肿瘤细胞治疗研究
英文原题：Phase I Trial of BCMA-TGF-BETA CAR-T Cells in Relapsed, Refractory Myeloma
这是一项 I 期注册临床试验，评估 BCMACAR-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：招募中。计划入组 30 例。试验地点：美国 · 密尔沃基（共 1 个中心）。登记号：NCT05976555。
不限性别 · ≥ 18 Years 且 ≤ 80 Years
纳入标准：
1. 患者年龄必须≥18岁至80岁。
2. 患者必须接受过三种既往疗法，包括蛋白酶体抑制剂、免疫调节剂和分化簇（CD）38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后或治疗结束后60天内出现疾病进展。
3. 患者必须具有可测量疾病，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. 绝对CD 3计数≥50 mm^3。
5. Karnofsky体能状态评分≥70。
6. 肝功能充分，定义为：
1. 天冬氨酸氨基转移酶（AST）、丙氨酸转氨酶（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。
7. 绝对中性粒细胞计数（ANC）≥1,000，且72小时内未使用粒细胞集落刺激因子（G-CSF）或10天内未使用聚乙二醇化G-CSF。
8. 血小板≥50,000/µL，且资格检测前72小时内未输血。
9. 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。
10. 能够提供书面知情同意。
11. 同意在研究期间采取避孕措施。
12. 心功能充分，表现为纽约心脏协会（NYHA）分级I或II级，且左心室射血分数≥45%（通过心脏超声心动图（ECHO）或门控血池显像（MUGA）），并且肺功能充分，表现为室内空气氧饱和度≥90%。
13. 预期生存期>12周。
14. 有生育能力的女性在研究入组时尿或血清妊娠试验阴性。
15. 符合下文详述的关于生育和避孕的标准。
16. 无中心静脉置管禁忌症。
I期剂量扩展队列A：BCMA初治 剂量扩展队列A的纳入标准与上述相同，但限于BCMA初治患者。
I期剂量扩展队列B：BCMA经治 剂量扩展队列B的纳入标准与上述相同，但要求既往暴露于BCMA靶向治疗（例如，CAR-BCMA、BCMA双特异性T/自然杀伤（NK）细胞衔接器）。
允许既往接受过抗体药物偶联物、双特异性T和NK细胞衔接器以及针对BCMA的基因修饰细胞免疫治疗的患者。患者必须距治疗结束>3个月，且既往BCMA靶向治疗必须达到疾病稳定或更好。
排除标准：
1. 有生育能力的女性根据事件时间表定义的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，或存在活动性、未控制的自身免疫现象且需要类固醇治疗，定义为每日泼尼松>20 mg或等效剂量。
4. 既往任何治疗导致根据CTCAE 5.0版评估的≥3级非血液学毒性，除非认为该毒性由基础疾病所致。
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。在单采前至少需洗脱14天或5个药物半衰期（以较短者为准）。
6. 拒绝参加长期随访方案。
7. 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疾病已获有效治疗的患者，若末次治疗在单采前≥2周，且在计划CAR T细胞输注前4周内通过脑部MRI和CSF分析证实缓解，则符合入选条件。
8. 既往接受过异基因造血干细胞移植（AHCT）者，若移植后<6个月、存在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（仅在剂量扩展阶段的队列B中允许）。
11. 既往接受过BCMA靶向治疗（仅在剂量扩展阶段的队列B中允许）。
12. 在单采前14天内或单采后接受细胞毒性化疗、口服化疗药物或抗体导向治疗。
1. 允许在单采前7天内及单采后为控制疾病使用皮质类固醇，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。
13. 实体器官移植后发生高级别淋巴瘤或白血病的患者。
14. 除皮肤基底细胞癌或鳞状细胞癌外，同时存在活动性恶性肿瘤。
15. 需要全身治疗的活动性细菌、病毒或真菌感染。
16. 在白细胞单采前1周内及淋巴细胞清除前3周内接受过大手术的患者。
17. 过去2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，或不需要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。
关于生育力和避孕的特殊标准
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，即在前24个月内有过月经，或未接受过绝育手术[子宫切除术或双侧卵巢切除术]）必须进行血清或尿液妊娠试验，结果为阴性，作为合格性标准的一部分。哺乳期女性有资格参加本研究，但将被要求从CAR T细胞治疗前第-4天至治疗后第+90天期间不向孩子提供母乳。
由于本研究的高风险水平，在入组期间，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、捐精、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（男性或女性），含或不含杀精剂。
* 子宫帽或宫颈帽加杀精剂。
* 宫内节育器（IUD）。
* 激素类避孕。无生育潜力的受试者（月经初潮前的女性或已绝经至少连续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）有资格参加，无需使用避孕措施。
Inclusion Criteria:
1. Patients must be aged ≥18 years to 80 years old.
2. Patients must have received three prior lines of therapies, including proteasome inhibitor, immunomodulator and a cluster of differentiation (CD) 38 monoclonal antibody:
• International Myeloma Working Group (IMWG) criteria defines 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. Absolute CD 3 count ≥50 mm\^3.
