肿瘤细胞治疗研究
英文原题：Efficacy and Safety of MB-CART2019.1 vs. SoC in Lymphoma Patients
这是一项 II 期注册临床试验，评估细胞治疗用于弥漫大 B 细胞淋巴瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 213 例。试验地点：欧洲 · 格拉茨、因斯布鲁克、林茨、维也纳（共 51 个中心）。登记号：NCT04844866。
不限性别 · ≥ 18 Years 且 ≤ 70 Years
第一部分：
1. 根据世界卫生组织（WHO）2016年分类，组织学证实的DLBCL及相关亚型，包括：
* 非特指型DLBCL（NOS）。
* 伴有MYC和BCL2和/或BCL6重排的高级别B细胞淋巴瘤（HGBL），具有DLBCL/母细胞样/中间型组织学，或伴有MYC和BCL2和/或BCL6重排的HGBL（双打击淋巴瘤/三打击淋巴瘤）。
* 非特指型高级别BCL。
* 原发性（胸腺）纵隔大B细胞淋巴瘤。
* 由先前诊断的低级别淋巴瘤（例如滤泡性淋巴瘤、边缘区淋巴瘤等惰性病理）转化为DLBCL，且在DLBCL导向的系统性治疗后出现DLBCL疾病进展。
* 滤泡性淋巴瘤3B级。
2. 一线化学免疫治疗后复发或难治性疾病：
* 难治性疾病定义为一线治疗未达CR（例如R-CHOP[利妥昔单抗、环磷酰胺、柔红霉素、长春新碱和泼尼松]）。
* 至少2个完整周期一线治疗后出现疾病进展（PD）。
* 4个周期一线治疗后疾病稳定（SD）。
* 至少6个周期一线治疗后最佳疗效为PR，且活检证实持续存在疾病（因合并症被禁止的情况除外），距一线治疗开始≤ 24个月。
* 复发性疾病定义为一线治疗达完全缓解后，活检证实疾病进展（因合并症被禁止的情况除外），距一线治疗开始≤ 24个月。
3. 受试者必须接受过充分的一线治疗，至少包含以蒽环类药物为基础的方案与利妥昔单抗（抗CD20单克隆抗体）的联合治疗。若局部治疗（例如放疗）在同一线治疗期间进行，则不视为一线治疗。
4. 必须提供筛选前≤ 2年（优选：≤ 2个月）获取的存档石蜡包埋肿瘤组织，用于中心病理学复核以确认DLBCL诊断，方可参与本研究。若无法获得存档石蜡包埋肿瘤组织，则必须提供新鲜肿瘤组织样本（优选）或粗针穿刺活检组织用于中心病理学复核。
5. 根据治疗医师的评估，认为不适合接受HDC后ASCT，且符合以下标准的受试者：
或
* 年龄≥ 18岁且
* 既往接受过ASCT（作为一线巩固治疗）或
* 造血细胞移植特异性合并症指数（HCT-CI）> 3。或
* 年龄≥ 65岁且符合以下至少1项标准：
* 心功能受损（左心室射血分数[LVEF] < 50%），或
* 肾功能受损（估算肾小球滤过率[eGFR] < 60 mL/min），根据改良的肾脏病饮食改良（MDRD）公式计算，或
* 肺功能受损（一氧化碳弥散量或第1秒用力呼气容积<80%）或轻度活动即出现呼吸困难，或
* 东部肿瘤协作组（ECOG）体能状态>1。或
* 年龄≥70岁。参与者源数据中必须有不符合ASCT条件的记录。
此外，所有参与者必须符合以下标准：
6. 年龄≥18岁。
7. 根据Lugano标准可测量疾病。病灶必须可测量（淋巴结长轴>1.5 cm；结外病灶长轴>1 cm）且正电子发射断层扫描阳性。
8. 因原发疾病以外的其他原因，预计生存期>3个月。
9. 有生育能力的女性（WOCBP）必须同意在研究开始前至少1个月、研究期间以及研究治疗末次给药后12个月内使用高效避孕措施（Pearl指数<1）或实行真正的性禁欲，避免任何异性性交（只有在符合参与者偏好和通常生活方式的情况下，才可接受真正的禁欲），或必须仅有已接受输精管切除术的伴侣作为唯一性伴侣（该伴侣必须已接受手术成功的医学评估）。女性在初潮后至绝经前被视为WOCBP，即有生育能力，除非永久绝育。高效避孕方法包括与抑制排卵相关的激素避孕药（口服、阴道内、透皮、注射、植入）和宫内节育器或系统（例如激素和非激素）以及双侧输卵管闭塞。永久绝育方法包括子宫切除术、双侧输卵管切除术和双侧卵巢切除术。绝经后状态定义为无其他医学原因的情况下12个月无月经。希望在完成治疗后怀孕的WOCBP应在治疗前寻求关于卵母细胞冷冻保存的建议，因为可能发生不可逆的不孕。WOCBP在研究期间至研究治疗末次给药后12个月内必须避免捐献卵子。
