肿瘤细胞治疗研究
英文原题：A Clinical Study Evaluating the Safety and Preliminary Efficacy of Universal Allogeneic CAR T-cell Therapy Targeting CD19 and BCMA(QT-019C)in Patients With Refractory Primary Immune Thrombocytopenia
A Clinical Study Evaluating the Safety and Preliminary Efficacy of Universal Allogeneic CAR T-cell Therapy Targeting CD19 and BCMA(QT-019C)in Patients With Refractory Primary Immune Thrombocytopenia
这是一项早期 I 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：尚未开始招募。计划入组 27 例。试验地点：中国 · 武汉（共 1 个中心，其中中国 1 个）。登记号：NCT07416032。
不限性别 · ≥ 18 Years 且 ≤ 75 Years
纳入标准：
* 1. 年龄≥18岁且≤75岁，性别不限。
* 2. 临床诊断为原发性免疫性血小板减少症不少于6个月，在研究治疗开始前15天内进行的两次独立检测中血小板计数< 30×10^9/L，两次检测之间至少间隔7天。
* 3. 存在任何抗血小板糖蛋白自身抗体（GPIb/GPIX/GPIIb/GPIIIa/GMP140）阳性。
* 4. 符合难治性ITP标准：既往接受过一线和/或二线ITP治疗（一线治疗包括糖皮质激素或免疫球蛋白；二线治疗包括血小板生成素受体激动剂（如艾曲泊帕、罗米司亭）、利妥昔单抗、脾切除等），但无效（治疗后血小板计数<30×10^9/L，或血小板计数升高不足基线值的两倍，或存在出血），或初始反应后复发或停药后难以维持。
* 5. 筛选期重要器官功能基本正常：
1. 超声心动图提示射血分数>50%，心电图无明显异常；
2. 肌酐清除率（CrCl）（Cockcroft-Gault公式）>30 mL/min；
3. 丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）<3.0倍正常值上限（ULN）；
4. 总胆红素（TBIL）和碱性磷酸酶（AKP或ALP）<2.0倍ULN（Gilbert综合征<3.0倍UN）；
5. 绝对淋巴细胞计数（ALC）>0.5×10^9；绝对中性粒细胞计数（ANC）>1×10^9；血红蛋白（Hb）>60g；
6. 血氧饱和度>92%。
* 6. 有生育能力的女性参与者和育龄女性伴侣的男性参与者必须在研究治疗期间及之后至少12个月内采用医学上认可的避孕措施或禁欲；育龄女性参与者在研究入组前7天内血清HCG检测必须为阴性，且不得处于哺乳期。
* 7. 自愿参加本临床研究，签署知情同意书，依从性良好，并配合随访。
排除标准：
* 1. 由骨髓增生异常综合征、脾功能亢进、自身免疫性疾病、早期再生障碍性贫血、非典型再生障碍性贫血和血栓性血小板减少性紫癜等原因引起的继发性血小板减少症。
* 2. 筛选期骨髓检查结果提示骨髓纤维化MF>2（骨髓纤维化欧洲专家共识评分标准，Thiele等，2005）或骨髓检查提示除ITP外存在其他导致血小板减少的原发疾病。
* 3. 有以下任何心脏病史：
1. NYHA II级或IV级充血性心力衰竭；
2. 签署ICF前6个月内发生心肌梗死，或曾接受冠状动脉旁路移植术（CABG）或冠状动脉支架植入术；
3. 具有临床意义的室性心律失常，或不明原因晕厥史（血管迷走性或脱水所致者除外）；
4. 严重非缺血性心肌病病史。
* 4. 既往接受过基因修饰细胞治疗（如 TCR-T、CAR-T、CAR-NK 等）的患者。
* 5. 乙肝表面抗原（HBsAg）阳性或乙肝核心抗体（HBcAb）阳性且外周血 HBV DNA 超过检测上限的患者；丙肝病毒（HCV）抗体阳性且外周血 HCV RNA 阳性的患者；人类免疫缺陷病毒（HIV）抗体阳性的患者；以及梅毒检测阳性的患者。
* 6. 研究开始前接受过以下药物治疗的受试者将排除：
1. B 细胞及抗体分泌细胞（ASC）清除治疗：
i. 筛选前 3 个月内接受过抗 CD20 单克隆抗体治疗（如利妥昔单抗）的受试者将排除。若该治疗发生在筛选前 3 个月以上但不超过 6 个月，且外周血 CD19⁺ B 细胞绝对计数高于正常值下限（由当地或中心实验室测定），经研究者和申办方医学总监（或指定代表）确认后可允许入组。
ii. 既往同时接受过 CD19 靶向和 BCMA 靶向治疗的受试者将排除。筛选前 6 个月内接受过 CD19 靶向或 BCMA 靶向治疗（任一种）的受试者也将排除。若该治疗发生在筛选前 6 个月以上，且外周血 CD19⁺ B 细胞绝对计数高于正常值下限（由当地或中心实验室测定），经研究者和申办方医学总监（或指定代表）确认后可允许入组。
iii. 筛选前 2 周内使用或调整过 BTK 和 SyK 抑制剂剂量的受试者应排除。若筛选前剂量已稳定 ≥ 2 周，则可纳入。
2. 筛选前 2 周内使用或调整过 TPO-RA 治疗的受试者应排除。但筛选前稳定剂量超过 2 周者可继续治疗。
3. 筛选前 4 周内使用过 IVIG 或接受过血浆置换的受试者应排除。
4. 淋巴细胞清除前 2 周内使用过免疫抑制剂（如环磷酰胺、霉酚酸酯（MMF）、硫唑嘌呤和甲氨蝶呤）的受试者将排除。
* 7. 筛选前2周内使用过泼尼松>10 mg/天或进行过剂量调整的受试者。入组时可接受相当于泼尼松≤10 mg/天的口服糖皮质激素治疗，前提是入组前剂量已稳定至少2周。
* 8. 筛选前6个月内有症状性深静脉血栓或肺栓塞病史的受试者，或目前需要抗凝治疗的受试者。
* 9. 过去5年内有任一器官系统恶性肿瘤病史（除预后良好的肿瘤如局限性皮肤基底细胞癌、宫颈原位癌、乳腺导管原位癌、滤泡性或乳头状甲状腺癌等外）的受试者，无论是否有局部复发或转移的证据；或已知合并危及生命的疾病。
* 10. 筛选前30天内有任何活动性感染或需要全身抗感染治疗的任何感染的受试者。
