肿瘤细胞治疗研究
英文原题：Clinical Study of BCMA-Targeted CAR T-Cell Injection in the Treatment of Patients With Relapsed/Refractory Multiple Myeloma
这是一项早期 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 3 例。试验地点：亚太其他 · 曼谷（共 1 个中心）。登记号：NCT07458659。
不限性别 · ≥ 18 Years
纳入标准： 1. 年龄在18岁以上（含18岁），性别不限。 2. 患有至少接受过三线治疗的多发性骨髓瘤患者，且至少在接受蛋白酶体抑制剂和免疫调节剂治疗后失败；每线治疗至少完成一个完整周期，除非该治疗的最佳反应被记录为疾病进展（PD）（根据2016年发布的IMWG疗效评价标准，附录4）；患者必须在末次治疗期间或治疗后12个月内有PD记录，或末次治疗后60天内无反应（未达到MR或更好反应）。 3. 筛选时存在可测量病灶，定义为以下任一情况： * 血清M蛋白 ≥ 1 g/dL（≥ 10 g/L） * 尿M蛋白水平 ≥ 200 mg/24小时 * 血清游离轻链（FLC）：血清FLC比值异常（< 0.26或> 1.65）且受累FLC ≥ 10 mg/dL（100 mg/L） 4. ECOG体能状态（附录1）为0-1。 5. 预期生存时间 ≥ 3个月。 6. 在单核细胞采集前符合以下标准： 血液学 * 淋巴细胞绝对计数 ≥ 0.5×109/L [允许使用粒细胞集落刺激因子（G-CSF），但受试者在筛选期实验室检查前7天内不得接受该支持治疗]； * 中性粒细胞绝对计数 ≥ 1.0 ×109/L [允许使用粒细胞集落刺激因子（G-CSF），但受试者在筛选期实验室检查前7天内不得接受该支持治疗]； * 血小板计数 ≥ 50×109/L（受试者在筛选实验室检查前7天内不得接受输血支持）； * 血红蛋白 ≥ 8.0 g/dL（允许使用重组人促红细胞生成素）[受试者在筛选实验室检查前7天内未接受红细胞（RBCS）输注]；心脏 * 射血功能：左心室射血分数（LVEF）≥ 50% 肺 * 氧饱和度：非氧疗状态下血氧饱和度 ≥ 91% 肾 * 肌酐清除率（CrCl）或肾小球滤过率（GFR）（Cockcroft-Gault公式）≥ 30 mL/min 肝 * 总胆红素（血清）≤ 1.5 × ULN 吉尔伯特病患者血清胆红素水平超过1.5 × ULN，经申办方批准后可入组 * AST和ALT ≤ 3× ULN 凝血 * PT ≤ 1.5× ULN，APTT ≤ 1.5×ULN，INR ≤ 1.5×ULN 7. 外周静脉通路能满足采集和静脉输注的要求。 8. 受试者同意自签署知情同意书起至回输后1年内采用可靠的避孕方法进行避孕。包括但不限于：禁欲、男性输精管切除术、抑制排卵的植入式孕激素避孕药；宫内节育器；释放激素的宫内节育器；性伴侣绝育；铜质宫内节育器、正确使用已证明可抑制排卵的复方激素避孕药；抑制排卵的孕激素类避孕药。女性受试者应同时承诺回输后1年内不捐献卵子（卵细胞、卵母细胞）用于辅助生殖。 9. 自愿参加临床试验并签署知情同意书。 排除标准： 1. 已知对CART-BCMA的任何成分或研究可能使用的药物（包括氟达拉滨、环磷酰胺、托珠单抗）有过敏史、超敏反应、不耐受或禁忌症的受试者；或对β-内酰胺类抗生素过敏的受试者；或有严重过敏反应史的受试者。 2. 既往接受过任何CAR-T治疗或BCMA靶向治疗的受试者。 3. 在单采前规定时间内接受过以下抗多发性骨髓瘤（抗MM）治疗的受试者： * 4周内或5个半衰期内（以较长者为准）接受过小分子靶向治疗 * 4周内或2个半衰期内（以较长者为准）接受过大分子药物治疗 * 2周内接受过细胞毒性治疗或蛋白酶体抑制剂 * 1周内接受过免疫调节药物治疗 * 1周内接受过放疗 4. 在单采前4周内接受过任何研究性药物，或同时参加另一项临床研究的受试者（以下情况除外：参加观察性、非干预性临床研究的受试者，或处于干预性临床研究随访期的受试者）。 5. 在单采前12周内接受过自体造血干细胞移植（ASCT），或既往接受过异基因干细胞移植（无时间限制）的患者。 6. 在CART-BCMA单采前4周内接受过活疫苗或减毒疫苗的受试者。 注：允许通过注射方式接种季节性流感灭活病毒疫苗；但不允许使用鼻内减毒活流感疫苗。 7. 