与未怀孕的WOCBP伴侣的男性必须同意使用高效避孕措施（Pearl指数< 1，例如杀精剂和避孕套或由其WOCBP伴侣采取的其他高效避孕措施（Pearl指数< 1））或在研究期间及研究治疗末次给药后12个月内实行真正的禁欲（真正禁欲仅在符合参与者偏好和通常生活方式的情况下可接受），除非他们已手术绝育（意味着输精管切除术后至少连续2次分析显示精液中无精子）。由于可能不可逆的不育，男性应在治疗前寻求关于精子保存的建议。此外，男性必须在整个研究期间直至研究治疗末次给药后12个月内避免捐献精子。
10. 根据研究者的判断，参与者必须能够遵守所有研究相关程序、药物使用和评估。
11. 具有同意参加临床研究的精神能力和法律能力。
排除标准：
1. 根据治疗医生的判断，存在R-GemOx、BR联合polatuzumab vedotin、环磷酰胺和氟达拉滨的禁忌症。
2. 既往接受过嵌合抗原受体治疗或其他基因修饰T细胞治疗。
3. 已接受超过一线DLBCL或相关亚型治疗的参与者。
4. 白细胞分离术时，既往造血干细胞移植（HSCT；作为一线巩固治疗）< 3个月。
5. ECOG体能状态 > 2。
6. 绝对中性粒细胞计数 < 1,000/μL（除非继发于骨髓活检证实的DLBCL骨髓受累）。
7. 血小板计数 < 50,000/μL（除非继发于骨髓活检证实的DLBCL骨髓受累）。
8. 绝对淋巴细胞计数 < 100/μL。
9. 当前或既往病史中有中枢神经系统（CNS）淋巴瘤受累的参与者。
10. 因肿瘤占位效应需要紧急治疗的参与者。
11. 人类免疫缺陷病毒感染。
12. 血清学指示存在活动性或既往乙型或丙型肝炎（详细标准见第10.2.7.10节）。已治疗的乙型或丙型肝炎病毒感染，除非确认聚合酶链反应阴性。
13. 严重急性呼吸综合征冠状病毒2（SARS-CoV-2）活动性感染。
14. 活动性、严重的全身性真菌、病毒或细菌感染。
15. 已知病史或证据表明存在严重免疫抑制状态，即皮质类固醇治疗 > 10 mg/天超过6个月。
16. 随机化前6周内已接种活病毒疫苗。
17. 既往接受过CD19靶向治疗。
18. 已知病史或存在癫痫发作活动，或在前12个月内正在使用抗癫痫药物。
19. 研究者判断可能影响神经毒性评估能力的非恶性CNS疾病史或现症。
20. 已知自身免疫性CNS疾病史或现症，如多发性硬化、视神经炎或其他免疫性或炎症性疾病。
21. 随机化前12个月内已知脑血管意外（CVA）史或现症。
注：若白细胞分离术前CVA史超过12个月，则受试者不得存在任何不稳定或危及生命的神经功能缺损。
22. 患有Richter转化或Richter综合征的受试者。
23. 同时正在接受任何其他实验性治疗，或在前4周或5个半衰期内接受过此类治疗的受试者。
24. 纽约心脏协会分级≥2级的临床心力衰竭，或LVEF<30%，或严重心律失常，或QT间期延长（筛选时静息QTcF≥450毫秒[男性]或≥460毫秒[女性]），且（根据研究者的评估）因接受试验中给予的药物而面临不可控风险。
25. 室内空气下静息外周血氧饱和度<90%。
26. 肝功能异常，表现为总胆红素>2.5×机构正常值上限（ULN），天冬氨酸氨基转移酶和/或丙氨酸氨基转移酶>5×ULN，或出现黄疸等典型症状。
27. 血清肌酐≥2.0×ULN，或根据改良MDRD公式计算的eGFR<30 mL/min。
28. 妊娠或哺乳期女性。
