肿瘤细胞治疗研究
英文原题：Testing Drug Treatments After CAR T-cell Therapy in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma
这是一项 II 期注册临床试验，评估细胞治疗用于弥漫大 B 细胞淋巴瘤、滤泡性淋巴瘤、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 396 例。试验地点：美国 · 图森、费耶特维尔、小石城、罗杰斯（共 87 个中心）。登记号：NCT05633615。
不限性别 · ≥ 18 Years
步骤1：登记 • 组织学确诊DLBCL、3b级滤泡性淋巴瘤或原发纵隔大B细胞淋巴瘤（PMBCL）；转化性DLBCL须由滤泡性或边缘区淋巴瘤转化。系统性疾病双径线可测量（至少1个病灶最长径>1.5 cm）。继发CNS淋巴瘤（脑实质、脊髓、脑膜或脑脊液受累）患者CNS病须无症状。 • 已签署机构CAR-T单采同意，并须在商业CAR-T淋巴清除化疗开始前完成步骤1登记。研究医生认为适合CAR-T，计划使用FDA批准的商业CD19 CAR-T且符合说明书标准。若产品不符合FDA规格、改按扩大使用或单患者IND输注，则退出研究，不能参加步骤2随机。 • 单采后可接受桥接治疗，但不得含polatuzumab vedotin或mosunetuzumab。桥接治疗指单采至LD化疗前的淋巴瘤治疗，包括化疗、放疗、类固醇、BTK抑制剂、免疫调节剂、单抗、抗体药物偶联物、检查点抑制剂或试验治疗。使用上述两种研究药物作桥接者不得继续步骤1/步骤2。 • 计划LD前60天内完成PET-CT，且记录CAR-T前疾病状态。接受桥接治疗者结束后须做PET-CT；若按Lugano标准完全缓解，则不符合步骤2随机。单采后可用类固醇而无需重复PET-CT，但须计划在CAR-T前至少3天停药。中央阅片如无法评估（如图像质量差/超窗），记为评估不足，不可随机。 • 单采前既往使用polatuzumab vedotin或mosunetuzumab治疗惰性/侵袭性NHL者可参加，前提是末次输注后未难治，且6个月内未进展/复发。 • 计划在末次LD化疗后第2至14天输注CAR-T；超窗者不得步骤2随机。LD须计划在步骤1登记后60天内开始。 • 登记时年龄≥18岁；Zubrod体能状态0至2。登记前14天内总胆红素≤机构ULN的2倍（Gilbert病或淋巴瘤肝受累除外），AST/ALT≤3倍ULN，Cockcroft-Gault肌酐清除率≥40 mL/min（按实际体重）。登记前60天内ECHO/MUGA显示LVEF≥40%；有心脏症状者NYHA功能分级须≤II级。登记前6个月内不得有心肌梗死及PCI；无PCI心梗须距登记>3个月，且无不稳定心绞痛。周围神经病变<2级。 • HBV感染者登记前14天内病毒载量不可检出，接受抑制治疗且无HBV肝损伤；HCV感染者须完成根治治疗、无肝损伤，且前14天病毒载量不可检出。HIV感染者登记时接受有效抗逆转录病毒治疗，且过去6个月内最近检测病毒载量不可检出。 • 提供参加转化医学/未来研究样本库的机会；经同意后强制组织样本余量可入库。受试者须知研究具有试验性并按机构/联邦要求签署同意；决策能力受损者可由法定代表人同意。 步骤2：随机 须满足步骤1全部条件；商业CAR-T产品符合FDA批准规格。CAR-T后第25至40天PET-CT经中央评估，相对LD/CAR-T前最近一次PET-CT为稳定疾病或部分缓解。若“第+30天”PET-CT后>21天才随机且出现疑似进展症状，须复查PET-CT；影像评估不足不得随机。须在CAR-T后60天内随机，且LD须在步骤1同意后60天内开始；随机前向SWOG提交S2114 CAR-T治疗表。桥接治疗结束后须做PET-CT（最多允许7天类固醇例外）；若完全缓解或中央评估不足，不可随机。体能状态Zubrod 0至2。随机前7天内ANC≥1.0×10³/μL（抽血前72小时未用髓系生长因子）；血小板≥75×10³/μL（抽血前72小时未输血小板）；总胆红素≤2×ULN（Gilbert病/淋巴瘤肝受累例外），AST/ALT≤3×ULN，肌酐清除率≥40 mL/min；周围神经病变<2级；有心脏症状者NYHA≤II级。HBV既往感染者须持续抑制治疗且随机前14天病毒载量不可检出；HCV既往感染者随机前14天病毒载量不可检出；HIV患者继续抗逆转录病毒治疗且随机前14天病毒载量不可检出。 步骤3：交叉登记（仅观察组/第IV臂） 须有方案观察期间疾病进展记录，进展的随访肿瘤评估表须先提交SWOG；进展日起28天内登记。影像须清楚显示较CAR-T后第+30天PET-CT进展；非计划评估影像仅在常规照护需要且出现疑似进展症状时进行。Zubrod 0至2；登记前14天内ANC≥1.0×10³/μL（抽血前72小时未用髓系生长因子）、血小板≥75×10³/μL（抽血前72小时未输注）；总胆红素≤2×ULN（Gilbert/淋巴瘤肝受累除外），AST/ALT≤3×ULN，肌酐清除率≥40 mL/min；周围神经病变<2级；有心脏症状者NYHA≤II级。HBV/HCV病毒载量须不可检出，HBV接受抑制治疗，HIV患者接受抗逆转录病毒治疗且病毒不可检出。 步骤3其余资格按方案步骤2及交叉登记标准执行。 治疗药物及观察期间，按方案进行血象、生化、心功能、病毒学和影像学评估；如观察组在CAR-T后12个月内进展，可交叉至联合治疗组。
Inclusion Criteria:
