据表明感染在研究治疗开始前已清除或得到良好控制 * 活动性COVID-19感染 * 未控制的人类免疫缺陷病毒（HIV）、乙型肝炎病毒（HBV）或丙型肝炎病毒（HCV）感染 * 感染已控制的HIV参与者（病毒载量检测不到且CD4计数高于350个细胞/µL，无论是自发还是通过稳定的抗病毒方案）允许入组。 * 乙型肝炎表面抗原阳性或乙型肝炎核心抗体阳性的参与者应接受专科医生评估，并在允许进入研究前被认为感染已控制（血清乙型肝炎病毒脱氧核糖核酸[DNA]聚合酶链反应[PCR]低于检测限且正在接受乙型肝炎抗病毒治疗） * 丙型肝炎抗体阳性且感染已控制的参与者（通过PCR检测丙型肝炎核糖核酸[RNA]检测不到，无论是自发还是对既往成功的抗HCV治疗有应答）允许入组 * 巨细胞病毒（CMV）感染，表现为外周血聚合酶链反应（PCR）检测可检测到水平。筛查时显示CMV可检测到水平的患者需要接受适当的抗病毒治疗，并在重新考虑合格性前证明至少2次PCR检测CMV检测不到（至少间隔7天） * 在开始指定治疗前72小时内持续接受全身性皮质类固醇治疗，泼尼松/泼尼松龙剂量超过每天10 mg或等效抗炎剂量 * 近期大手术（研究治疗开始前4周内） * 首次给予研究治疗前14天内接受标准放疗 * 既往器官移植 * 研究首次给药前28天内接种活疫苗 * 在开始研究治疗前28天内（或药物的5个半衰期，以较短者为准）使用任何其他试验性药物或治疗 * 合并使用其他抗癌治疗，但根据治疗医生的判断，某些治疗（例如，维持性激素治疗）除外 * 未控制的全身性真菌、细菌或病毒感染（定义为尽管使用了适当的抗生素、抗病毒治疗和/或其他治疗，与感染相关的体征/症状持续存在且无改善） * 妊娠或哺乳 * 已知对别嘌醇、拉布立酶或具有相似化学或生物成分的化合物有过敏反应或超敏反应
Inclusion Criteria: * Aged ≥ 18 at the time of consent * Patients must have histologically or cytologically confirmed relapsed/ refractory (R/R) diffuse large B-cell lymphoma (DLBCL); transformed follicular lymphoma patients are eligible * Patients must have failed at least 2 prior therapies * Life expectancy ≥ 3 months * Candidate for any Food and Drug Administration (FDA)-approved chimeric antigen receptor (CAR) T cell therapy as per institutional guidelines * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 50%) * Leukocytes ≥ 2,500/µL * Absolute neutrophil count ≥ 1,000/µL or \> 500/µL for patients with bone marrow involvement * A participant may not have received granulocyte colony stimulating factor within 2 days prior to first dose of odronextamab in order to meet the absolute neutrophil count (ANC) eligibility criterion * Platelets ≥ 50,000/µL or ≥ 25,000/µL for patients with bone marrow involvement * A patient may not have received platelet transfusion therapy within 2 days prior to first dose of odronextamab in order to meet the platelet eligibility criterion * Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) * NOTE: patients with known Gilbert disease who have serum bilirubin level ≤ 3 x institutional ULN may be enrolled. Patients with known Gilbert syndrome will be excluded if the total bilirubin value is \> 4 x ULN * Irrespective of the presence of lymphoma infiltration of the liver, a participant with an aspartate aminotransferase (AST) \> 3 x ULN and/or alanine aminotransferase (ALT) \> 3 x ULN concurrent with a total bilirubin \> 1.5 x ULN will be excluded * AST(serum glutamic oxaloacetic transaminase \[SGOT\])/ALT(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN (AST and/or ALT ≤ 5 x ULN for patients with liver involvement) * Irrespective of the presence of lymphoma infiltration of the liver, a participant with an AST \> 3 x ULN and/or ALT \> 3 x ULN concurrent with a total bilirubin \> 1.5 x ULN will be excluded * Creatinine clearance ≥ 30 mL/min/1.73 m\^2 by Cockcroft-Gault * Hemoglobin ≥ 8 g/dL or ≥ 7 g/dL for patients with bone marrow involvement * NOTE: Growth factor or transfusion support is allowed as per treating physician's discretion * Alkaline phosphatase 2.5 x ULN (≤ 5 x ULN for patients with documented liver involvement or bone metastases) * International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN * NOTE: This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose * Cardiac ejection fraction \> 50% by echocardiogram or multigated acquisition (MUGA) scan * Serum creatinine ≤ 1.5 x ULN, or calculated creatinine clearance by Cockcroft Gault formula ≥ 50 mL/min * For participants infected with HIV: * No history of AIDS-defining conditions other than lymphoma or history of CD4+ T-cells below 200/mm\^3 prior to beginning combination antiretroviral therapy (ART) * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * At time of study entry CD4+ T-cells must have recovered from prior lymphoma therapy to ≥ 250/mm\^3 * At the time of study entry, the HIV viral load must be undetectable by standard laboratory assay * During prior lymphoma therapy, patients must not have experienced documented infections attributed to the HIV+ status * No history of non-adherence to ART and willing to adhere to ART while on study * Antiretroviral drugs with overlapping or similar toxicity profiles as study agents not allowed * People with hepatitis B or C on suppressive therapy with a negative viral load and no evidence of hepatic damage are eligible * People of child-bearing potential and reproductive partners must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 6 months (180 days) after the last dose of study agent. Egg and sperm donation is prohibited during the study and for 6 months after the last dose of study agent * Willing and able to provide informed consent Exclusion Criteria: * Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she/they were to participate in the study or confounds the ability to interpret data from the study as determined by the study principal investigator (PI) or enrolling physician * Known involvement by primary central nervous system (CNS) lymphoma or known uncontrolled involvement by non-primary CNS non-Hodgkin lymphoma (NHL) at the time of study entry * Known history (within last 12 months) of or current relevant CNS pathology, such as: * Epilepsy, seizure, paresis, aphasia, apoplexy, severe brain injury, cerebellar disease, organic brain syndrome, psychosis, cerebrovascular stroke or * Evidence for presence of inflammatory lesions and/or vasculitis on cerebral magnetic resonance imaging (MRI) * Another active malignancy (aside from B-cell NHL) in the past 5 years, with the following exceptions: non-melanoma skin cancer that has undergone potentially curative therapy, in situ cervical carcinoma, or any other tumor that has been deemed to be effectively treated with definitive local control and with curative intent as per treating investigator * Evidence of any active infection (bacterial, viral, fungal, mycobacterial, parasitic, or other) at study enrollment or within 2 weeks of study enrollment, if requiring ongoing treatment and/or has the potential to cause disseminated disease or severe infection upon immunosuppression. There should be evidence that the infection has cleared or is well controlled by start of study therapy * Active COVID-19 infection * Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) * Participants with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/µL either spontaneously or on a stable antiviral regimen) are permitted. * Participants who are hepatitis B surface antigen positive or who are hepatitis B core antibody positive should undergo evaluation by a specialist and be considered to have controlled infection (serum hepatitis B virus deoxyribonucleic acid \[DNA\] polymerase chain reaction \[PCR\] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) before they are permitted onto study * Participants who are HCV antibody positive who have controlled infection (undetectable HCV ribonucleic acid \[RNA\] by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted * Cytomegalovirus (CMV) infection as noted by detectable levels on peripheral blood polymerase chain reaction (PCR) assay. Patients who show detectable levels of CMV at screening will need to be treated with appropriate antiviral therapy and demonstrate at least 2 undetectable levels of CMV by PCR assay (at least 7 days apart) before being re-considered for eligibility * Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone/prednisolone or anti-inflammatory equivalent within 72 hours of start of assigned treatment * Recent major surgery (within 4 weeks prior to the start of study treatment) * Standard radiotherapy