29. 除DLBCL外其他恶性肿瘤的既往史。例外情况包括筛选前无病生存≥3年的受试者，以及接受充分治疗并切除的皮肤基底细胞癌、皮肤鳞状细胞癌、宫颈原位癌、乳腺原位癌、膀胱原位癌受试者，或监测下偶然组织学发现未经治疗的局限性（T1a、T1b或T1c）前列腺癌受试者。
30. 对任何计划在研究参与期间给予的研究性药品（IMP）、辅助药品（AxMP）、预给药或抢救药物或其辅料有严重速发型超敏反应史。
31. 治疗开始前30天内接受过大手术。
32. 任何可能干扰研究治疗安全性或有效性评估的医学状况。
第二部分：
1. 根据WHO 2016分类，组织学证实的DLBCL及相关亚型，包括：
* DLBCL，NOS。
* 伴有MYC和BCL2和/或BCL6重排的HGBL，具有DLBCL/母细胞样/中间型组织学，或伴有MYC和BCL2和/或BCL6重排的HGBL（双打击淋巴瘤/三打击淋巴瘤）。
* 高级别BCL，NOS。
* 原发性（胸腺）大纵隔BCL。
* 由既往诊断为低级别淋巴瘤（例如滤泡性淋巴瘤、边缘区淋巴瘤等惰性病理类型）转化为DLBCL，且在接受DLBCL导向的全身治疗后出现DLBCL疾病进展。
* 滤泡性淋巴瘤3B级。
2. 一线化学免疫治疗后复发或难治性疾病：
* 难治性疾病定义为一线治疗（例如R-CHOP）未达到CR。
* 至少2个完整周期一线治疗后出现PD。
* 4个周期一线治疗后出现SD。
* 至少6个周期一线治疗后最佳疗效为PR，且一线治疗完成后≤ 12个月内活检证实存在持续性疾病（因合并症而无法活检者除外）。
* 复发性疾病定义为一线治疗达到完全缓解后，在一线治疗完成后≤ 12个月内活检证实疾病进展（因合并症而无法活检者除外）。
3. 参与者必须接受过充分的一线治疗，至少包含以蒽环类药物为基础的方案与利妥昔单抗（抗CD20单克隆抗体）的联合治疗。若局部治疗（例如放疗）与同一线治疗同时进行，则不视为单独的一线治疗。
4. 必须提供筛选前≤ 2年（首选：≤ 2个月）获取的存档石蜡包埋肿瘤组织，用于中心病理学审查以确认DLBCL诊断，方可参与本研究。若无法获得存档石蜡包埋肿瘤组织，则必须提供新鲜肿瘤组织样本（首选）或空心针活检样本用于中心病理学审查。
5. 根据Lugano标准存在可测量病灶。病灶必须可测量（淋巴结长径> 1.5 cm；结外病灶长径> 1 cm）且正电子发射断层扫描阳性。
6. 根据研究者评估，已获批的治疗方案不适用。
此外，所有参与者必须满足以下标准：
7. 年龄≥ 18岁且≤ 70岁。
8. 因非原发疾病原因，预计生存期> 3个月。
9. ECOG 0-1。
10. 骨髓功能充分，定义为：
* 中性粒细胞绝对计数≥ 1,000/μL（除非继发于骨髓活检证实的DLBCL骨髓受累）。
* 血小板计数≥ 50,000/μL（除非继发于骨髓活检证实的DLBCL骨髓受累）。
* 淋巴细胞绝对计数≥ 100/μL。
11. 器官功能充分，定义为：
* 纽约心脏协会分级< 2级或LVEF ≥ 50%。
* 无严重心律失常或QT间期延长（筛选时静息QTcF < 450毫秒[男性]或< 460毫秒[女性]）。
* 无临床相关的胸腔积液或心包积液。
* 室内空气中静息外周血氧饱和度≥ 92%。
* 总胆红素≤ 2.0 × ULN，AST和/或ALT ≤ 5 × ULN
* 血清肌酐 < 1.0 × ULN 或 eGFR（根据改良 MDRD 公式）≥ 60 mL/min。
