肿瘤细胞治疗研究
英文原题：FT836 CAR T-cell Therapy in Combination With Daratumumab in Patients With Relapsed and/or Refractory Multiple Myeloma
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗多发性骨髓瘤的安全性、可行性及初步疗效。当前状态：尚未开始招募。计划入组 12 例。试验地点：美国 · 密尔沃基（共 1 个中心）。登记号：NCT07221032。
不限性别 · ≥ 18 Years 且 ≤ 80 Years
纳入标准：
1. 患者必须≥18岁且<80岁。
2. 患者必须已接受过≥3线既往治疗，包括蛋白酶体抑制剂、免疫调节剂和CD38单克隆抗体：
• 国际骨髓瘤工作组（IMWG）标准将难治性疾病定义为在接受治疗时或治疗结束后60天内出现疾病进展。
3. 患者必须具有可测量病灶，包括至少符合以下标准中的一项或多项：
1. 血清M蛋白≥0.5 g/dl；
2. 尿M蛋白≥200 mg/24小时；
3. 受累血清轻链≥100 mg/L且轻链比值异常；
4. Karnofsky体能状态评分≥70。
5. 肝功能充分，定义为：
1. 天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）和碱性磷酸酶<3倍正常上限（ULN）；
2. 血清胆红素<2.0 mg/dL，但Gilbert综合征患者除外，其血清胆红素必须<3 mg/dL。
6. 绝对中性粒细胞计数（ANC）≥1,000，且72小时内未使用G-CSF或10天内未使用聚乙二醇化G-CSF。
7. 血小板≥50,000，且资格检测前72小时内未输血。
8. 肾功能充分，定义为使用Cockroft-Gault公式计算的肌酐清除率≥50 mL/min。
9. 能够提供书面知情同意。
10. 同意在研究期间采取避孕措施。
11. 心功能充分，表现为纽约心脏协会（NYHA）分级I或II级，且通过心脏超声心动图（ECHO）或门控血池扫描（MUGA）测得的左心室射血分数≥45%——并且肺功能充分，表现为室内空气氧饱和度≥90%。
12. 预期生存期>12周。
13. 有生育能力的女性在入组研究时尿妊娠试验或血清妊娠试验阴性。
14. 无中心静脉置管禁忌证。有生育潜力的女性受试者（已达到月经初潮的女性，或未绝经至少连续24个月的女性，即过去24个月内有月经，或未接受过绝育手术[子宫切除术或双侧卵巢切除术]）必须进行血清或尿妊娠试验且结果为阴性，作为资格标准的一部分。哺乳期女性可参加本研究，但将被要求从CAR T细胞治疗前第-11天至治疗后第+90天期间不向孩子提供母乳。她们在接受化疗和治疗后可能不再能够泌乳。
由于本研究的高风险水平，入组期间，所有受试者必须同意不参与受孕过程（例如，积极尝试怀孕或使他人受孕、捐献精子、体外受精）。此外，如果参与可能导致怀孕的性活动，研究受试者必须同意在方案随访期间使用可靠的双重屏障避孕方法。
可接受的避孕措施包括以下方法中的两种组合：
* 避孕套（男用或女用），含或不含杀精剂。
* 带有杀精剂的阴道隔膜或宫颈帽。
* 宫内节育器（IUD）。
* 激素类避孕。无生育能力的受试者（月经初潮前的女性或已连续绝经至少24个月或已接受子宫切除术、输卵管结扎术、输卵管切除术和/或双侧卵巢切除术的女性，或已记录无精子症的男性）无需使用避孕措施即可入组。
排除标准：
1. 有生育能力的女性β-人绒毛膜促性腺激素（HCG）阳性。
2. 确诊活动性人类免疫缺陷病毒（HIV）、乙型肝炎或丙型肝炎感染。
3. 有显著自身免疫性疾病史，或需要类固醇治疗的活动性、未控制的自身免疫现象，定义为每日泼尼松>20 mg或等效剂量。
4. 根据不良事件通用术语标准（CTCAE）5.0版，既往任何治疗导致的≥3级非血液学毒性，除非认为是由基础疾病所致。
5. 同时使用研究性治疗药物或在任何机构参加另一项治疗性临床试验。在开始daratumumab前至少需14天或五个药物半衰期（以较短者为准）的洗脱期。
6. 拒绝参加长期随访方案。
7. 磁共振成像（MRI）或腰椎穿刺显示恶性肿瘤活动性中枢神经系统（CNS）受累的患者。
a. 既往CNS疾病已得到有效治疗的患者可入组，前提是末次治疗距开始daratumumab≥2周，且通过脑部MRI和脑脊液（CSF）分析记录到在计划CAR T细胞输注前四周内达到缓解。
8. 既往接受过异基因造血干细胞移植（AHCT）的受者，如果移植后<6个月、有任何级别的活动性移植物抗宿主病（GVHD）证据，或目前正在接受免疫抑制治疗，则被排除。
9. 浆细胞白血病、华氏巨球蛋白血症、POEMS综合征和AL淀粉样变性。
10. 既往接受过基因治疗或任何基因修饰细胞治疗。
11. 在开始daratumumab前14天内或开始daratumumab后接受细胞毒性化疗、口服化疗药物或抗体导向治疗。
1. 允许使用皮质类固醇直至开始daratumumab前七天，以及开始daratumumab后用于疾病控制直至细胞输注前一天（第-1天）。
2. 允许对单个有症状部位进行放疗。
12. 实体器官移植后发生高级别淋巴瘤或白血病的患者。
13. 除皮肤基底细胞癌或鳞状细胞癌外的并发活动性恶性肿瘤。
14. 需要全身治疗的活动性细菌、病毒或真菌感染。
15. 在开始daratumumab前一周及淋巴细胞清除前三周内接受过大手术的患者。
16. 过去两年内需要治疗的活动性恶性肿瘤，但成功治疗的非转移性基底细胞癌或鳞状细胞癌，或无需治疗的前列腺癌除外。其他类似情况可与医学监查员讨论并经其允许。
Inclusion Criteria:
1. Patients must ≥18 years and \< 80 years old.
2. Patients must have received \>=3 prior lines of therapies, including proteasome inhibitor, immunomodulator and a CD38 monoclonal antibody:
• International Myeloma Working Group (IMWG) criteria define refractory disease as disease progression on or within 60 days of receiving therapy.