* STEP 1: REGISTRATION: Participants must have a histologically confirmed diagnosis of diffuse large B-cell lymphoma or follicular lymphoma grade 3b or primary mediastinal large B-cell lymphoma (PMBCL)
* STEP 1: REGISTRATION: Participants with transformed DLBCL must have transformed DLBCL from follicular or marginal zone lymphoma
* STEP 1: REGISTRATION: Participant must have bi-dimensionally measurable systemic disease (at least one lesion with longest diameter \> 1.5 cm)
* STEP 1: REGISTRATION: Participants with secondary central nervous system (CNS) lymphoma (parenchymal, spinal cord, meningeal, cerebrospinal fluid involvement) must be asymptomatic from their CNS disease
* STEP 1: REGISTRATION: Participants must be registered for step 1 after they have signed institutional consent for CAR T-cell leukapheresis but prior to the start of lymphodepleting (LD) chemotherapy for commercial CAR T-cell product
* STEP 1: REGISTRATION: In the opinion of the enrolling physician, participants must be felt to be a candidate for CAR T-cell therapy with plans to be treated with Food and Drug Administration (FDA) approved commercially available CD19 CAR T-cell construct.
* Participants must qualify for commercially approved CD19 CAR T-cell therapy per FDA package insert.
* If the CAR T-cell product does not meet parameters to be given as an FDA approved product (i.e. does not meet specification criteria mandated by FDA and is infused under an expanded access protocol \[EAP\] or single participant investigational new drug \[IND\]) the participant will be taken off of study and no longer be eligible for step 2 randomization
* STEP 1: REGISTRATION: Participants are permitted to receive or have received 'bridging therapy' after CAR T-cell leukapheresis. However, participants must not receive polatuzumab vedotin, and/or mosunetuzumab as part of bridging therapy.
* Bridging therapy is defined as lymphoma directed therapy administered between leukapheresis and the start of LD chemotherapy. This includes cytotoxic chemotherapy (e.g.: bendamustine and rituximab \[BR\], rituximab, gemcitabine and oxaliplatin \[R-gem/ox\]), radiation, corticosteroids, as well as novel therapies such as BTK inhibitors (e.g.: Ibrutinib), immunomodulators (e.g.: lenalidomide), monoclonal antibodies (e.g.: rituximab, obinutuzumab, tafasitamab) antibody drug conjugates (e.g: loncastuximab), checkpoint inhibitors (e.g.: pembrolizumab, nivolumab), clinical trial treatments, etc.