12. WOCBP 必须同意在研究开始前至少 1 个月、研究期间以及研究治疗末次给药后 12 个月内使用高效避孕措施（Pearl 指数 < 1）或实行真正的性禁欲，即避免任何异性性交（只有在符合受试者偏好和通常生活方式的情况下，才可接受真正的禁欲），或必须仅有已接受输精管切除术的伴侣作为唯一性伴侣（该已接受输精管切除术的伴侣必须已接受手术成功的医学评估）。女性自月经初潮后至绝经前，除非永久绝育，否则被视为 WOCBP，即有生育能力。高效避孕方法包括与抑制排卵相关的激素避孕药（口服、阴道内、透皮、注射、植入）和宫内节育器或系统（例如激素和非激素）以及双侧输卵管闭塞。永久绝育方法包括子宫切除术、双侧输卵管切除术和双侧卵巢切除术。绝经后状态定义为无其他医学原因的情况下连续 12 个月无月经。希望在完成治疗后怀孕的 WOCBP 应在治疗前咨询卵母细胞冷冻保存，因为可能发生不可逆不孕。WOCBP 必须在整个研究期间至研究治疗末次给药后 12 个月内避免捐献卵子。其伴侣为非妊娠 WOCBP 的男性必须同意在研究期间以及研究治疗末次给药后 12 个月内使用高效避孕措施（Pearl 指数 < 1，例如杀精剂和避孕套，或其 WOCBP 伴侣采取的其他高效避孕措施（Pearl 指数 < 1））或实行真正的性禁欲，即避免任何异性性交（只有在符合受试者偏好和通常生活方式的情况下，才可接受真正的禁欲），除非他们已手术绝育（指输精管切除术后至少连续 2 次分析显示精液中无精子）。男性应在治疗前咨询精子保存，因为可能发生不可逆不孕。此外，男性必须在整个研究期间至研究治疗末次给药后 12 个月内避免捐献精子。
13. 根据研究者的判断，受试者必须能够遵守所有研究相关程序、药物使用和评估。
14. 具有同意参加临床研究的精神能力和法律行为能力。
排除标准：
1. 根据治疗医生的判断，存在环磷酰胺和氟达拉滨的禁忌症。
2. 既往接受过嵌合抗原受体治疗或其他基因修饰 T 细胞治疗。
3. 既往因 DLBCL 或相关亚型接受过一线以上治疗的受试者。
4. 白细胞分离时，既往作为一线巩固治疗的HSCT < 3个月。
5. 当前或既往病史中有CNS淋巴瘤受累的受试者。
6. 因肿瘤占位效应需要紧急治疗的受试者。
7. 人类免疫缺陷病毒感染。
8. 血清学提示存在活动性或既往乙型或丙型肝炎。除非确认聚合酶链反应阴性，否则视为已治疗的乙型或丙型肝炎病毒感染。
9. 梅毒螺旋体（引起梅毒的病原体）感染。
10. 人类T淋巴细胞病毒1型感染。
11. SARS-CoV-2活动性感染。
12. 活动性、严重的全身性真菌、病毒或细菌感染。
13. 已知病史或证据表明存在严重免疫抑制状态，即皮质类固醇治疗 > 10 mg/天持续超过6个月。
14. 随机化前6周内接种过活病毒疫苗。
15. 既往接受过CD19靶向治疗。
16. 已知病史或存在癫痫发作活动，或在前12个月内正在使用抗癫痫药物。
17. 研究者判断可能损害神经毒性评估能力的非恶性CNS疾病病史或存在。
18. 已知病史或存在自身免疫性CNS疾病，如多发性硬化、视神经炎或其他免疫性或炎症性疾病。
19. 已知病史或存在随机化前12个月内的CVA。注：若白细胞分离前CVA病史 > 12个月，则受试者不得有任何不稳定或危及生命的神经功能缺损。
20. 患有Richter转化或Richter综合征的受试者。
21. 受试者同时正在接受任何其他实验性治疗，或在前4周或5个半衰期内接受过此类治疗。
22. 妊娠或哺乳期女性。
23. 除DLBCL外的既往恶性肿瘤史。例外包括筛选前无病生存 ≥ 3年的受试者，以及已充分治疗并切除的皮肤基底细胞癌、皮肤鳞状细胞癌、宫颈原位癌、乳腺原位癌、膀胱原位癌或监测中偶然组织学发现未经治疗的局限性（T1a、T1b或T1c）前列腺癌的受试者。
24. 对任何IMP、AxMP、预给药或补救药物或其辅料有严重速发型超敏反应史，且计划在研究参与期间给予。
25. 开始治疗前30天内接受过大手术。
26. 任何可能干扰研究治疗安全性或有效性评估的医学状况。
Part I:
1. Histologically proven DLBCL and associated subtypes, according to the World Health Organization (WHO) 2016 classification including:
* DLBCL not otherwise specified (NOS).
