肿瘤细胞治疗研究
英文原题：Study of AIC100 CAR T Cells in Relapsed/Refractory Thyroid Cancer
⚠ 该试验的登记信息已有 18 个月未更新， 页面上显示的「进行中（不再招募）」可能已经失效。联系研究中心之前，建议先到 ClinicalTrials.gov 核对登记原文的最新状态与联系方式。
这是一项 I 期注册临床试验，评估 CAR-T 细胞治疗甲状腺癌的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 70 例。试验地点：美国 · 杜阿尔特、芝加哥、纽约、休斯顿（共 4 个中心）。登记号：NCT04420754。
不限性别 · ≥ 18 Years
纳入标准：
1. 愿意且能够参加研究并提供书面知情同意。
2. 签署知情同意书当天年龄≥18岁。
3. 患者须符合以下任一甲状腺癌诊断，并在淋巴清除化疗（LDC）前提供可用的新鲜或存档活检样本：
1. 任一分期的BRAF野生型未分化甲状腺癌，包括新诊断患者。
2. BRAF突变型未分化甲状腺癌，既往BRAF靶向治疗失败或无法耐受。
3. 低分化甲状腺癌，既往手术、放射性碘、化疗、放疗和/或靶向治疗失败。
4. 根据RECIST 1.1标准，CT或PET/PET-CT显示可测量疾病。
a. 筛查时无可测量疾病的未分化甲状腺癌患者，须在基线第-7天时有可测量疾病方可继续参加研究。
5. ECOG体能状态0–2。
6. 预期寿命>8周。
7. 肝、肾、骨髓、心脏及凝血功能总体充分，具体如下：
1. 估算肌酐清除率≥50 mL/min。
2. ALT和AST为正常或1级。注：LDC药物可能导致肝酶波动。
3. 血清总胆红素为正常或1级。注：LDC药物可能导致肝酶波动。
4. 血清白蛋白为正常或1级。筛查评估前2周内不得补充人血白蛋白。
5. 血流动力学稳定，左心室射血分数≥45%。
6. 血液学指标：
i. 无髓系生长因子支持至少2周时，ANC>1,000/μL。
ii. 筛查及单采时绝对淋巴细胞计数≥100/μL。
iii. 无血小板输注至少2周时，血小板计数≥50×1,000/μL。
iv. 未输注红细胞至少2周时，血红蛋白浓度>7 g/dL。
8. 白细胞单采或LDC前已满足既往癌症治疗的最低洗脱期；研究者判断患者能够安全接受该操作。
9. 已并入纳入标准第7条。
10. 有生育能力女性（定义为生理上可能妊娠者）须同意从入组/单采前至少30天起，直至AIC100 CAR T细胞输注后至少1年，使用1种高效避孕方法及另外1种有效避孕方法。
11. 有生育能力女性筛查时血清β-人绒毛膜促性腺激素妊娠试验阴性。
排除标准：
1. 妊娠或哺乳期女性。
2. 具有临床意义、活动性、未控制的全身感染。以下情况不作为排除标准：
1. HIV患者须在入组前接受有效抗逆转录病毒治疗≥4周；HIV病毒载量<400拷贝/μL；过去12个月无艾滋病相关机会性感染；CD4+细胞计数≥350个/μL。
2. 慢性乙肝病毒（HBV）感染者须接受抗病毒治疗，且HBV病毒载量低于检测限。
3. 慢性丙肝病毒（HCV）感染者须已完成治疗，且HCV病毒载量低于检测限。
3. 既往接受过研究性基因治疗或CAR T细胞治疗。
4. 存在活动性且具有临床意义的CNS疾病，如癫痫、卒中或有症状/未控制的脑转移。
5. 筛查前2年内有其他恶性肿瘤证据；非黑色素瘤皮肤原位癌、局部且已控制的前列腺癌、复发风险低且治疗充分的I期子宫癌，或结局相似的其他恶性肿瘤除外。
6. 已并入排除标准第2条。
7. 活动性自身免疫疾病（包括但不限于系统性红斑狼疮、干燥综合征、类风湿关节炎[RA]、银屑病、多发性硬化、炎症性肠病），且在资格确认前4周内需要免疫抑制治疗。
8. 患有严重慢性肾、肝、心、肺疾病，或研究者认为可能影响治疗、随访或评估的其他严重疾病，包括未控制且有临床意义的神经/精神疾病或代谢性疾病。
9. 需要长期使用每天>10 mg泼尼松或等效剂量的全身性皮质类固醇。
10. 对淋巴清除期间使用的化疗药物过敏，或已知对AIC100 CAR T细胞任何组分（包括辅料）过敏。
11. 筛查前4周内接种COVID-19疫苗。
12. 研究期间同时参加其他介入性临床研究。
1. 既往接受任何基因治疗或基因改造细胞治疗，包括CAR T细胞治疗。
2. 既往接受靶向ICAM-1的抗体、双特异性T细胞衔接器或抗体药物偶联物治疗者排除；但若在最近一次ICAM-1靶向治疗后进展或复发，免疫组化确认ICAM-1表达者除外。
Inclusion Criteria:
1. Willing and able to participate in the study and provide written informed consent
2. Be ≥ 18 years of age on the day of signing the Informed Consent Form
3. Patients must have thyroid cancer that meets one of the following diagnoses, and, prior to lymphodepleting chemotherapy (LDC), have an identified available fresh or archival biopsy sample:
1. Anaplastic Thyroid Cancer BRAF wild-type at any stage, including newly diagnosed
2. Anaplastic Thyroid Cancer BRAF mutant after failure of or inability to tolerate BRAF- specific therapy
3. Poorly Differentiated Thyroid Cancer that has failed any of the following treatments: surgery radioactive iodine, chemotherapy, radiation therapy, and/or targeted therapies
4. Measurable disease by Computed Tomography (CT) or Positron Emission Tomography (PET) PET/CT per RECIST v1.1
a. For ATC patients who do not have measurable disease at Screening, they are required to have measurable disease at Baseline Day -7 to proceed in the study.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
6. Life expectancy greater than 8 weeks
7. Overall adequate hepatic, renal, bone marrow, cardiac, and coagulation function, defined as the following:
1. Estimated creatinine clearance ≥ 50 mL/minute
2. Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST): normal or Grade 1. Note: Lymphodepleting Chemotherapy (LDC) agents can cause fluctuations in hepatic enzymes.