在单采前7天内接受过以下任何治疗，或经研究者判断在研究期间需要长期接受此类治疗的受试者： * 单采前7天内累积使用相当于≥ 70 mg泼尼松的皮质类固醇，或经研究者判断在研究期间长期接受治疗剂量的皮质类固醇 * 免疫抑制治疗 * 移植物抗宿主病治疗 * 中枢神经系统（CNS）预防性治疗 8. 既往治疗引起的毒性反应（包括周围神经病变）未完全缓解或未稳定至1级（根据NCI-CTCAE v5.0），但研究者判断不影响患者安全接受治疗的情况除外（如脱发）。 9. 任何临床显著的既往或当前中枢神经系统疾病史，如精神状态改变、精神病、痴呆、神经认知、神经退行性或神经炎症性疾病（如阿尔茨海默病、帕金森病、多发性硬化症）、癫痫、惊厥、偏瘫、失语、卒中、蛛网膜下腔出血或其他中枢神经系统出血，以及严重创伤性脑损伤。对于有此类中枢神经系统改变病史的受试者，必须在给药前至少完全恢复1年。 10. 存在脑膜、脑干、脊髓转移和/或压迫，或活动性中枢神经系统转移；或经磁共振成像（MRI）或计算机断层扫描（CT）证实疑似多发性骨髓瘤（MM）累及中枢神经系统或脑膜。 11. 经MRI或CT证实疑似MM累及中枢神经系统或脑膜，或存在其他活动性中枢神经系统疾病。 12. 筛选时患有浆细胞白血病、华氏巨球蛋白血症、POEMS综合征（多发性神经病、器官肿大、内分泌病、单克隆蛋白、皮肤改变）或淀粉样变性的患者。 13. 心脏疾病：当前心力衰竭（纽约心脏协会[NYHA]分级≥II级，附录2）；研究者判定的严重心脏疾病；单采前≤6个月发生心肌梗死；单采前≤3个月发生不稳定型心绞痛、严重心律失常（由研究者判定）或接受冠状动脉旁路移植术（CABG）。 14. 高血压控制不佳（收缩压>160 mmHg和/或舒张压>100 mmHg），或有高血压危象或高血压脑病史。 15. 在单采前4周内接受过大手术（诊断性操作或活检除外）或血浆置换，或预计在研究期间接受大手术的患者。注：计划在局部麻醉下进行手术操作的患者可参加研究。后凸成形术或椎体成形术不被视为大手术。 16. 目前正在接受溶栓、抗凝或抗血小板治疗的受试者。 17. 需要静脉注射抗生素或住院治疗的感染受试者。 18. 活动性乙型肝炎受试者；丙型肝炎病毒（HCV）抗体阳性且HCV RNA阳性的受试者；人类免疫缺陷病毒（HIV）抗体阳性的受试者；梅毒筛查抗体阳性的受试者； a) 非活动性/无症状携带者、慢性或活动性HBV感染者，若符合以下标准可入组：筛选时HBV脱氧核糖核酸（DNA）< 500 IU/mL（或2500 copies/mL）。 19. 妊娠或哺乳期女性。 20. 诊断为其他侵袭性恶性肿瘤或接受过治疗者，多发性骨髓瘤除外，但以下情况除外：已手术切除的非黑色素瘤皮肤癌、已治愈的宫颈原位癌、局限性前列腺癌、低分期膀胱癌、乳腺导管原位癌，或入组前2年内无复发且未接受治疗的恶性肿瘤。 21. 研究者认为因任何临床或实验室异常或其他原因不适合参加本临床研究的受试者。
Inclusion Criteria:
1. Age above 18 years old (inclusive), regardless of gender.
2. Patients with multiple myeloma who have received at least three lines of treatment for multiple myeloma and have failed at least after treatment with proteasome inhibitors and immunomodulators; At least one complete cycle of each line of therapy, unless the best response to that therapy was documented as progressive disease (PD) (according to the 2016 published IMWG criteria for efficacy evaluation, Appendix 4); Patients must have PD records during or within 12 months after the last treatment or no response (no MR or better response) within 60 days after the last treatment.