* High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements with DLBCL/blastoid/intermediate histology or HGBL with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma/triple hit lymphoma).
* High-grade BCL, NOS.
* Primary (thymic) large mediastinal BCL.
* Disease transformed from an earlier diagnosis of low-grade lymphoma (e.g. an indolent pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with DLBCL disease progression subsequent to DLBCL-directed systemic treatment.
* Follicular lymphoma Grade 3B.
2. Relapsed or refractory disease after first-line chemoimmunotherapy:
* Refractory disease defined as no CR to first-line therapy (e.g. R-CHOP \[rituximab, cyclophosphamide, daunorubicin, vincristine and prednisone\]).
* Progressive disease (PD) after at least 2 full cycles of first-line therapy.
* Stable disease (SD) after 4 cycles of first-line therapy.
* PR as best response after at least 6 cycles of first-line therapy and biopsy-proven persistent disease (except where prohibited due to comorbidities) within ≤ 24 months from the start of the first-line therapy.
* Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease progression (except where prohibited due to comorbidities) within ≤ 24 months from the start of the first-line therapy.
3. Participants must have received adequate first-line therapy containing at least the combination of an anthracycline-based regimen and rituximab (anti-CD20 monoclonal antibody). Local therapies (e.g. radiotherapies) will not be considered as line of therapy if performed during the same line of treatment.
4. Archival paraffin-embedded tumour tissue acquired ≤ 2 years (preferred: ≤ 2 months) prior to screening for the central pathology review to confirm DLBCL diagnosis must be made available for participation in this study. If archival paraffin-embedded tumour tissue is not available, fresh tumour tissue sample (preferred) or core-needle biopsy must be made available for the central pathology review.
5. Participants deemed ineligible to receive HDC followed by ASCT based on the treating physician's assessment and meeting the following criteria:
EITHER
* Age ≥ 18 years and
* Prior ASCT (as first-line consolidation) or
* Haematopoietic cell transplantation-specific comorbidity index (HCT-CI) \> 3. OR
* Age ≥ 65 years and ≥ 1of the criteria below:
* Impaired cardiac function (left ventricular ejection fraction \[LVEF\] \< 50%), or
* Impaired renal function (estimated glomerular filtration rate \[eGFR\] \< 60 mL/min) calculated according to the modified Modification of Diet in Renal Disease (MDRD) formula, or
* Impaired pulmonary function (diffusing capacity for carbon monoxide or forced expiratory volume in 1 second \< 80%) or dyspnoea on slight activity, or
* Eastern Cooperative Oncology Group (ECOG) performance status \> 1. OR
* Age ≥ 70 years. Documentation of the reason for ineligibility for ASCT must be present in the participant's source data.
In addition, all participants must fulfil the following criteria:
6. Age ≥ 18 years.
7. Measurable disease according to Lugano criteria. The lesion must be measurable (nodes \> 1.5 cm in the long axis; extranodal lesions \> 1 cm in the long axis) and positive on a positron emission tomography scan.
8. Estimated life expectancy of \> 3 months for other reasons than the primary disease.
9. Women of childbearing potential (WOCBP) must agree to use highly effective contraceptive measures (Pearl index \< 1) or practice true sexual abstinence from any heterosexual intercourse (True abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.) or must have a vasectomised partner as the sole sexual partner (The vasectomised partner must have received medical assessment of the surgical success.) for at least 1 month before the study start, during the study and in the 12 months following the last dose of study treatment. A woman is considered a WOCBP, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Highly effective methods of contraception include hormonal contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal, injectable, implantable) and intrauterine devices or systems (e.g. hormonal and non-hormonal) and bilateral tubal occlusion. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. WOCBP who want to become pregnant after completing treatment should seek advice about oocyte cryoconservation prior to treatment because of possible irreversible infertility. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment.
Men with non-pregnant WOCBP partners must agree to use highly effective contraceptive measures (Pearl index \< 1, e.g. spermicide and condom or other highly effective contraceptive measures (Pearl index \< 1) taken by their WOCBP partner) or practice true sexual abstinence from any heterosexual intercourse (True abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.), unless they are surgically sterile (meaning at least 2 consecutive analyses following vasectomy demonstrate absence of sperms in the ejaculate), during the study and in the 12 months following the last dose of study treatment. Men should seek advice about sperm conservation prior to treatment because of possible irreversible infertility. Men must furthermore refrain from sperm donation throughout the study until 12 months after the last administration of study treatment.
