肿瘤细胞治疗研究
英文原题：A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Cilta-cel, a CAR-T Therapy Directed Against BCMA Versus VRd Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With Newly Diagnosed Multiple Myeloma for Whom ASCT is Not Planned as Initial Therapy
这是一项 III 期注册临床试验，评估细胞治疗用于多发性骨髓瘤的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 743 例。试验地点：美国 · 旧金山、纽黑文、迈阿密、奥兰多（共 136 个中心）。登记号：NCT04923893。
不限性别 · ≥ 18 Years
纳入标准： * 根据国际骨髓瘤工作组（IMWG）诊断标准确诊多发性骨髓瘤（MM） * 筛选期存在可测量病灶，定义为以下任一情况：血清单克隆副蛋白（M-protein）水平大于或等于（>=）1.0 克/分升（g/dL），或尿 M-protein 水平 >=200 毫克（mg）/24 小时；或仅以血清游离轻链（FLC）水平作为可测量病灶的轻链型 MM：血清免疫球蛋白（Ig）游离轻链 >=10 毫克/分升（mg/dL）且血清 Ig kappa/lambda FLC 比值异常 * 美国东部肿瘤协作组（ECOG）体能状态评分为 0 或 1 * 不考虑接受大剂量化疗联合自体干细胞移植（ASCT），原因如下：因高龄不符合条件；或因存在可能对大剂量化疗联合 ASCT 的耐受性产生负面影响的合并症而不符合条件；或推迟将大剂量化疗联合 ASCT 作为初始治疗 * 有生育能力的女性（WOCBP）在开始硼替佐米、来那度胺和地塞米松（VRd）治疗前必须进行2次高敏感血清或尿妊娠试验（β-人绒毛膜促性腺激素）且结果均为阴性，并必须同意在研究期间接受进一步检测。 * 筛选期临床实验室检查值符合以下标准：血红蛋白大于等于（>=）8.0 g/dL（>=5 毫摩尔/升 [mmol/L]），允许使用重组人促红细胞生成素；血小板 >=75 *10^9/L；绝对淋巴细胞计数 >=0.3 *10^9/L；绝对中性粒细胞计数（ANC）>=1.0 ×10^9/L（允许既往使用生长因子支持，但实验室检查前 7 天内不得使用）；天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）小于等于（<=）3.0 * 正常值上限（ULN）；基于肾脏病饮食改良公式（MDRD-4）计算或 24 小时尿液收集法估算的肾小球滤过率 >=40 毫升/分钟/1.73 平方米（mL/min/1.73 m^2）；总胆红素 <=2.0 * ULN；先天性高胆红素血症受试者（如 Gilbert 综合征）除外（此类受试者要求直接胆红素 <=2.0 * ULN） 排除标准： * 根据 Myeloma Geriatric Assessment 评分，衰弱指数 >=2 * 周围神经病变或神经性疼痛≥2级，依据美国国家癌症研究所-不良事件通用术语标准（NCI-CTCAE）第5版定义 * 已知有活动性或既往中枢神经系统（CNS）受累病史，或MM脑膜受累的临床体征 * 签署知情同意书（ICF）前6个月内发生卒中或癫痫发作 * 人类免疫缺陷病毒（HIV）血清学阳性 * 首次给药VRd前4周内接种过活减毒疫苗 * 受试者不得需要持续吸氧 * 乙型肝炎感染 * 丙型肝炎感染 * 既往接受过靶向任何靶点的嵌合抗原受体T（CAR-T）细胞治疗 * 任何靶向B细胞成熟抗原（BCMA）的治疗
Inclusion Criteria: * Documented diagnosis of multiple myeloma (MM) according to International Myeloma Working Group (IMWG) diagnostic criteria * Measurable disease at screening as defined by any of the following: Serum monoclonal paraprotein (M-protein) level greater than or equal to (\>=)1.0 gram per deciliter (g/dL) or urine M-protein level \>=200 milligram (mg)/24 hours; or Light chain MM in whom only measurable disease is by serum free light chain (FLC) levels: Serum immunoglobin (Ig) free light chain \>=10 milligrams per deciliter (mg/dL) and abnormal serum Ig kappa/lambda FLC ratio * Eastern Cooperative Oncology Group Performance Status grade of 0 or 1 * Not considered for high-dose chemotherapy with Autologous Stem Cell Transplant (ASCT) due to: Ineligible due to advanced age; or Ineligible due to presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT; or Deferral of high-dose chemotherapy with ASCT as initial treatment * A woman of childbearing potential (WOCBP) must have 2 negative highly sensitive serum or urine pregnancy tests (beta-human chorionic gonadotropin) prior to starting Bortezomib, Lenalidomide and Dexamethasone (VRd) and must agree to further testing during the study. * Clinical laboratory values meeting the following criteria during the screening phase: hemoglobin greater than or equal to (\>=) 8.0 g/dL (\>=5 millimoles per liter \[mmol/L\]), recombinant human erythropoietin use is permitted; platelets \>=75 \*10\^9/L; absolute lymphocyte count \>=0.3 \*10\^9/L; absolute neutrophil count (ANC) \>=1.0 ×10\^9/L (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to (\<=) 3.0 \* upper limit of normal (ULN); estimated glomerular filtration rate \>=40 milliliter per minute/1.73 meter square (mL/min/1.73 m\^2) based upon modified diet in renal disease formula (MDRD-4) calculation or a 24-hour urine collection; total bilirubin \<=2.0 \* ULN; except in participants with congenital hyperbilirubinemia, such as Gilbert syndrome (in which case direct bilirubin \<=2.0 \* ULN is required) Exclusion Criteria: * Frailty index of \>=2 according to Myeloma Geriatric Assessment score * Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5 * Known active, or prior history of central nervous system (CNS) involvement or clinical signs of meningeal involvement of MM * Stroke or seizure within 6 months of signing Informed Consent Form (ICF) * Seropositive for human immunodeficiency virus (HIV) * Vaccinated with live, attenuated vaccine within 4 weeks prior to first dose of VRd * Participant must not require continuous supplemental oxygen * Hepatitis B infection * Hepatitis C infection * Prior treatment with chimeric antigen receptor T (CAR-T) therapy directed at any target * Any therapy that is targeted to B-cell maturation antigen (BCMA)
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) · Progression-free survival is defined as the time from the date of randomization to the date of first documented Progressive Disease (PD), as defined in the International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. · Up to 4 years and 5 months
次要终点：Sustained Minimal Residual Disease (MRD) Negative CR；MRD Negative CR at 9 Months；Overall MRD Negative CR；Overall Survival (OS)；Complete Response or Better；Time to Subsequent Anti-myeloma Therapy；Progression Free Survival on Next-line Therapy (PFS2)；Number of Participants with Adverse Events (AEs), Abnormalities in Laboratory Parameters, 12-Lead Electrocardiogram (ECG), Physical Examination, and Vital Signs
受试者将在随机化前接受硼替佐米、来那度胺和地塞米松（VRd）方案治疗6个周期。随机化后，A组受试者将再接受2个周期的VRd治疗。在VRd治疗中，受试者将在每个周期的第1、4、8和11天（第1至8周期）接受硼替佐米1.3毫克/平方米（mg/m^2）皮下注射（SC），在每个周期的第1至14天（第1至8周期）口服来那度胺25毫克，并在每个周期的第1、2、4、5、8、9、11和12天（第1至8周期）口服地塞米松20毫克。每个周期为21天。完成8个周期的VRd治疗后，将继续接受来那度胺和地塞米松（Rd）维持治疗。在Rd治疗中，受试者将在每个周期的第1至21天口服来那度胺25毫克，并在每个周期的第1、8、15和22天口服地塞米松40毫克。每个周期为28天。受试者将持续接受Rd治疗，直至确认疾病进展或出现不可耐受的毒性。
受试者将在随机化前接受VRd方案治疗6个周期。随机化后，B组受试者将进行单采术，并再接受2个周期的VRd作为桥接治疗。在VRd治疗中，受试者将在每个周期的第1、4、8和11天接受硼替佐米1.3 mg/m^2皮下注射（第1至8周期）；在每个周期的第1至14天口服来那度胺25毫克（第1至8周期），并在每个周期的第1、2、4、5、8、9、11和12天口服地塞米松20毫克（第1至8周期）。每个周期为21天。完成8个周期的VRd治疗后，受试者将接受预处理方案（环磷酰胺300 mg/m^2静脉注射[IV]和氟达拉滨30 mg/m^2 IV，每日一次，连续3天）以及Cilta-cel输注，剂量为0.75*10^6个嵌合抗原受体（CAR）阳性活T细胞/千克（kg）。
本研究的目的是比较在新诊断且不计划以ASCT作为初始治疗的多发性骨髓瘤受试者中，Bortezomib、Lenalidomide和Dexamethasone（VRd）诱导后单次输注ciltacabtagene autoleucel（cilta-cel）与VRd诱导后Lenalidomide和Dexamethasone（Rd）维持治疗的疗效，评价指标为无进展生存期（PFS）。
The purpose of this study is to compare the efficacy of Bortezomib, Lenalidomide and Dexamethasone (VRd) induction followed by a single administration of ciltacabtagene autoleucel (cilta-cel) versus VRd induction followed by Lenalidomide and Dexamethasone (Rd) maintenance in newly diagnosed multiple myeloma participants for whom ASCT is not planned as initial therapy in terms of Progression Free Survival (PFS).
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