within 14 days of first administration of study treatment * Prior organ transplantation * Administration of live vaccination within 28 days of study first dose * Use of any other experimental drug or therapy within 28 days (or 5 half-lives of the drug, whichever is shorter) of initiating study treatment * Concurrent use of other anti-cancer treatments except for certain therapeutics (e.g., maintenance hormonal-based therapy) per the treating physician's discretion * Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment) * Pregnancy or lactation * Known allergic reactions or hypersensitivity to allopurinol, rasburicase, or compounds of similar chemical or biological components
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：Complete response rate (CRR) · Will be assessed by Lugano 2014. Will calculate the uniformly minimum variance unbiased estimator, p-value, and confidence intervals for CRR. The calculation will be performed using R clinfun package. · From first dose through completion of 5 cycles (cycle length = 21 days for cycles 1-4 and 14 days for cycle 5) of odronextamab and chimeric antigen receptor (CAR) T cell infusion
次要终点：Number of participants experiencing treatment-related adverse events (AEs)；Number of participants with progression-free survival；Objective response rate；Number of minimal residual disease (MRD) negative targets detected
患者在周期1的第1、2、8、9、15和16天，周期2-4的第1、8和15天，以及后续周期的第1和15天接受odronextamab IV输注，输注时间超过1-4小时，直至达到持久CR。在没有持久CR、疾病进展或不可接受的毒性的情况下，周期每21天重复一次。达到持久CR ≥ 9个月的患者随后可在每个后续周期的第1天接受odronextamab IV输注，输注时间超过1-4小时。在没有疾病进展或不可接受的毒性的情况下，这些周期每28天重复一次，最多总共2年。如果第4周期后疾病评估显示未达到CR，或第5周期后任何时间疾病评估显示PD，则患者接受SOC CAR T细胞疗法。
这项II期试验测试odronextamab在标准治疗（SOC）嵌合抗原受体（CAR）T细胞疗法前后治疗弥漫性大B细胞淋巴瘤（DLBCL）患者的效果，这些患者经过一段时间的改善后复发（relapsed），或对既往治疗无反应（refractory）。CAR-T细胞疗法是大多数患者在其他治疗失败后接受的标准治疗。CAR-T细胞疗法是一种治疗方法，其中患者的T细胞（一种免疫系统细胞）在实验室中被改变，使其能够攻击癌细胞。T细胞取自患者的血液。然后，在实验室中将一种特殊受体的基因添加到T细胞中，该受体能与患者癌细胞上的某种蛋白质结合。这种特殊受体称为CAR。大量CAR T细胞在实验室中培养，并通过输注给予患者以治疗某些癌症。Odronextamab是一种单克隆抗体，被称为双特异性抗体，因为它分别靶向2种细胞蛋白，CD20和CD3。蛋白质是体内每个细胞的一部分，它们像小机器一样协同工作，使细胞发挥功能。CD20是一种存在于正常B细胞和构成某些癌症（如DLBCL）的B细胞表面的蛋白质。CD3是一种存在于T细胞表面的蛋白质。T细胞和正常B细胞是体内白细胞的类型，是免疫系统的一部分，负责抵抗感染。Odronextamab旨在帮助T细胞找到并杀死B细胞，包括DLBCL中的癌细胞。在CAR T细胞疗法前后给予odronextamab可能会改善复发或难治性DLBCL患者的缓解。
This phase II trial tests how well odronextamab works before and after standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapy in treating patients with diffuse large B-cell lymphoma (DLBCL) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). CAR-T cell therapy is the SOC treatment most patients receive when other treatments have failed. CAR-T cell therapy is a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells. T cells are taken from a patient's blood. Then the gene for a special receptor that binds to a certain protein on the patient's cancer cells is added to the T cells in the laboratory. The special receptor is called a CAR. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Odronextamab is a monoclonal antibody that is called bispecific, as it individually targets 2 cell proteins, CD20 and CD3. Proteins are part of each cell in the body, which work together like little machines for the cell to function. CD20 is a protein that is found on the surface of both normal B-cells and B-cells that make up certain cancers, like DLBCL. CD3 is a protein that is found on the surface of T cells. T-cells and normal B-cells are types of white blood cells in the body and are a part of the immune system that fights infections. Odronextamab is designed to help T-cells find and kill the B-cells including the cancer cells in DLBCL. Giving odronextamab before and after CAR T-cell therapy may improve response in patients with relapsed or refractory DLBCL.
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