* If a participant receives polatuzumab vedotin or mosunetuzumab as bridging they will ineligible to continue on step 1 registration portion of the study and be ineligible for step 2 randomization
* STEP 1: REGISTRATION: PET-CT scan must be planned for completion within 60 days prior to the start of LD chemotherapy.
* All pre-CAR T-cell therapy disease must be assessed and documented on the baseline/pre-registration tumor assessment form.
* If receiving bridging therapy, participants must have a PET-CT scan upon completion of all planned bridging therapy. If the PET-CT scan after completion of bridging therapy is consistent with complete remission per Lugano criteria as determined by enrolling physician, that participant will be ineligible for step 2 randomization.
* Participants are permitted to receive corticosteroids after leukapheresis without the need to repeat a PET-CT scan. If steroids are used, they must be planned to stop no later than 3 days before CAR -T cell infusion.
* If response assessment by central review cannot be completed (I.e., poor quality of PET-CT scan, PET-CT performed out of window, etc.) this would be recorded as 'inadequate assessment' and patient would not be eligible for randomization
* STEP 1: REGISTRATION: Participants that have previously been treated with polatuzumab vedotin or mosunetuzumab prior to CAR T-cell leukapheresis for either indolent or aggressive NHL are eligible as long as the participant did not have refractory disease or progression/relapse within 6 months of the last infusion with either agent
* STEP 1: REGISTRATION: Participants must be planning to receive CAR T-cell infusion no earlier than 2 days and no later than 14 days after completion of the last day of lymphodepleting chemotherapy. Any participant receiving CAR T-cell infusion outside of this window will be ineligible for step 2 randomization
* STEP 1: REGISTRATION: LD chemotherapy prior to CAR T-cell infusion must be planned to start within 60 days after step 1 registration
* STEP 1: REGISTRATION: Participants must be \>= 18 years of age at the time of registration
* STEP 1: REGISTRATION: Participants must have Zubrod performance score (PS) of 0, 1, or 2
* STEP 1: REGISTRATION: Total bilirubin =\< 2 x institutional upper limit of normal (ULN) (within 14 days prior to registration)
* Unless due to Gilbert's disease or lymphomatous involvement of liver
* STEP 1: REGISTRATION: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3 x institutional ULN (within 14 days prior to registration)
* STEP 1: REGISTRATION: Creatinine clearance \>= 40 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 14 days prior to registration. Estimated creatinine clearance is based on actual body weight
* STEP 1: REGISTRATION: Participants must have an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 60 days prior to registration with a cardiac ejection fraction \>= 40%.
* Participants with current symptoms of cardiac disease must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better.
* Participants must not have documented myocardial infarction and percutaneous coronary intervention (PCI) within 6 months prior to registration or myocardial infarction without PCI within 3 months of registration, or unstable angina
* STEP 1: REGISTRATION: Participants with peripheral neuropathy must have \< grade 2
* STEP 1: REGISTRATION: Participants with hepatitis B virus infection must have undetectable viral load within 14 days prior to registration, be on suppressive therapy and have no evidence of hepatitis B virus (HBV) related hepatic damage
* STEP 1: REGISTRATION: Participants with hepatitis C infection must have eradication therapy completed, have no evidence of hepatitis C infection (HCV) related damage and have undetectable viral load within 14 days prior to registration
* STEP 1: REGISTRATION: Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at time of registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration
* STEP 1: REGISTRATION: Participants must be offered the opportunity to participate in banking for planned translational medicine and future research. With participant consent, any residuals from the mandatory tissue submission will also be banked for future research.
* Note: Streck tubes must be ordered in advance. Please allow 5-7 days for shipment of the collection kits
* STEP 1: REGISTRATION: NOTE: As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.
* Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines.
* For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
* STEP 2: RANDOMIZATION: Participants must have met all eligibility criteria for step 1 registration
* STEP 2: RANDOMIZATION: Participant's CAR T-cell product must have met specification parameters to be given as an FDA approved commercial product
* STEP 2: RANDOMIZATION: Participants must have a PET-CT scan between days 25-40 after CAR T-cell infusion and determined to have a response consistent with stable disease or partial remission by central review compared to most recent pre-LD chemo/CAR T-cell PET-CT scan.