5. Karnofsky performance score ≥70.
6. Adequate hepatic function, defined as:
1. aspartate aminotransferase (AST), alanine transaminase (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.
7. Absolute neutrophil count (ANC) ≥1,000 with no Granulocyte colony-stimulating factor (G-CSF) within 72 hours or pegylated G-CSF within 10 days.
8. Platelets ≥50,000/µL with no transfusion within 72 hours of eligibility testing.
9. Adequate renal function, defined as creatinine clearance ≥50 mL/min calculated using the Cockroft-Gault formula.
10. Able to provide written informed consent.
11. Agree to practice birth control during the study.
12. 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 (MUGA)) and adequate pulmonary function as indicated by room air oxygen saturation of ≥90%.
13. Expected survival \>12 weeks.
14. Negative urine or serum pregnancy test in females of childbearing potential at study entry.
15. Meet criteria for regarding fertility and contraception detailed below.
16. No contraindication to central line access.
Phase I Dose-Expansion Cohort A: BCMA Naïve The inclusion criteria for dose-expansion Cohort A are the same as that listed above but are limited to BCMA naïve patients.
Phase I Dose-Expansion Cohort B: BCMA Exposed The inclusion criteria for dose expansion Cohort B are the same as that above but require prior exposure to BCMA directed therapies (e.g., CAR-BCMA, bispecific T/ Natural Killer (NK) cell engagers of BCMA).
Patients with prior antibody drug conjugate, bispecific T and NK cell engager and prior gene-modified cellular immune therapy against BCMA are allowed. Patients must be \> 3 months out from therapy and must have achieved stable disease or better with prior BCMA-directed therapy.
Exclusion Criteria:
1. Positive beta- Human chorionic gonadotropin (HCG) in female of child-bearing potential defined as per the Schedule of Events table.
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 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 on another therapeutic clinical trial at any institution. Minimum of 14 days or 5 half-lives of the drug (whichever is shorter) washout prior to apheresis.
6. Refusal to participate in the long-term follow-up protocol.
7. Patients with active central nervous system (CNS) involvement by malignancy on 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 apheresis and a remission documented within 4 weeks of planned CAR T-cell infusion by MRI brain and 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 (only permitted in cohort B for the dose expansion phase).
11. Prior BCMA-directed therapy (only permitted in cohort B for the dose expansion phase).
12. Cytotoxic chemotherapy, oral chemotherapeutic agents, or antibody-directed treatment within 14 days of apheresis or after apheresis.
1. Corticosteroids are allowable up until 7 days prior to apheresis and after apheresis for disease control up until the day prior to cell infusion (Day -1).
2. Radiation is allowed to a single symptomatic site.
13. Patients post solid organ transplant who develop high grade lymphomas or leukemias.
14. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.
15. Active bacterial, viral, or fungal infection requiring systemic treatment.
16. Patients who have received major surgery 1 week prior to leukapheresis and 3 weeks prior to lymphodepletion.
17. Active malignancy that required therapy in the last 2 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.
Special Criteria Regarding Fertility and Contraception
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 eligibility criteria. Lactating women are eligible for this study but will be asked to not provide breast milk to their child from Day -4 through Day +90 after CAR T-cell therapy.
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.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 of Adverse Events After BCMA-TGFβ CAR-T Cell Infusion · Incidence of adverse events with grade 3 to 5 severity using NCI CTCAE version 5.0 and the Lee et al. consensus manuscript (which outlines the defining characteristics of each grade for cytokine release syndrome; please refer to the reference below). · from infusion until Day +28 post CAR T infusion
BCMA-TGFβ CAR-T细胞将以新鲜状态或冷冻保存后解冻的状态通过静脉注射给药。根据剂量递增设计，受试者将接受四个剂量水平之一的BCMA-TGFβ CAR-T细胞。
BCMA-TGFβ CAR-T细胞将以新鲜状态或冷冻保存后解冻的状态通过静脉注射给药。根据剂量递增设计，受试者将接受四个剂量水平之一的BCMA-TGFβ CAR-T细胞。
BCMA-TGFβ CAR-T细胞将以新鲜状态或冷冻保存后解冻的状态通过静脉注射给药。根据剂量递增设计，受试者将接受四个剂量水平之一的BCMA-TGFβ CAR-T细胞。
BCMA-TGFβ CAR-T细胞将以新鲜状态或冷冻保存后解冻的状态通过静脉注射给药。根据剂量递增设计，受试者将接受四个剂量水平之一的BCMA-TGFβ CAR-T细胞。
在确定最大耐受剂量（MTD）后，可能在该剂量下额外入组一个剂量扩展队列，最多9例患者（3例BCMA初治和6例BCMA暴露）。
这是一项I期、干预性、单臂、开放标签、剂量探索的治疗研究，旨在评估白细胞介素-7（IL-7）/白细胞介素-15（IL-15）制备的CAR T细胞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有效性。
This is a phase I, interventional, single-arm, open-label, dose-finding treatment study designed to evaluate the safety and efficacy of interleukin-7(IL-7) / interleukin-15 (IL-15) manufactured CAR T cells in adult patients with relapsed and/or refractory myeloma that have failed prior therapies.
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