3. The presence of measurable lesions at screening was defined as any of the following:
* Serum M protein ≥ 1 g/dL (≥ 10 g/L)
* Urinary M-protein level ≥ 200 mg/24 hours
* Serum free light chains (FLC): abnormal serum FLC ratio (\< 0.26 or \> 1.65) with involved FLC ≥ 10 mg/dL (100 mg/L)
4. ECOG Performance Status (Appendix 1) of 0-1.
5. Expected survival time ≥ 3 months.
6. Meets the following criteria prior to mononuclear cell apheresis:
Hematology
* Absolute count of lymphoid cells ≥ 0.5×109/L \[Granulocyte colony-stimulating factor (G-CSF) is allowed, but this supportive treatment shall not be received by the test subjects within 7 days before laboratory tests during the screening period\];
* Absolute neutrophil count ≥ 1.0 ×109/L \[Granulocyte colony-stimulating factor (G-CSF) is allowed, but the subjects shall not receive this supportive treatment within 7 days before laboratory tests during the screening period\];
* Platelet count ≥ 50×109/L (subjects must not receive blood transfusion support within 7 days before the screening laboratory test);
* Hemoglobin ≥ 8.0 g/dL (recombinant human erythropoietin is allowed) \[subjects have not received red blood cells (RBCS) within 7 days prior to screening laboratory testing\]; Heart
* Ejection function: Left ventricular ejection fraction (LVEF) ≥ 50% Lungs
* Oxygen saturation: A blood oxygen saturation of ≥ 91% on non-oxygen therapy Kidneys
* Creatinine clearance (CrCl) or glomerular filtration rate (GFR) (Cockcroft-Gault formula) ≥ 30 mL/min Liver
* Total bilirubin (serum) ≤ 1.5 × ULN Patients with Gilbert's disease and a serum bilirubin level of more than 1.5 × ULN could be enrolled after approval from the sponsor
* AST and ALT ≤ 3× ULN Clotting
* PT ≤ 1.5× ULN, APTT ≤ 1.5×ULN, INR ≤ 1.5×ULN
7. Peripheral venous access can meet the requirements of apheresis and intravenous infusion.
8. Subjects agreed to use a reliable contraceptive method for contraception from the time they signed the informed consent form until 1 year after infusion. These include, but are not limited to: abstinence, vasectomy in men, and an implantable progestin-based contraceptive that suppresses ovulation; Intrauterine contraceptive devices; Hormone-releasing intrauterine devices; Sexual partner sterilization; Copper intrauterine devices, proper use of combined hormonal contraceptives that have been shown to inhibit ovulation; Progestin-based contraceptives that inhibit ovulation. Female subjects should be at the same time commitment to lose after 1 year not to donate eggs (eggs, oocyte) used for assisted reproduction.
9. They should voluntarily participate in the clinical trial and sign the informed consent.
Exclusion Criteria:
1. Subjects with a known history of allergy, hypersensitivity, intolerance, or contraindication to any component of CART-BCMA or drugs that may be used in the study (including fludarabine, cyclophosphamide, tocilizumab); or subjects allergic to beta-lactam antibiotics; or subjects with a history of severe allergic reactions.
2. Subjects who have previously received any CAR-T therapy or BCMA-targeted therapy.
3. Subjects who have received the following anti-multiple myeloma (anti-MM) treatments within the specified time frame before apheresis:
* Small-molecule targeted therapy within 4 weeks or five half-lives, whichever was longer
* Macromolecular drug therapy within 4 weeks or 2 half-lives (whichever is longer)
* Cytotoxic therapy or proteasome inhibitor within 2 weeks
* Immunomodulatory drug therapy within 1 week
* Radiotherapy within 1 week
4. Subjects who have received any investigational drug within 4 weeks prior to apheresis or are concurrently participating in another clinical study (except for the following: subjects participating in observational, non-interventional clinical studies, or those in the follow-up period of an interventional clinical study).
5. Patients who have received autologous hematopoietic stem cell transplantation (ASCT) within 12 weeks prior to apheresis or have previously received allogeneic stem cell transplantation (with no time limit).
6. Subjects who have received live vaccines or attenuated vaccines within 4 weeks prior to CART-BCMA apheresis.
Note: Administration of inactivated viral vaccines for seasonal influenza via injection is permitted; however, intranasal attenuated live influenza vaccines are not permitted.
7. Subjects who have received any of the following treatments within 7 days prior to apheresis, or are judged by the investigator to require long-term receipt of such treatments during the study:
* Cumulative corticosteroids use equivalent to ≥ 70 mg prednisone within 7 days prior to apheresis, or long-term receipt of therapeutic-dose corticosteroids during the study as judged by the investigator
* Immunosuppressive therapy
* Graft-versus-host disease therapy
* Central nervous system (CNS) prophylactic therapy
8. Toxicities resulting from previous treatments (including peripheral neuropathy) have not fully resolved or stabilized to Grade 1 (per NCI-CTCAE v5.0), except for those judged by the investigator to not affect the patient's safe receipt of treatment (e.g., alopecia).
