肿瘤细胞治疗研究
英文原题：Efficiency of Vaccination with Lysate-loaded Dendritic Cells in Patients with Newly Diagnosed Glioblastoma
⚠ 该试验的登记信息已有 22 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 II 期注册临床试验，评估自体树突状细胞治疗胶质母细胞瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 136 例。试验地点：欧洲 · 波鸿、杜伊斯堡、杜塞尔多夫、吕嫩（共 6 个中心）。登记号：NCT03395587。
不限性别 · ≥ 18 Years
纳入标准： 术前预筛选（第-3至-1周）判定： * 手术时年龄≥18岁。 * 受试者认知能力足以理解并签署知情同意书，且知晓本研究的试验性质和研究程序。 * 首次书面知情同意须涵盖资格筛选，包括肿瘤组织采集、转运和处理，肿瘤样本中央神经病理学评估，切除范围中央神经放射学评估，感染性疾病检测（HIV、HBV、HCV、梅毒螺旋体），MGMT启动子甲基化状态测定及妊娠检测。 手术当日及术后筛选（第0日至第3周）判定： * 新诊断、单灶、IDH野生型胶质母细胞瘤（GBM，WHO IV级），包括胶质肉瘤和巨细胞型胶质母细胞瘤等组织学变异型；由中央神经病理学家依据2016年WHO中枢神经系统肿瘤分类确认。肿瘤可累及胼胝体，但不得超出胼胝体。 * 术后72小时内的MRI经中央神经放射学家确认达到近全切除（残余强化肿瘤体积≤5 ml）；如有医学指征，可进行清醒手术或二次手术。 * 有可供疫苗制备的无菌肿瘤样本，质量≥150 mg，且中央神经病理学家确定肿瘤细胞比例≥60%。 * 成功制备出无菌、失活的肿瘤裂解物。 * Karnofsky体能状态评分≥70%。 * 肝功能和肾功能充分：血清谷丙转氨酶/丙氨酸氨基转移酶（SGPT/ALT）、血清谷草转氨酶/天冬氨酸氨基转移酶（SGOT/AST）及碱性磷酸酶≤正常值上限（ULN）的3倍；胆红素≤ULN的1.5倍；肌酐≤ULN的1.5倍。 * 骨髓功能充分：血红蛋白≥10 g/dl、血小板≥100,000/μl、白细胞计数≥3,000/μl、中性粒细胞计数≥1,500/μl。 * 凝血酶原时间（PT）和活化部分凝血活酶时间（PTT）≤ULN的1.6倍，除非有治疗需要；未接受抗凝治疗者的国际标准化比值（INR）≤1.5。 * 术后7天内将全身糖皮质激素逐渐减至地塞米松或等效药物≤2 mg/日。治疗期间应避免使用糖皮质激素；如有临床指征仍可使用，但可能需要中断树突状细胞疫苗接种。 * 有生育能力的女性患者、有生育能力的男性患者及其女性伴侣须同意在试验期间严格禁欲或使用高效避孕方法（Pearl指数<1%）。 * 受试者认知能力足以理解并签署知情同意书，且知晓本研究的试验性质和研究程序。 * 书面知情同意参加本研究。 排除标准： 术前预筛选（第-3至-1周）判定： * 有预后不良的严重急性或慢性疾病史，例如严重冠心病、心力衰竭（纽约心脏协会III/IV级）、严重且控制不佳的糖尿病、严重智力障碍，或研究者认为与本研究不相容的其他严重合并全身性疾病。 * 有严重自身免疫性疾病或免疫缺陷病史，或接受过器官异体移植。 * 有出血倾向或凝血障碍病史。 * 过去3年内患过恶性肿瘤，但非黑色素瘤皮肤癌、宫颈原位癌、已治疗的浅表性膀胱癌，或已治愈的早期前列腺癌（患者前列腺特异性抗原[PSA]低于ULN）除外。 * 既往接受过头颈部放疗。 * 已知对替莫唑胺（TMZ）、达卡巴嗪、造影剂或树突状细胞疫苗成分过敏或不耐受。 * 正在参加另一项有治疗性干预的胶质母细胞瘤临床试验，或目前正在使用其他研究性药物。 * 已知妊娠或正在哺乳。 * 无需要治疗的严重感染。 * 因法律命令而被安置于机构内（《药品法》第40(4)条）。 * 有当前药物或酒精滥用证据。 手术当日及术后筛选（第0日至第3周）判定： * 感染人类免疫缺陷病毒（HIV）、乙型肝炎病毒（HBV）、丙型肝炎病毒（HCV）或梅毒螺旋体，或患有其他需要治疗的严重感染。 * 因法律命令而被安置于机构内（《药品法》第40(4)条）。 * 妊娠或哺乳期女性患者。对绝经前且有生育能力的女性，须取得阴性妊娠试验结果。 * 任何妨碍遵守研究方案的心理社会状况。 * MGMT启动子甲基化状态结果不确定。
Inclusion Criteria: Determined at pre-screening (prior to surgery; wk-3 - wk-1): * Patients ≥ 18 years of age at surgery. * Patients must be in a cognitive state to understand and sign the informed consent indicating that they are aware of the investigational nature and procedures of the study. * First written informed consent for screening for eligibility, including tumor tissue collection, transfer and processing, central neuropathological evaluation of Tumor sample, central neuroradiological assessment of extent of resection, infectious disease (HIV, HBV, HCV, Treponema pallidum) testing, determination of MGMT promoter methylation status and pregnancy testing. Determined at screening (at and post-surgery; d0 - wk3): * Newly diagnosed, monofocal GBM, IDH wildtype (WHO grade IV), including the histological variants of gliosarcoma and giant cell glioblastoma, confirmed by central neuropathologist according to the WHO classification of central nervous System tumors 2016. Tumors may cross into, but not beyond the corpus callosum. * Near-complete resection (≤ 5 ml residual contrast enhancing tumor volume) confirmed by central neuroradiologist on MRI scan within 72 h postoperative; awake surgery and second look surgery are possible, if medically indicated. * Sterile tumor sample of ≥ 150 mg with tumor cell frequency ≥ 60% as determined by central neuropathologist available for vaccine production. * Successful production of sterile, avital tumor lysate. * Karnofsky performance status ≥ 70%. * Adequate hepatic (serum glutamate pyruvate transferase/alanine transaminase (SGPT/ALT), serum glutamic oxaloacetate transaminase/aspartate transaminase (SGOT/AST) and alkaline phosphatase ≤ 3-times upper limit of normal (ULN); bilirubin ≤ 1.5-times ULN) and renal functions (creatinine ≤ 1.5-times ULN). * Adequate bone marrow function (hemoglobin ≥ 10 g/dl, thrombocytes ≥ 100,000/μl, white blood cell count ≥ 3,000/μl; neutrophil count ≥ 1,500/μl). * Prothrombin time (PT) and activated partial thromboplastin time (PTT) ≤ 1.6x ULN unless therapeutically