10. In the opinion of the investigator, the participant must be able to comply with all study-related procedures, medication use and evaluations.
11. Mental capacity and legal ability to consent to participation in the clinical study.
Criteria for Exclusion:
1. Contraindications for R-GemOx, BR plus polatuzumab vedotin, cyclophosphamide and fludarabine as judged by the treating physician.
2. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
3. Participants who have received more than one line of treatment for DLBCL or associated subtypes.
4. Prior haematopoietic stem cell transplantation (HSCT; as first-line consolidation) \< 3 months at the time of leukapheresis.
5. ECOG performance status \> 2.
6. Absolute neutrophil count \< 1,000/μL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy).
7. Platelet count \< 50,000/μL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy).
8. Absolute lymphocyte count \< 100/μL.
9. Participants who have central nervous system (CNS) lymphoma involvement in present or past medical history.
10. Participants with the requirement for urgent therapy due to tumour mass effects.
11. Infection with human immunodeficiency virus.
12. Presence of active or prior hepatitis B or C as indicated by serology (for detailed criteria see Section 10.2.7.10). Treated infection with hepatitis B or C virus unless confirmed to be polymerase chain reaction negative.
13. Active infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
14. Active, severe systemic fungal, viral or bacterial infection.
15. Known history or evidence of severely immunocompromised state, i.e. corticosteroid treatment \> 10 mg/day for more than 6 months.
16. Has received vaccination with live virus vaccines 6 weeks prior to randomisation.
17. Prior CD19-targeted therapy.
18. Known history or presence of seizure activities or on active anti-seizure medications within the previous 12 months.
19. History or presence of non-malignant CNS disease that, in the judgement of the investigator, may impair the ability to evaluate neurotoxicity.
20. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease.
21. Known history or presence of cerebral vascular accident (CVA) within 12 months prior to randomisation.
Note: In case of history of CVA \> 12 months prior to leukapheresis, then the participant must not have any unstable or life-threatening neurological deficits.
22. Participants with Richter's transformation or Richter's syndrome.
23. Participants who are concurrently on any other experimental treatments or during the previous 4 weeks or 5 half-lives.
24. Clinical heart failure with New York Heart Association class ≥ 2 or LVEF \< 30% or severe cardiac arrhythmias or QT prolongation (resting QTcF ≥ 450 msec \[male\] or ≥ 460 msec \[female\] at screening) that would (according to the evaluation of the investigator) face an uncontrollable risk by receiving the medications administered in the trial.
25. Resting peripheral oxygen saturation \< 90% on room air.
26. Liver dysfunction as indicated by total bilirubin \> 2.5 × institutional upper limit of normal (ULN), aspartate aminotransferase and/or alanine aminotransferase \> 5 × ULN or typical symptoms like jaundice.
27. Serum creatinine ≥ 2.0 × ULN or eGFR \< 30 mL/min calculated according to the modified MDRD formula.
28. Pregnant or breast-feeding women.
29. Prior history of malignancies other than DLBCL. Exceptions include participants who have been free of the disease for ≥ 3 years prior to screening and participants with adequately treated and removed basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, carcinoma in situ of the bladder or incidental histological finding of untreated localised (T1a, T1b or T1c) prostate cancer under surveillance.
30. History of severe immediate hypersensitivity to any investigational medicinal product (IMP), auxiliary medicinal product (AxMP), premedication or rescue medication or its excipients that is scheduled to be given during study participation.
31. Major surgery less than 30 days before start of treatment.
32. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
Part II:
1. Histologically proven DLBCL and associated subtypes, according to the WHO 2016 classification including:
* DLBCL, NOS.
* HGBL with MYC and BCL2 and/or BCL6 rearrangements with DLBCL/blastoid/intermediate histology or HGBL with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma/triple hit lymphoma).
* High-grade BCL, NOS.
* Primary (thymic) large mediastinal BCL.
* Disease transformed from an earlier diagnosis of low-grade lymphoma (e.g., an indolent pathology such as follicular lymphoma, marginal zone lymphoma) into DLBCL with DLBCL disease progression subsequent to DLBCL-directed systemic treatment.
* Follicular lymphoma Grade 3B.
2. Relapsed or refractory disease after first-line chemoimmunotherapy:
* Refractory disease defined as no CR to first-line therapy (e.g., R-CHOP).
