肿瘤细胞治疗研究
英文原题：ENABLE-1 (Engaging Toll-like Receptor Signalling for B-cell Lymphoma Chimeric Antigen Receptor Therapy)
⚠ 该试验的登记信息已有 26 个月未更新， 页面上显示的「进行中（不再招募）」可能已经失效。联系研究中心之前，建议先到 ClinicalTrials.gov 核对登记原文的最新状态与联系方式。
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗淋巴瘤、弥漫大 B 细胞淋巴瘤、B 细胞淋巴瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 30 例。试验地点：亚太其他 · 惠灵顿（共 1 个中心）。登记号：NCT04049513。
不限性别 · ≥ 16 Years 且 ≤ 75 Years
纳入标准： * 年龄16–75岁（含）。 * 活检证实复发或治疗难治性侵袭性B细胞非霍奇金淋巴瘤，WHO分类亚型包括DLBCL及其变异型、原发性纵隔大B细胞淋巴瘤（PMBCL）、转化型滤泡性淋巴瘤（tFL）、滤泡性淋巴瘤（FL）或套细胞淋巴瘤（MCL）。 * 研究者认为需要治疗。 * 按2014年Lugano标准存在可测量疾病。 * 无其他可治愈治疗，或因患者/疾病特征或缺乏干细胞供者而不适合其他治疗。 * 流式细胞术或免疫组化证实恶性肿瘤表达CD19。 * 已签署本研究书面知情同意书。 * 淋巴瘤相关预期生存期至少12周，非淋巴瘤相关原因预期生存期>12个月。 * ECOG体能状态评分0–2（含）。 * 骨髓功能充分：中性粒细胞≥1.0×10^9/L，血小板≥50×10^9/L。 * 无严重心、肺、肝或肾疾病：总胆红素<ULN的2.5倍；按修订Cockcroft–Gault公式估算或直接测得的肌酐清除率≥50 mL/min；超声心动图或MUGA显示射血分数≥50%；室内空气下血氧饱和度>92%；经血红蛋白和/或肺容量校正后肺功能检查显示DLCO或KCO、FEV1及FVC均≥预测值的50%。 排除标准： * 已确认当前或既往淋巴瘤累及CNS。怀疑CNS疾病者须接受腰椎穿刺和脑MRI检查。 * 活动性CNS病变，包括癫痫、过去1年内惊厥、失语、轻瘫、卒中、痴呆、过去1年内精神病、严重脑损伤、帕金森病或小脑疾病。 * Richter转化综合征。 * 需要全身免疫抑制的活动性自身免疫病。 * 既往实体器官移植。 * 过去3个月内接受异基因干细胞移植，或仍需全身免疫抑制治疗。 * 当前II–IV级急性GVHD、既往任何IV级急性GVHD，或当前中/重度慢性GVHD。 * 入组前7天内全身使用≥20 mg/日泼尼松或等效剂量的皮质类固醇。 * 全血细胞计数显示外周血淋巴细胞<0.3×10^9/L。 * 淋巴细胞亚群检测显示外周血CD3+ T细胞<150/μL。 * 妊娠或哺乳期女性。 * 有生育能力女性不同意研究期间及WZTL-002给药后至少1年使用高效避孕方法。 * 男性不同意研究期间及WZTL-002给药后至少1年使用高效避孕方法。 * 男性伴侣妊娠且不同意研究期间及WZTL-002给药后至少3个月性活动时使用避孕套。 * 已知对免疫球蛋白或研究产品成分过敏。 * 入组前2年内有活动性B细胞恶性肿瘤以外的活动性恶性肿瘤史；宫颈原位癌经充分治疗、皮肤基底细胞癌或局限性鳞状细胞癌经充分治疗、或其他局限性恶性肿瘤经根治性手术/其他方式治疗者除外。 * 当前或既往HIV感染。 * 过去4周内接种活病毒疫苗。 * 过去4周内接受嘌呤类似物治疗。 * 过去12周内接受阿仑单抗治疗。 * 入组前2周内接受细胞毒化疗、放疗或单克隆抗体治疗（阿仑单抗除外）。 * 既往基因治疗，包括抗CD19 CAR-T治疗。 * 过去4周内在其他临床试验中接受研究性药物。 * 全身感染控制不充分。 * 血清学提示活动性乙肝或有任何丙肝感染史：HBsAg或乙肝核心抗体（HBcAb）阳性。仅HBcAb阳性、HBsAg阴性者，如HBV DNA不可检出（<20 IU）且愿意接受适当抗病毒预防治疗，可入组；或HCV抗体阳性。 * NYHA II级或以上且非淋巴瘤所致的心脏症状。 * 研究者认为会使患者不适合参加试验的显著合并疾病。 * 受试者同意能力受损，或存在任何妨碍其按ICH-GCP要求理解并提供知情同意的情况。 * 不同意登记至国际细胞治疗注册系统。
Inclusion Criteria: * Age 16 to 75 years (inclusive) * Biopsy-proven relapsed or treatment refractory aggressive B-cell non-Hodgkin lymphoma of the following subtypes per World Health Organisation (WHO) classification: DLBCL and its variants, PMBCL, tFL, FL, MCL * Requirement for treatment in the opinion of the investigator * Presence of measurable disease as per Lugano 2014 Criteria * No other curative treatments available, or not suitable due to patient or disease characteristics or lack of stem cell donor * Malignancy documented to express CD19 based on flow cytometric or immunohistochemical staining * Provision of written informed consent for this study * Lymphoma-related life expectancy at least 12 weeks, and life-expectancy from non-lymphoma related causes of \> 12 months * European Cooperative Oncology Group (ECOG) performance status of 0 to 2 inclusive * Adequate haematologic function, defined by neutrophils ≥ 1.0 × 10\^9/L and platelets ≥ 50 × 10\^9/L * No serious cardiac, pulmonary, hepatic or renal disease. * Serum bilirubin \< 2.5 times Upper limit of normal (ULN) * Estimated creatinine clearance (CrCl) ≥ 50 mL/min using the modified Cockroft Gault estimation or as assessed by direct measurement * Cardiac Ejection Fraction ≥ 50% as determined by Echocardiogram or MUGA Scan * Oxygen saturations \> 92% on room air * Diffuse Capacity of the lungs for carbon monoxide (DLCO) or Carbon monoxide transfer coefficient (KCO), Forced expiratory volume in one second (FEV1) and Forced Vital Capacity (FVC) are all ≥ 50% of predicted by spirometry after correcting for haemoglobin and/or volume on lung function testing. Exclusion Criteria: * Confirmed active or prior central nervous system (CNS) involvement by lymphoma. In patients with a clinical suspicion of CNS disease, lumbar puncture and MRI brain must be performed * Active CNS pathology including: epilepsy, seizure within the preceding year, aphasia, paresis, stroke, dementia, psychosis within the preceding year, severe brain injury, Parkinson disease, or cerebellar disease * Richter Syndrome * Active autoimmune disease requiring systemic immunosuppression * Prior solid organ transplantation * Allogeneic stem cell transplantation within the preceding three months or still requiring