* Note: Patients with delayed enrollment \> 21 days after 'day +30' PET-CT scan will necessitate a repeat PET-CT scan if concerning signs or symptoms of lymphoma progression develop.
* Note: If response assessment by central review cannot be completed (I.e., poor quality of PET-CT scan, PET-CT performed out of window, etc.) this would be recorded as 'inadequate assessment' and patient would not be eligible for randomization
* STEP 2: RANDOMIZATION: Eligible participants must be randomized no later than 60 days after CAR -T infusion
* STEP 2: RANDOMIZATION: Participants must have started LD chemotherapy within 60 days of signing consent for step 1 registration
* STEP 2: RANDOMIZATION: Participants must have S2114 CAR T-cell therapy form submitted to Southwest Oncology Group (SWOG) prior to step 2 randomization
* STEP 2: RANDOMIZATION: Participants must have had a PET-CT scan upon completion of all planned bridging therapy if received, with the exception of up to 7 days of corticosteroids. If the PET-CT scan after completion of bridging therapy was consistent with complete remission per Lugano criteria as determined by enrolling physician, that participant will be ineligible for step 2 randomization.
* If response assessment by central review cannot be completed (I.e., poor quality of PET-CT scan, PET-CT performed out of window, etc.) this would be recorded as 'inadequate assessment' and patient would not be eligible for randomization
* STEP 2: RANDOMIZATION: Participants must have Zubrod PS of 0, 1, or 2
* STEP 2: RANDOMIZATION: Absolute neutrophil count (ANC) \>= 1.0 x 10\^3/uL and participants must not have received myeloid growth factor within 72 hours prior to this lab being drawn (within 7 days prior to step 2 randomization)
* STEP 2: RANDOMIZATION: Platelets \>= 75 x 10\^3/uL and participants must not have received platelet transfusion within 72 hours prior to this lab being drawn (within 7 days prior to step 2 randomization)
* STEP 2: RANDOMIZATION: Total bilirubin =\< 2 x institutional ULN (within 7 days prior to step 2 randomization)
* Unless due to Gilbert's disease or lymphomatous involvement of liver
* STEP 2: RANDOMIZATION: AST and ALT =\< 3 x institutional ULN (within 7 days prior to step 2 randomization)
* STEP 2: RANDOMIZATION: Creatinine clearance \>= 40 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within 7 days prior to step 2 randomization. Estimated creatinine clearance is based on actual body weight (within 7 days prior to step 2 randomization)
* STEP 2: RANDOMIZATION: Participants with peripheral neuropathy must have \< grade 2
* STEP 2: RANDOMIZATION: Participants with current symptoms of cardiac disease must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
* STEP 2: RANDOMIZATION: Participants with history of hepatitis B viral infection must have undetectable viral load within 14 days prior to step 2 randomization and on suppressive therapy
* STEP 2: RANDOMIZATION: Participants with history of hepatitis C viral infection must have undetectable viral load within 14 days prior to step 2 randomization
* STEP 2: RANDOMIZATION: Participants with known human immunodeficiency virus (HIV)-infection must be continuing to receive anti-retroviral therapy and have an undetectable viral load test within 14 days prior to step 2 randomization
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must have documented disease progression while on Arm 4 (observation) on this protocol. The follow-up tumor assessment form documenting disease progression must be submitted to SWOG prior to step 3 crossover registration
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must be registered within 28 days of the date of progression
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must have imaging that clearly demonstrates progression compared to day +30 PET-CT scan
* Note: These scans should be performed as standard of care and only performed between scheduled response assessments required for study if symptoms arise that are concerning for progression
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants must have Zubrod PS of 0, 1, or 2
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): ANC \>= 1.0 x 10\^3/uL and participants must not have received myeloid growth factor within 72 hours prior to this lab being drawn (within 14 days prior to step 3 crossover registration)
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Platelets \>= 75 x 10\^3/uL and participants must not have received platelet transfusion within 72 hours prior to this lab being drawn (within 14 days prior to step 3 crossover registration)