3. Patients must have measurable disease, including at least one or more of the following criteria:
1. Serum M-protein ≥ 0.5 g/dl;
2. Urine M-protein ≥ 200 mg/24 hrs;
3. Involved serum light chain ≥100 mg/L with abnormal light chain ratio;
4. Karnofsky performance score ≥70.
5. Adequate hepatic function, defined as:
1. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase \<3x upper limit of normal (ULN);
2. Serum bilirubin \<2.0 mg/dL except for patients with Gilbert's syndrome, who must have serum bilirubin of \<3 mg/dL.
6. Absolute neutrophil count (ANC) ≥1,000 with no G-CSF within 72 hours or pegylated G-CSF within 10 days.
7. Platelets ≥50,000 with no transfusion within 72 hours of eligibility testing.
8. Adequate renal function, defined as creatinine clearance ≥50 mL/min calculated using the Cockroft-Gault formula.
9. Able to provide written informed consent.
10. Agree to practice birth control during the study.
11. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥45% -- by cardiac echocardiogram (ECHO) or multigated acquisition scan (MUGA) -- and adequate pulmonary function as indicated by room air oxygen saturation of ≥90%.
12. Expected survival \>12 weeks.
13. Negative urine or serum pregnancy test in females of childbearing potential at study entry.
14. No contraindication to central line access. Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure \[hysterectomy or bilateral oophorectomy\]) must have a negative serum or urine pregnancy test performed as part of the eligibility criteria. Lactating women are eligible for this study but will be asked not to provide breast milk to their child from Day -11 through Day +90 after CAR T-cell therapy. It is possible they may no longer be able to lactate after receiving chemotherapy and treatment.
Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double-barrier methods of contraception during the follow-up period of the protocol.
Acceptable birth control includes a combination of two of the following methods:
* Condoms (male or female) with or without a spermicidal agent.
* Diaphragm or cervical cap with spermicide.
* Intrauterine device (IUD).
* Hormonal-based contraception. Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy, tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception.
Exclusion Criteria:
1. Positive beta-Human Chorionic Gonadotropin (HCG) in female of child-bearing potential.
2. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.
3. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon requiring steroid therapy defined as \>20 mg of prednisone or equivalent daily.
4. Presence of ≥ Grade 3 non-hematologic toxicities as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 from any previous treatment unless it is felt to be due to underlying disease.
5. Concurrent use of investigational therapeutic agents or enrollment in another therapeutic clinical trial at any institution. A minimum of 14 days or five half-lives of the drug (whichever is shorter) washout prior to start of daratumumab.
6. Refusal to participate in the long-term follow-up protocol.
7. Patients with active Central Nervous System (CNS) involvement by malignancy on magnetic resonance imaging (MRI) or by lumbar puncture.
a. Patients with prior CNS disease that has been effectively treated will be eligible providing last treatment was ≥2 weeks before start of daratumumab and a remission documented within four weeks of planned CAR T-cell infusion by MRI brain and Cerebrospinal Fluid (CSF) analysis.
8. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are \<6 months post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.
9. Plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome, and AL amyloidosis.
10. Prior treatment with gene therapy or any gene-modified cellular therapy.
11. Cytotoxic chemotherapy, oral chemotherapeutic agents, or antibody-directed treatment within 14 days of starting daratumumab or after starting daratumumab.
1. Corticosteroids are allowable up until seven days prior to starting daratumumab and after starting daratumumab for disease control up until the day prior to cell infusion (Day -1).
2. Radiation is allowed to a single symptomatic site.
12. Patients post solid organ transplant who develop high-grade lymphomas or leukemias.
13. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.
14. Active bacterial, viral, or fungal infection requiring systemic treatment.
15. Patients who have received major surgery one week prior to starting daratumumab and three weeks prior to lymphodepletion.
16. Active malignancy that required therapy in the last two years except successfully treated non-metastatic basal or squamous cell carcinoma, or prostate carcinoma that does not require therapy. Other similar conditions may be discussed with and permitted by the medical monitor.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：Incidence of Grade 3 or higher adverse events · This measure is the number of Grade 3 or higher adverse events possibly, probably, or definitely related to the study therapy. Adverse events will be graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) will be graded and assessed using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading systems. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) will be graded and assessed using the ASTCT panel guidelines. · start of therapy through 30 days after the end of study therapy, up to 2 years
这是剂量水平0（递减剂量）。
这是剂量水平1（起始剂量）。
这是剂量水平2，即≤3倍剂量水平1。
这是一项I期、干预性、单臂、开放标签、剂量探索的治疗研究，旨在评估FT836联合daratumumab在既往治疗失败的复发和/或难治性骨髓瘤成年患者中的安全性和初步疗效。
This is a phase I, interventional, single-arm, open-label, dose-finding treatment study designed to evaluate the safety and preliminary efficacy of FT836 in combination with daratumumab in adult patients with relapsed and/or refractory myeloma who have failed prior therapies.
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