* PD after at least 2 full cycles of first-line therapy.
* SD after 4 cycles of first-line therapy.
* PR as best response after at least 6 cycles of first-line therapy and biopsy-proven persistent disease (except where prohibited due to comorbidities) within ≤ 12 months after completion of first-line treatment.
* Relapsed disease defined as complete remission to first-line therapy followed by biopsy-proven disease progression (except where prohibited due to comorbidities) within ≤ 12 months after completion of first-line treatment.
3. Participant must have received adequate first-line therapy containing at least the combination of an anthracycline-based regimen and rituximab (anti-CD20 monoclonal antibody). Local therapies (e.g., radiotherapies) will not be considered as line of therapy if performed during the same line of treatment.
4. Archival paraffin-embedded tumour tissue acquired ≤ 2 years (preferred: ≤ 2 months) prior to screening for the central pathology review to confirm DLBCL diagnosis must be made available for participation in this study. If archival paraffin-embedded tumour tissue is not available, fresh tumour tissue sample (preferred) or core-needle biopsy must be made available for the central pathology review.
5. Measurable disease according to Lugano criteria. The lesion must be measurable (nodes \> 1.5 cm in the long axis; extranodal lesions \> 1 cm in the long axis) and positive on a positron emission tomography scan.
6. Approved treatment options not suitable according to investigator's assessment.
In addition, all participants must fulfil the following criteria:
7. Age ≥ 18 and ≤ 70 years.
8. Estimated life expectancy of \> 3 months for other reasons than the primary disease.
9. ECOG 0-1.
10. Adequate bone marrow function, defined as:
* Absolute neutrophil count ≥ 1,000/μL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy).
* Platelet count ≥ 50,000/μL (unless secondary to bone marrow involvement by DLBCL as demonstrated by bone marrow biopsy).
* Absolute lymphocyte count ≥ 100/μL.
11. Adequate organ function, defined as:
* New York Heart Association class \< 2 or LVEF ≥ 50%.
* No severe cardiac arrhythmias or QT prolongation (resting QTcF \< 450 msec \[male\] or \< 460 msec \[female\] at screening).
* No clinically relevant pleural effusion or pericardial effusion.
* Resting peripheral oxygen saturation ≥ 92% on room air.
* Total bilirubin ≤ 2.0 × ULN, AST and/or ALT ≤ 5 × ULN
* Serum creatinine \< 1.0 × ULN or eGFR (according to modified MDRD formula) ≥ 60 mL/min.
12. WOCBP must agree to use highly effective contraceptive measures (Pearl index \< 1) or practice true sexual abstinence from any heterosexual intercourse (True abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.) or must have a vasectomised partner as the sole sexual partner (The vasectomised partner must have received medical assessment of the surgical success.) for at least 1 month before the study start, during the study and in the 12 months following the last dose of study treatment. A woman is considered a WOCBP, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Highly effective methods of contraception include hormonal contraceptives associated with inhibition of ovulation (oral, intravaginal, transdermal, injectable, implantable) and intrauterine devices or systems (e.g., hormonal and non-hormonal) and bilateral tubal occlusion. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. WOCBP who want to become pregnant after completing treatment should seek advice about oocyte cryoconservation prior to treatment because of possible irreversible infertility. WOCBP must refrain from egg donation throughout the study until 12 months after the last dose of study treatment. Men with non-pregnant WOCBP partners must agree to use highly effective contraceptive measures (Pearl index \< 1, e.g., spermicide and condom or other highly effective contraceptive measures (Pearl index \< 1) taken by their WOCBP partner) or practice true sexual abstinence from any heterosexual intercourse (True abstinence is only acceptable if it is in line with the preferred and usual life style of the participant.), unless they are surgically sterile (meaning at least 2 consecutive analyses following vasectomy demonstrate absence of sperms in the ejaculate), during the study and in the 12 months following the last dose of study treatment. Men should seek advice about sperm conservation prior to treatment because of possible irreversible infertility. Men must furthermore refrain from sperm donation throughout the study until 12 months after the last administration of study treatment.
13. In the opinion of the investigator, the participant must be able to comply with all study-related procedures, medication use and evaluations.