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Total bilirubin =\< 2 x institutional ULN (within 14 days prior to step 3 crossover registration)
* Unless due to Gilbert's disease or lymphomatous involvement of liver
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): AST and ALT =\< 3 x institutional ULN
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Creatinine clearance \>= 40 mL/min, as estimated by the Cockcroft and Gault formula. The creatinine value used in the calculation must have been obtained within days prior to step 3 crossover registration. Estimated creatinine clearance is based on actual body weight (within 14 days prior to step 3 crossover registration)
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with peripheral neuropathy must have \< grade 2
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with current symptoms of cardiac disease must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2B or better
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with history of hepatitis B viral infection must have undetectable viral load within 14 days prior to step 3 crossover registration and on suppressive therapy
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with history of hepatitis C viral infection must have undetectable viral load within 14 days prior to step 3 crossover registration
* STEP 3: CROSSOVER REGISTRATION (ARM 4 ONLY): Participants with known human immunodefici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：Progression free survival (PFS) · Will compare PFS in participants with relapsed/refractory large B-cell lymphoma or follicular lymphoma grade 3B with stable disease (SD) or partial remission (PR) on first imaging response (day +30 positron emission tomography \[PET\]/computed tomography \[CT\] scan) after commercial CD19 chimeric antigen receptor (CAR) T-cell therapy who are randomized to receive each consolidation therapy versus those that receive no consolidation therapy (i.e. control). Specifically, will compare the PFS of 1) mosunetuzumab consolidation to no consolidation, 2) polatuzumab vedotin consolidation to no consolidation, 3) mosunetuzumab + polatuzumab vedotin to no consolidation. Will analyze results by arm rather than assuming no-interactions in some factorial analyses. Will follow multi-step hypothesis testing procedure of Freidlin and Korn to compare the arms within this randomized Phase II study. Each of the primary comparisons has 81% power using a stratified logrank test at one-sided alpha of 0.05. · From date of randomization to date of first observation of progressive disease or death due to any cause, assessed up to 2 years
次要终点：Overall survival (OS)；Complete remission (CR) conversion rate；Incidence of adverse events；Association between total metabolic tumor volume (TMTV), standardized uptake value (SUV) max, and sum product (SPD) of diameters；Conversion of CR
接受静脉氟达拉滨和环磷酰胺淋巴清除化疗，随后静脉输注tisagenlecleucel、axicabtagene ciloleucel或lisocabtagene maraleucel。
静脉给予mosunetuzumab；研究期间进行PET-CT和/或CT，并采集血液及组织样本。
静脉给予polatuzumab vedotin；研究期间进行PET-CT和/或CT，并采集血液及组织样本。
静脉给予polatuzumab vedotin和mosunetuzumab；研究期间进行PET-CT和/或CT，并采集血液及组织样本。
接受观察；研究期间进行PET-CT和/或CT，并采集血液及组织样本。CAR-T后12个月内进展者可交叉至III组。
本II期研究评估DLBCL或3b级滤泡性淋巴瘤患者在氟达拉滨/环磷酰胺预处理及商业CAR-T治疗后，接受mosunetuzumab和/或polatuzumab vedotin巩固治疗，是否优于不巩固治疗。研究还评估观察组CAR-T后12个月内进展患者交叉接受联合治疗的效果。
This phase II trial tests whether mosunetuzumab and/or polatuzumab vedotin helps benefit patients who have received chemotherapy (fludarabine and cyclophosphamide) followed by chimeric antigen receptor (CAR) T-cell therapy (tisagenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel) for diffuse large B-cell lymphoma that has come back (recurrent) or that does not respond to treatment (refractory) or grade IIIb follicular lymphoma. Mosunetuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Polatuzumab vedotin is a monoclonal antibody, called polatuzumab, linked to a drug called vedotin. Polatuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, and delivers vedotin to kill them. Chemotherapy drugs, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. 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 chimeric antigen receptor. Large numbers of the CAR T cells are grown in the laboratory and given to the patient by infusion for treatment of certain cancers. Giving mosunetuzumab and/or polatuzumab vedotin after chemotherapy and CAR T-cell therapy may be more effective at controlling or shrinking the cancer than not giving them.
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