systemic immunosuppression * Current grade II - IV acute graft versus host disease (GVHD), any prior grade IV acute GVHD, or current moderate or severe chronic GVHD * Systemic corticosteroids at doses of ≥ 20mg prednisone daily or equivalent within 7 days of enrolment * Peripheral blood lymphocytes \< 0.3 x 10\^9/L as assessed by complete blood count * Peripheral blood CD3+ T cells \< 150/μL as assessed by lymphocyte subset analysis * Pregnant or lactating female * Women of child-bearing potential who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration * Men who are not willing to use highly effective methods of contraception during study participation and for at least 1 year after WZTL-002 administration * Men who have a pregnant partner and are not willing to use a condom while performing sexual activity during study participation and for at least 3 months after WZTL-002 administration * Participants with known sensitivity to immunoglobulin or to components of the investigational product (IP) * History of active malignancy other than B-cell malignancy within two years prior to enrolment, with the exception of: adequately treated in situ carcinoma of the cervix; adequately treated basal cell carcinoma (BCC) or localized squamous cell carcinoma (SCC) of the skin; other localised malignancy surgically resected (or radically treated with another treatment modality) with curative intent * Current or prior human immunodeficiency virus (HIV) infection * Vaccination with a live virus within the preceding four weeks * Treatment with a purine analogue within the preceding four weeks * Treatment with alemtuzumab within the preceding 12 weeks * Cytotoxic chemotherapy, radiotherapy or monoclonal antibody therapy (other than alemtuzumab) within 2 weeks of enrolment * Prior gene therapy, including prior anti-CD19 chimeric antigen receptor T-cell therapy * Receipt of an investigational medicine within another clinical trial within the preceding four weeks * Inadequately controlled systemic infection * Serologic status reflecting active viral hepatitis B or any history of hepatitis C infection as follows: * Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with presence of HBcAb, but absence of HBsAg, are eligible if hepatitis B virus (HBV) DNA is undetectable (\< 20 IU), and if they are willing to receive appropriate anti-viral prophylaxis. * Presence of hepatitis C virus (HCV) antibody * Presence of New York Heart Association (NYHA) class 2 or higher cardiac symptoms not related to lymphoma * Significant concomitant illnesses which would in the investigator's opinion make the patient an unsuitable candidate for the trial * Participants who have diminished capacity or any circumstance that would prohibit them from understanding and providing informed consent in accordance with ICH-GCP (International Conference on Harmonisation, Good Clinical Practice) * Participant does not provide consent to enrol onto International Cellular Therapy Registry
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：Number and severity of adverse events assessed by CTCAE v5.0, except for Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome, which will be assessed by ASTCT consensus grading criteria · Determine the safety profile of WZTL-002, anti-CD19 CAR T-cells by measuring frequency and severity of adverse events · 3 months after administration
次要终点：Feasibility of Manufacture；Overall Response Rate；Cumulative CR rate；Relapse-free survival；Overall survival；Recommended dose
WZTL-002起始剂量为5×10^4个CAR-T细胞/kg，计划设置4个剂量队列。根据剂量限制性毒性评估确定当前剂量的安全性后，决定是否递增至更高剂量队列。
这是一项单中心、开放标签、剂量递增Ⅰ期研究，旨在确定第三代抗CD19 CAR-T细胞（WZTL-002）治疗复发/难治性B细胞非霍奇金淋巴瘤的安全剂量，以供后续疗效试验使用。扩展队列还将评估使用自动化封闭系统制备WZTL-002及门诊管理受试者的可行性。
This Phase 1, single centre, open label dose escalation study aims to identify a safe dose of third-generation anti-CD19 CAR T-cells (WZTL-002) in the treatment of patients with relapsed or refractory (r/r) B-cell Non Hodgkin Lymphoma, for use in further efficacy trials. An expansion cohort will assess automated closed-system manufacture of WZTL-002 and outpatient management of participants.
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