9. Any clinically significant past or current history of CNS disorders, such as altered mental status, psychosis, dementia, neurocognitive, neurodegenerative, or neuroinflammatory diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis), epilepsy, seizures, hemiplegia, aphasia, stroke, subarachnoid hemorrhage or other CNS hemorrhage, and severe traumatic brain injury. For subjects with history of such CNS alterations, they must have fully recovered at least 1 year before administration.
10. Presence of meningeal, brainstem, spinal cord metastasis and/or compression, or active CNS metastasis; or suspected involvement of the CNS or meninges by multiple myeloma (MM), confirmed by magnetic resonance imaging (MRI) or computed tomography (CT).
11. Suspected involvement of the CNS or meninges by MM (confirmed by MRI or CT), or presence of other active CNS diseases.
12. Patients with plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes), or amyloidosis at screening.
13. Cardiac diseases: Current heart failure (New York Heart Association \[NYHA\] classification ≥ Class II, Appendix 2); severe cardiac diseases as determined by the investigator; myocardial infarction occurring ≤ 6 months before apheresis; unstable angina pectoris, severe arrhythmia (as judged by the investigator), or coronary artery bypass grafting (CABG) performed ≤ 3 months before apheresis.
14. Poorly controlled hypertension (systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 100 mmHg), or a history of hypertensive crisis or hypertensive encephalopathy.
15. Patients who have undergone major surgery (other than diagnostic procedures or biopsies) or plasmapheresis within 4 weeks before apheresis or are expected to undergo major surgery during the study. Note: Patients scheduled for surgical procedures under local anesthesia may participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery.
16. Subjects currently receiving thrombolytic, anticoagulant, or antiplatelet therapy.
17. Subjects with infections requiring intravenous antibiotic administration or hospitalization.
18. Subjects with active hepatitis B; subjects positive for hepatitis C virus (HCV) antibody and positive for HCV RNA; subjects positive for human immunodeficiency virus (HIV) antibody; subjects positive for syphilis screening antibody;
a) Non-active/asymptomatic carrier, chronic, or active HBV-infected subjects may be enrolled if they meet the following criteria: HBV deoxyribonucleic acid (DNA) \< 500 IU/mL (or 2500 copies/mL) at screening.
19. Pregnant or lactating women.
20. Subjects diagnosed with or treated for other invasive malignant tumors except multiple myeloma, except for the following cases: non-melanoma skin cancer that has been surgically removed, cured cervical carcinoma in situ, localized prostate cancer, low-stage bladder cancer, ductal carcinoma in situ of the breast, or malignant tumors with no recurrence and no treatment within 2 years before enrollment.
21. Subjects deemed by the investigator to be unsuitable for participation in this clinical study due to any clinical or laboratory abnormalities or other reasons.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：The safety of CART-BCMA in patients with relapsed or refractory multiple myeloma. · Number and percentage of participants experiencing treatment-emergent adverse events (AEs) and serious adverse events (SAEs) after CART-BCMA cell infusion. AEs will be graded according to CTCAE version 5.0 · Day 1 to Day 8, Day 14, Day 21, Day 28, Day 60, Day 90, Day 120, Day 180, Day 270, Day 360, and every 90 days from Day 450 to Day 720 after CART-BCMA cell infusion；Incidence of Dose-Limiting Toxicities (DLTs) · Number and percentage of participants experiencing dose-limiting toxicities (DLTs) during the DLT evaluation period following CART-BCMA cell infusion. DLTs will be defined according to protocol-specified criteria and graded using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 · From Day 1 to Day 28 after CART-BCMA cell infusion (DLT evaluation period)
次要终点：The overall response rate (ORR, at least PR or better) per IMWG 2016 Criteria；Complete Response (CR) or Stringent Complete Response (sCR) Rate per IMWG 2016 Criteria；Very Good Partial Response (VGPR) or Better Rate per IMWG 2016 Criteria；Time to First Documented Response (≥PR) per IMWG 2016 Criteria；Duration of Response per IMWG 2016 Criteria；Progression-Free Survival per IMWG 2016 Criteria；Overall Survival (OS)
靶向BCMA的嵌合抗原受体T细胞注射液（CART-BCMA）剂量水平：0.5×10e7细胞/Kg
一项1b期临床试验，旨在评估靶向BCMA的CAR-T细胞疗法在泰国复发或难治性多发性骨髓瘤患者中的安全性和疗效。
A Phase 1b clinical trial to evaluate the safety and efficacy of BCMA-targeted CAR T-cell therapy in Thai patients with relapsed or refractory multiple myeloma.
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