warranted. International normalized ratio (INR) (in absence of anticoagulation treatment) ≤ 1.5. * Systemic corticosteroids tapered down to ≤ 2 mg of dexamethasone or equivalent per day within 7 days postoperative (use of corticosteroids during the treatment period should be avoided, however it is possible if clinically indicated, but may require interruption of dendritic cell vaccination). * Female patients with reproductive potential and male generative patients and their female partners must agree to be true abstinent or to use a highly effective form of contraception (pearl index \< 1%) during the trial. * Patients must be in a cognitive state to understand and sign the informed consent indicating that they are aware of the investigational nature and procedures of the study. * Written informed consent to participate in study. Exclusion Criteria: determined at pre-screening (prior to surgery; wk-3 - wk-1): * Medical history of severe acute or chronic disease with poor prognosis, e.g. severe coronary heart disease, heart failure (New York Heart Association classes III/IV), severe poorly controlled diabetes, severe mental retardation or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator). * Medical history of severe autoimmune disorder or immunodeficiency or patients with organ allograft. * Medical history of bleeding diathesis or coagulopathy. * Prior malignancy during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer in a patient with prostate-specific antigen (PSA) level less than ULN. * Previous radiotherapy to head and neck. * Known allergy or intolerability to TMZ, dacarbazine, the contrast agent or to components of the dendritic cell vaccine. * Current treatment of glioblastoma in another clinical trial with therapeutic intervention or current use of any other investigational agent. * Known pregnancy or breast feeding. * No known severe infection requiring treatment. * Accommodation in an institution due to legal orders (§40(4) AMG). * Evidence of current drug or alcohol abuse. determined at screening (at and post-surgery; d0 - wk3): * Infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or Treponema pallidum or other severe infection requiring treatment. * Accommodation in an institution due to legal orders (§40(4) AMG). * Pregnant or breast feeding female patients. From pre-menopausal female patients with childbearing potential a negative pregnancy test must be obtained. * Any psycho-social condition hampering compliance with the study protocol. * MGMT promoter methylation status equivocal.
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：Overall survival (OS) · Overall survival as measured from the day of surgery until death from any cause assessed up to 34 months · Day of surgery until death of any cause assessed up to 34 months
次要终点：Progression free survival (PFS)；OS rates；PFS rates；Frequency and severity of adverse events；Karnofsky Performance Status；MMSE-2；Quality of life of cancer patients；Quality of life in patients with brain cancer
第0天进行荧光引导手术；第4周进行白细胞单采；第5至10周接受分割放疗（总剂量60 Gy，每次2 Gy，每周5天，共6周），并同期接受替莫唑胺（TMZ）化疗（75 mg/m²/日，共6周）；第11至14周每周接种自体肿瘤裂解物负载的成熟树突状细胞（DC）疫苗，此后于第17、21和25周接种，共7次，每次2–10×10^6个DC，经皮内注射；随后接受辅助TMZ化疗（150–200 mg/m²/日，每28天周期的第1至5天给药，共6个周期：第15、19、23、27、31和35周）。
标准治疗：第0天进行荧光引导手术；第5至10周接受分割放疗（总剂量60 Gy，每次2 Gy，每周5天，共6周），并同期接受TMZ化疗（75 mg/m²/日，共6周）；随后接受辅助TMZ化疗（150–200 mg/m²/日，每28天周期的第1至5天给药，共6个周期：第15、19、23、27、31和35周）。
本研究的主要目的是确定：对新诊断胶质母细胞瘤患者，在切除手术、放疗及同期替莫唑胺化疗、随后辅助替莫唑胺化疗这一标准治疗基础上加用负载肿瘤裂解物的成熟树突状细胞疫苗，是否比单独接受标准治疗更能延长总生存期。
The primary objective of the study is to determine whether overall survival of newly diagnosed glioblastoma patients treated with lysate-loaded, mature dendritic cell vaccines as add-on to the standard of care consisting of resection, radiotherapy with concomitant temozolomide chemotherapy and subsequent adjuvant temozolomide chemotherapy is superior to the treatment with the standard of care alone.
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