肿瘤细胞治疗研究
英文原题：MB-CART19.1 r/r CD19+ B-cell Malignancies (BCM)
这是一项 I 期注册临床试验，评估细胞治疗用于急性淋巴细胞白血病、B 细胞淋巴瘤、慢性淋巴细胞白血病的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 48 例。试验地点：欧洲 · 柏林、埃尔朗根、哥廷根、慕尼黑（共 9 个中心）。登记号：NCT03853616。
不限性别 · ≥ 1 Year
纳入标准： • 男性或女性患者患有复发或难治性、表达CD19的急性淋巴细胞白血病（ALL）或非霍奇金淋巴瘤（NHL）/慢性淋巴细胞白血病（CLL）。 • 须通过流式细胞术（白血病或NHL恶性积液）或免疫组化（NHL）在恶性细胞上检测到CD19表达。 • 年龄≥1岁（由治疗研究者评估适合者）。 • CD3+ T细胞绝对计数≥100/μL。 • 筛查时，>16岁者ECOG体能状态评分0–2；≤16岁者Lansky体能评分>50。 • 无活动性乙型肝炎、丙型肝炎或HIV-1/2感染。 • 无生育能力，或有生育能力女性筛查时及化疗前妊娠试验阴性。 • 患者已签署并注明日期的知情同意书/儿童同意书，并符合以下疾病特定条件： ALL： • 至少接受过一种标准化疗和一种挽救治疗后，骨髓原始细胞>5%（M2或M3），且不适合异基因干细胞移植（alloSCT），或目前存在妨碍alloSCT的难治性疾病；或 • alloSCT后复发，且距移植至少100天，无活动性移植物抗宿主病（GVHD）证据，并在入组前至少30天未使用免疫抑制药物；或 • Ph+ ALL患者对酪氨酸激酶抑制剂（TKI）不耐受，或在至少接受过两种不同TKI治疗后仍为复发/难治性疾病；或 • ALL患者出现骨髓与中枢神经系统（CNS）和/或睾丸联合复发时，仅当入组时已通过常规治疗（如鞘内化疗、睾丸切除术）成功清除髓外病灶方可入组。 儿童侵袭性NHL（1–17岁）： • 至少接受过一种挽救性化疗，作为alloSCT的桥接治疗；或不适合alloSCT；或alloSCT后复发且距移植至少100天、无活动性GVHD证据，并在入组前至少30天未使用免疫抑制药物。 • 有CNS病灶者（孤立性CNS淋巴瘤除外），仅当入组时已通过鞘内化疗成功清除病灶方可入组。 成人NHL： • 至少接受过一种标准化疗和一种挽救方案，作为alloSCT的桥接治疗；或不适合alloSCT；或alloSCT后复发且距移植至少100天、无活动性GVHD证据，并在入组前至少30天未使用免疫抑制药物。 • 有CNS病灶者（孤立性CNS淋巴瘤除外），仅当入组时已通过鞘内化疗成功清除病灶方可入组。 CLL： • 既定且已获批的治疗方案均已失败，疾病仍为复发/难治性。 • 不符合接受常规alloSCT的条件，或不适合接受该治疗。 排除标准： • ALL孤立性CNS或睾丸复发。 • 孤立性CNS淋巴瘤。 • 活动性实质性脑转移，或有实质性脑转移史。 • 当前患有自身免疫性疾病，或既往自身免疫性疾病可能累及CNS。 • 活动性且具有临床意义的CNS功能障碍，包括但不限于未控制的癫痫、脑血管缺血或出血、痴呆、瘫痪。 • 除非黑色素瘤性皮肤癌或原位癌外，既往患有其他恶性肿瘤，且无病生存不足3年。 • 肺功能：既往有严重肺病、需接受>28%氧浓度补充，或胸部X线显示活动性肺浸润。 • 心功能：超声心动图测得短轴缩短率<28%或左心室射血分数<50%。 • 肾功能：18岁及以上患者按CKD-EPI公式计算的GFR≤29 mL/min/1.73 m²；18岁以下患者按Schwartz公式计算的肌酐清除率≤29 mL/min/1.73 m²。 • 肝功能：血清胆红素>ULN的3倍，或AST/ALT>ULN的5倍；研究者判断由白血病肝浸润所致者除外。 • 研究者判断疾病进展迅速，可能影响完成研究治疗。 • 妊娠或哺乳女性。 • 用药限制：白细胞单采前7天内使用全身化疗、除生理替代剂量外的皮质类固醇或TKI；单采前30天内使用氟达拉滨/氯法拉滨、免疫抑制药物或抗体（如利妥昔单抗、钙调神经磷酸酶抑制剂、倍林妥莫双抗）、研究药物、供者淋巴细胞输注或放疗；单采前3个月内使用阿仑单抗。例外：治疗前允许鞘内化疗，但ALL和伯基特淋巴瘤（BL）患者须在MB-CART19.1输注前10天停用，以降低神经毒性风险。 • 对试验期间计划或可能使用的任何药物及其成分/杂质过敏，例如淋巴细胞清除方案、输注前用药，以及治疗相关毒性的抢救/挽救治疗药物。 • 因超敏反应以外的原因禁忌合并用药，例如活疫苗或氟达拉滨。 • 研究者判断存在研究相关操作禁忌，例如无法进行脑脊液采样所需的腰椎穿刺。 • 有生育能力女性不愿从入组起至研究药物（IMP）给药后12个月采取高效避孕措施。 • 有生育能力男性不愿从入组起至IMP给药后12个月采取高效避孕措施。 • 同时参加可能与本研究相互作用的其他干预性试验，例如CAR-T试验。 • 存在脑功能障碍；成人患者无完全民事行为能力。 • 依据司法或行政命令被收容于机构。
Inclusion Criteria: * Male or female patients must have r/r CD19-expressing ALL or NHL/CLL * CD19 expression must be detected on the malignant cells by flow cytometry (leukemia, malignant effusion in NHL) or immunohistochemistry (NHL); * Age ≥ 1 year (if deemed fit by treating investigator); * Absolute CD3+ T cell count ≥100/μl; * ECOG performance score of 0-2 if \>16 years old, or Lansky performance score of \>50 if ≤16 years old at screening; * No active Hepatitis B, Hepatitis C, HIV1/2; * No childbearing potential or negative pregnancy test at screening and before chemotherapy in women with childbearing potential; * Signed and dated informed consent/assent by patients * and meet the following disease-specific criteria: ALL: * patients with \>5% blasts in BM (M2 or M3) after at least one standard chemotherapy and one salvage regimen who are ineligible for allogeneic stem cell transplant (alloSCT) or have refractory disease activity precluding alloSCT at this time, or * patients who have relapsed post alloSCT at least 100 days posttransplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to enrollment. * patients with Ph+ ALL if they are intolerant to tyrosine kinase inhibitor (TKI) therapy, or if they have r/r disease after treatment with at least 2 different TKIs. * ALL patients with combined bone marrow and CNS and/or testicular relapse are eligible only if the extramedullary disease has been successfully cleared by conventional therapy at the time of inclusion (e.g. intrathecal chemotherapy, orchiectomy). Pediatric aggressive NHL (1-17 years): * patients after at least one salvage chemotherapy as bridge to alloSCT or * patients ineligible for alloSCT or * patients who have relapsed post alloSCT at least 100 days posttransplant, with not evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to