* 11. 研究者认为可能使受试者处于风险、干扰治疗依从性、研究实施或结果的任何已知因素、疾病或临床相关医学状况或手术情况。
Inclusion Criteria:
* 1\. Participants aged ≥18 years and ≤75 years, regardless of gender.
* 2\. Clinically diagnosed with primary immune thrombocytopenia for no less than 6 months, with platelet counts \< 30×10\^9/L in two separate tests conducted within 15 days before the initiation of study treatment, with at least 7 days between the tests.
* 3\. Presence of any anti-platelet glycoprotein autoantibody (GPIb/GPIX/GPIIb/GPIIIa/GMP140) positive.
* 4\. Meet the criteria for refractory ITP: previously received first-line and/or second-line ITP treatment (first-line treatment includes corticosteroids or immunoglobulins; second-line treatment includes thrombopoietin receptor agonists (such as eltrombopag, romiplostim), rituximab, splenectomy, etc.), but ineffective (post-treatment platelet count \<30×10\^9/L, or platelet count increase less than twice the baseline value, or presence of bleeding), or relapse after initial response or difficult to maintain after discontinuation.
* 5\. Important organ functions are basically normal during the selection period:
1. Echocardiogram indicates ejection fraction \>50%, ECG shows no significant abnormalities;
2. Creatinine clearance (CrCl) (Cockcroft-Gault formula) \>30 mL/min;
3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<3.0x the upper limit of normal (ULN);
4. Total bilirubin (TBIL) and alkaline phosphatase (AKP or ALP) \<2.0x ULN (Gilbert's syndrome \<3.0x UN);
5. Absolute lymphocyte count (ALC) \>0.5x10\^9; absolute neutrophil count (ANC) \>1x10\^9; hemoglobin (Hb) \>60g;
6. Oxygen saturation \>92%.
* 6\. Female participants of childbearing potential and male participants who are partners of women of childbearing age must use medically accepted contraceptive measures or abstain for at least 12 months during and after the study treatment; female participants of childbearing age must have a negative serum HCG test within 7 days before study enrollment and must not be breastfeeding.
* 7\. Volunteer to participate in this clinical study, sign informed consent, demonstrate good compliance, and cooperate with follow-up.
Exclusion Criteria:
* 1\. Secondary thrombocytopenia caused by myelodysplastic syndromes, splenic hyperfunction, autoimmune diseases, early aplastic anemia, atypical aplastic anemia, and thrombotic thrombocytopenic purpura, among other causes.
* 2\. Bone marrow examination results during the screening phase indicate bone marrow fibrosis MF\>2 (European expert consensus scoring criteria for bone marrow fibrosis, Thiele et al., 2005) or the bone marrow examination suggests the presence of other primary conditions causing thrombocytopenia aside from ITP.