14. Mental capacity and legal ability to consent to participation in the clinical study.
Criteria for Exclusion:
1. Contraindications for cyclophosphamide and fludarabine as judged by the treating physician.
2. Prior chimeric antigen receptor therapy or other genetically modified T-cell therapy.
3. Participants who have received more than one line of prior therapy for DLBCL or associated subtypes.
4. Prior HSCT (as first-line consolidation) \< 3 months at the time of leukapheresis.
5. Participants who have CNS lymphoma involvement in present or past medical history.
6. Participants with the requirement for urgent therapy due to tumour mass effects.
7. Infection with human immunodeficiency virus.
8. Presence of active or prior hepatitis B or C as indicated by serology. Treated infection with hepatitis B or C virus unless confirmed to be polymerase chain reaction negative.
9. Infection with Treponema pallidum (pathogen causing syphilis).
10. Infection with human T-lymphotropic virus 1.
11. Active infection with SARS-CoV-2.
12. Active, severe systemic fungal, viral, or bacterial infection.
13. Known history or evidence of severely immunocompromised state, i.e. corticosteroid treatment \> 10 mg/day for more than 6 months.
14. Has received vaccination with live virus vaccines within 6 weeks prior to randomisation.
15. Prior CD19-targeted therapy.
16. Known history or presence of seizure activities or on active anti-seizure medications within the previous 12 months.
17. History or presence of non-malignant CNS disease that, in the judgement of the investigator, may impair the ability to evaluate neurotoxicity.
18. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease.
19. Known history or presence of CVA within 12 months prior to randomisation. Note: In case of history of CVA \> 12 months prior to leukapheresis, then the participant must not have any unstable or life-threatening neurological deficits.
20. Participants with Richter's transformation or Richter's syndrome.
21. Participants who are concurrently on any other experimental treatments or during the previous 4 weeks or 5 half-lives.
22. Pregnant or breastfeeding woman.
23. Prior history of malignancies other than DLBCL. Exceptions include participants who have been free of the disease for ≥ 3 years prior to screening and participants with adequately treated and removed basal cell carcinoma of the skin, squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, carcinoma in situ of the bladder or incidental histological finding of untreated localised (T1a, T1b or T1c) prostate cancer under surveillance.
24. History of severe immediate hypersensitivity to any IMP, AxMP, premedication or rescue medication or its excipients that is scheduled to be given during study participation.
25. Major surgery less than 30 days before start of treatment.
26. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.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：Part I: Event-free survival · Event-free survival (EFS), defined as the time between the date of randomisation and the date of objective disease progression, failure to achieve partial response (PR) or complete response (CR) at or beyond Week 8 after randomisation leading to a new anti-lymphoma therapy or death of any cause, whichever occurs first, based on independent review committee (IRC) assessment. · up to 30 weeks after randomisation；Part II: Best objective response rate · Best objective response rate (BORR), defined as the proportion of participants with at least one CR or PR between the date of MB-CART2019.1 infusion and the date of objective disease progression, the start of new anti-lymphoma therapy or the date of death from any cause, whichever occurs first, based on IRC assessment. · up to 30 weeks after administration of MB-CART2019.1
次要终点：Part I: Progression-free survival (PFS)；Part I: Best complete response rate；Part I: Duration of complete response；Part I: Overall Survival；Part II: Duration of Response (DOR)；Part II: Progression-free survival (PFS)；Part II: Overall Survival (OS)；Part II: Best Complete Response Rate (BCRR)
单次输注每公斤体重2.5 × 10^6个CAR转导的自体T细胞。
单次输注每公斤体重2.5 × 10^6个CAR转导的自体T细胞。
R-GemOx R-Pola
在当前方案版本中，研究分为两部分。第一部分是一项关键性II期随机、多中心、开放标签研究，旨在评估MB-CART2019.1与标准治疗相比，在不符合高剂量化疗和自体干细胞移植条件的复发/难治性弥漫性大B细胞淋巴瘤受试者中的疗效和安全性。 第二部分是一项II期单臂、开放标签、多中心研究，评估MB-CART2019.1在较年轻、体能状况良好的R-R DLBCL受试者中的疗效和安全性。第二部分将在第一部分入组完成后开始。
In the current protocol version, there are two parts. Part I is a pivotal Phase II randomised, multi-centre, open-label study to evaluate the efficacy and safety of MB-CART2019.1 compared to standard of care therapy in participants with relapsed/refractory diffuse large B-cell lymphoma, who are not eligible for high-dose chemotherapy and autologous stem cell transplantation. Part II is a Phase II single-arm, open-label, multi-centre study evaluating the efficacy and safety of MB-CART2019.1 in younger, fit participants with R-R DLBCL. Part II will start after completion of enrolment in Part I.
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