enrollment. * patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if disease has been successfully cleared by intrathecal chemotherapy at the time of inclusion. Adult NHL: * patients after at least one standard chemotherapy and one salvage regimen as bridge to alloSCT or * patients who are ineligible for alloSCT or * patients who have relapsed post alloSCT at least 100 days posttransplant, with no evidence of active GVHD, and no longer taking immunosuppressive agents for at least 30 days prior to enrollment. * patients with CNS disease (excluding isolated CNS lymphoma) are eligible only if disease has been successfully cleared by intrathecal chemotherapy at the time of inclusion. CLL: * patients with r/r disease after established and approved treatment options have failed. * patients not eligible or appropriate for conventional alloSCT. Exclusion Criteria: * Isolated CNS or testicular relapse in ALL; * Isolated CNS lymphomas; * Active solid brain metastases or history of solid brain metastases * Current autoimmune disease, or history of autoimmune disease with potential CNS involvement; * Active clinically significant CNS dysfunction (including but not limited to uncontrolled seizure disorders, cerebrovascular ischemia or hemorrhage, dementia, paralysis); * History of an additional malignancy other than non-melanoma skin cancer or carcinoma in situ unless disease free for ≥3 years; * Pulmonary function: Patients with pre-existing severe lung disease or an oxygen requirement of \>28% O2 supplementation or active pulmonary infiltrates on chest X-ray; * Cardiac function: Fractional shortening \<28% or left ventricular ejection fraction \<50% by echocardiography; * Renal function: GFR ≤29 mL/min/1.73 m2 by CKD-EPI for patients 18 yrs (Levey et al. 2009) or creatinine clearance ≤29 mL/min/1.73 m2 by Schwartz formula (Schwartz et al. 1976) for patients \<18 yrs of age; * Liver function: Patients with a serum bilirubin \>3 times upper limit of normal or an AST or ALT \> 5 times upper limit of normal, unless due to leukemic liver infiltration in the estimation of the investigator; * Rapidly progressive disease that in the estimation of the investigator would compromise ability to complete study therapy; * Pregnant or breast-feeding females; * Medications: * Systemic chemotherapies, corticosteroids with the exception of physiologic replacement dosing, tyrosine kinase inhibitors (TKI) within 7 days prior to leukapheresis, * Fludarabine/clofarabine or immunosuppressive drugs and antibodies (e.g. rituximab, calcineurin inhibitors, blinatumomab) or investigational drugs or donor lymphocyte transfusions or radiation therapy within 30 days prior to apheresis, * Alemtuzumab within 3 months prior to leukapheresis, * Exception: Intrathecal chemotherapy is allowed prior to treatment, but should be discontinued in ALL and BL 10 days prior to MB-CART19.1 infusion to limit risk of neurotoxicities; * Hypersensitivity against any drug or its ingredients/impurities that is scheduled or likely to be given during trial participation, e.g. as part of the mandatory lymphodepletion protocol, pre-medication for infusion, rescue medication/salvage therapies for treatment related toxicities; * Intake of concomitant medication contraindicated for other reasons than hypersensitivity, e.g. live vaccines and fludarabine; * Contraindication of trial related procedures as judged by the investigator, e.g. lumbar punctures for CSF sampling; * Female patients of child-bearing potential not willing to practice a highly effective form of birth control from the time of enrollment and for 12 months after dosing the IMP; * Male patients of fathering potential not willing to practice a highly effective form of birth control from the time of enrollment and for 12 months after dosing the IMP; * Concurrent participation in another interventional trial that could interact with this trial, e.g. CAR T trials; * Cerebral dysfunction, legal incapacity of adult patients; * Committal to an institution on judicial or official order.