* 3\. History of any of the following heart diseases:
1. NYHA class II or IV congestive heart failure;
2. Myocardial infarction within 6 months before signing the ICF, or having undergone coronary artery bypass grafting (CABG) or coronary artery stent implantation;
3. Clinically significant ventricular arrhythmias or a history of unexplained syncope (excluding cases caused by vasovagal or dehydration);
4. History of severe non-ischemic cardiomyopathy.
* 4\. Patients who have previously received gene-modified cell therapies such as TCR-T, CAR-T, CAR-NK, etc.
* 5\. Patients who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA levels exceeding the upper limit of detection; those who are positive for hepatitis C virus (HCV) antibodies and have positive peripheral blood HCV RNA; those who are positive for human immunodeficiency virus (HIV) antibodies; and those who test positive for syphilis.
* 6\. Subjects who have received the following drug treatments before the start of the study will be excluded:
1. B-cell and antibody-secreting cell (ASC) depletion therapy:
i. Subjects who have received anti-CD20 monoclonal antibody treatment (such as rituximab) within 3 months before screening will be excluded. If such treatment occurred more than 3 months but not more than 6 months before screening, and if the absolute count of peripheral blood CD19⁺ B cells is above the lower limit of normal (as determined by local or central laboratory), then enrollment may be allowed after confirmation by the investigator and the medical director of the sponsor (or designated representative).
ii. Subjects who have previously received simultaneous CD19-targeting and BCMA-targeting treatments will be excluded. Subjects who have received CD19-targeting or BCMA-targeting treatment (either one) within 6 months before screening will also be excluded. If such treatment occurred more than 6 months before screening, and if the absolute count of peripheral blood CD19⁺ B cells is above the lower limit of normal (as determined by local or central laboratory), then enrollment may be allowed after confirmation by the investigator and the medical director of the sponsor (or designated representative).
iii. Subjects who have used or adjusted the dosage of BTK and SyK inhibitors within 2 weeks before screening should be excluded. If the dosage has been stable for ≥ 2 weeks before screening, then they may be included.
2. Subjects who have used or adjusted TPO-RA treatment within 2 weeks before screening should be excluded. However, those who have been on a stable dose for more than 2 weeks before screening may continue treatment.
3. Subjects who have used IVIG or undergone plasma exchange within 4 weeks before screening should be excluded.
4. Subjects who have used immunosuppressants (such as cyclophosphamide, mycophenolate mofetil (MMF), azathioprine, and methotrexate) within 2 weeks before lymphocyte depletion will be excluded.
* 7\. Subjects who have used prednisone \> 10 mg/day or have had dosage adjustments within 2 weeks before screening. Oral glucocorticoid treatment equivalent to ≤ 10 mg/day of prednisone is acceptable at enrollment, provided the dosage has been stable for at least 2 weeks before enrollment.
* 8\. Subjects with a history of symptomatic deep vein thrombosis or pulmonary embolism within 6 months before screening, or who currently require anticoagulation therapy.
* 9\. Subjects with a history of any organ system malignancy (except well-prognosed tumors such as localized basal cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of the breast, follicular or papillary thyroid carcinoma, etc.) within the past 5 years, regardless of whether there is evidence of local recurrence or metastasis; or known concomitant life-threatening diseases.
* 10\. Subjects with any active infection or any infection requiring systemic anti-infective treatment within 30 days before screening.
* 11\. Any known factors, diseases, or clinically relevant medical conditions or surgical situations that the investigator believes may place the subjects at risk, interfere with treatment compliance, study implementation, or outcomes.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 number and severity of dose-limiting toxicity (DLT)events · DLT will be graded according to the NCl Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, andthe ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with lmmune Effector Cells. · Within 28 Days After QT-019C infusion；The total number, incidence, and severity of Adverse Events(AEs) · The total number, incidence, and severity of Adverse Events(AEs) · Within 28 Days After QT-019C infusion
次要终点：Clinical response of relapsed/refractory ITP
本研究包括两个阶段：剂量递增和剂量扩展。剂量递增将遵循3+3设计，该阶段将纳入10至21名受试者。将设置四个剂量组（A组、B组、C组和D组），QT-019C的给药剂量从1×10^6 cells/kg（A组）开始。受试者将接受定期检查，以评估治疗的安全性和耐受性，以及PK、PD和初步疗效数据。剂量递增完成后，安全审查委员会（SRC）将决定是结束研究还是选择一个剂量水平或范围作为剂量扩展研究的推荐剂量（RD）。该阶段将纳入6名受试者，以进一步评估QT-019C的安全性和早期疗效。所有受试者将完成长达24个月的随访。
这是一项研究者发起的试验，旨在评估通用型同种异体抗CD19/BCMA CAR T细胞（QT-019C）在难治性原发性免疫性血小板减少症患者中的安全性和有效性。
This is an investigator-initiated trial to evaluate the safety and efficacy of universal allogeneic anti-CD19/BCMA CAR T-cells(QT-019C) in Patients With Refractory Primary Immune Thrombocytopenia.
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