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：Determination of the recommended dose of MB-CART19.1 · Maximum tolerated dose (MTD), defined as the highest dose level of the two to three dose levels tested at which \<33% of patients experience DLT until day 28 after infusion of MB-CART19.1, on the basis of safety and toxicity assessment of MB-CART19.1 per adverse events (AE) reporting classified according to CTCAE version 5.0. · until day 28 after infusion of MB-CART19.1
次要终点：Overall incidence and severity of adverse events；Response to treatment for each timepoint；Response to treatment for each timepoint；Response to treatment for each timepoint；Occurence of B-cell depletion；Phenotype and persistence of MB-CART19.1；Number of patients with successful MB-CART19.1 production；Rate of ALL patients achieving MRD negative CR
在三个队列的各剂量水平中，按3+3设计治疗患者。某剂量水平的3名患者中如有1名发生剂量限制性毒性（DLT），该剂量水平将扩展至6名患者。在扩展队列证明该剂量安全前暂停进一步递增。若6名患者中有≥2名发生DLT，则不再递增，并将下一较低剂量水平扩展至共6名患者。在已测试剂量中，至多1/6患者发生DLT的最高剂量将作为最大耐受剂量（MTD）。
队列1和队列2从剂量水平1开始评估剂量。三个队列的各剂量水平均按3+3设计治疗患者。某剂量水平的3名患者中如有1名发生DLT，该剂量水平扩展至6名患者；在扩展队列证明剂量安全前暂停进一步递增。若6名患者中有≥2名发生DLT，则不再递增，并将下一较低剂量水平扩展至共6名患者。在已测试剂量中，至多1/6患者发生DLT的最高剂量作为MTD。
队列3从剂量水平2开始评估，暂不测试剂量水平1。如不能耐受剂量水平2，则测试剂量水平1。三个队列的各剂量水平均按3+3设计治疗患者。某剂量水平的3名患者中如有1名发生DLT，该剂量水平扩展至6名患者；在扩展队列证明剂量安全前暂停进一步递增。若6名患者中有≥2名发生DLT，则不再递增，并将下一较低剂量水平扩展至共6名患者。在已测试剂量中，至多1/6患者发生DLT的最高剂量作为MTD。
三个队列的各剂量水平均按3+3设计治疗患者。某剂量水平的3名患者中如有1名发生DLT，该剂量水平扩展至6名患者；在扩展队列证明剂量安全前暂停进一步递增。若6名患者中有≥2名发生DLT，则不再递增，并将下一较低剂量水平扩展至共6名患者。在已测试剂量中，至多1/6患者发生DLT的最高剂量作为MTD。剂量水平3如未发生DLT，将再治疗3名患者。仅在剂量水平1无法耐受时才测试剂量水平0。
这是一项I期、多中心、单臂、前瞻性、开放标签剂量递增研究，纳入复发或难治性CD19阳性B细胞恶性肿瘤（ALL、NHL、CLL）患者，包括成人和儿童，预计共纳入约48人。研究按疾病生物学特征分为三个队列：儿童ALL及儿童侵袭性NHL（队列1）、成人ALL（队列2）以及成人NHL/CLL（队列3）。
This is a phase l multi-centric, single arm, prospective open, dose-escalation study in patients with relapsed or refractory CD19-positive B cell malignancies (ALL, NHL, CLL). The trial will include adult and pediatric patients. In total approximately 48 patients will be included in the trial. There will be three individual cohorts, defined by disease biology: pediatric ALL and aggressive pediatric NHL (Cohort 1), adult ALL (Cohort 2) and adult NHL/CLL (Cohort 3).
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