3. Serum total bilirubin: normal or Grade 1. Note: LDC agents can cause fluctuations in hepatic enzymes.
4. Serum albumin: normal or Grade 1. (human albumin supplementation is not allowed within 2 weeks prior to Screening assessment)
5. Hemodynamically stable and left ventricular ejection fraction ≥ 45%
6. Hematological parameters
i. Absolute neutrophil count \> 1000/μL without myeloid growth factor support for ≥ 2 weeks
ii. Absolute lymphocyte count ≥ 100/μL at screening and at apheresis
iii. Platelet count ≥ 50 × 1000/μL without platelet transfusion for ≥ 2 weeks
iv. Hemoglobin concentration \> 7 g/dL without red blood cell transfusion for ≥ 2 weeks
8. Has met the minimum washout time for previous cancer treatments before undergoing apheresis or LDC, and in the Investigator's judgement, the patient is able to safely undergo the procedure
9. (incorporated into inclusion criteria #7)
10. Females of reproductive potential (defined as all females physiologically capable of becoming pregnant) must agree to use 1 highly effective method of contraception and 1 additional effective method from at least 30 days before enrollment/apheresis and for at least 1 year after the infusion of AIC100 CAR T Cells.
11. Females of reproductive potential must have a negative serum beta-human chorionic gonadotropin pregnancy test result at Screening
Exclusion Criteria:
1. Women who are pregnant or breastfeeding
2. Clinically significant, active, uncontrolled, systemic infection; the following are not exclusionary:
1. Patients with Human immunodeficiency virus (HIV) must have been on effective antiretroviral therapy for ≥ 4 weeks prior to enrollment; must have an HIV viral load \< 400 copies/µL; no acquired immunodeficiency syndrome related opportunistic infections in the previous 12 months; and a CD4+ cell count ≥ 350 cells/µL
2. Patients with chronic hepatitis B virus (HBV) infection must be on antiviral therapy and have an HBV viral load below the limits of detection
3. Patients with chronic hepatitis C virus (HCV) infection must have completed therapy and have an HCV viral load below the limits of detection
3. Prior treatment with investigational gene therapy or CAR T cell therapy
4. Presence of active and clinically relevant central nervous system disorder such as epilepsy, stroke, or symptomatic or uncontrolled brain metastases
5. Evidence of another malignancy within 2 years prior to Screening (except in-situ non melanoma skin cancers, localized controlled prostate cancer, adequately treated Stage 1 uterine cancer that has a low risk of recurrence, or any other malignancies with similar outcome)
6. (incorporated into exclusion criteria #2)
7. Active autoimmune disease (including but not limited to systemic lupus erythematosus, Sjögren's Syndrome, rheumatoid arthritis (RA), psoriasis, multiple sclerosis, inflammatory bowel disease) requiring immunosuppressive therapy within 4 weeks prior to eligibility confirmation
8. Patients with severe chronic diseases of the kidney, liver, heart, lung; or any other serious illness that, in the opinion of the Investigator, may affect the patient's treatment, follow up, or assessments, including but not limited to uncontrolled clinically significant neurological or psychiatric disorders or metabolic diseases
9. Patients who need long-term use of systemic corticosteroids \> 10 mg/day prednisone or equivalent
10. Allergy to the chemotherapy drugs given during lymphodepletion or known hypersensitivity to any component of AIC100 CAR T Cells, including excipients
11. Receipt of a COVID-19 vaccine within 4 weeks before Screening
12. Concurrent participation in another interventional clinical study during participation in this study
1. Prior treatment with any gene therapy or genetically modified cell therapy, including CAR T cells
2. Prior treatment with ICAM-1 directed antibody, bispecific T cell engager, or antibody drug conjugate, unless there is confirmed ICAM-1 expression (by immunohistochemistry) after progression or relapse following most recent ICAM-1 directed treatment.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 overall Grade >=3 Adverse Events (AE) and Serious Adverse Events (SAE) · The number of Grade 3, 4 and 5 AEs and SAEs that occur throughout the study. · Up to 1 year post-infusion；Incidence of anticipated AIC100 CAR T Cell related AEs, SAEs and adverse events of special interest (AESI) (infusion-related reactions, CRS, ICANS, HLH/MAS, TLS, new malignancies, AEs leading to death and DLT AEs) · The number of CAR T related adverse events that occur throughout the study, including AESIs, infusion-related reactions, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), tumor lysis syndrome (TLS) and new malignancies. · Up to 15 years post-infusion；Determine recommended phase 2 dose · The recommended phase 2 dose will be determined through the dose escalation process · Up to 1 year post infusion
次要终点：Assessment of presence and frequency of AIC100 CAR T cells in peripheral blood and tumor samples (when available)
AIC100 CAR T细胞剂量水平-1（固定剂量）：1×10^6个CAR T细胞。
AIC100 CAR T细胞剂量水平1（固定剂量）：1×10^7个CAR T细胞。
AIC100 CAR T细胞剂量水平2（固定剂量）：1×10^8个CAR T细胞。
AIC100 CAR T细胞剂量水平3（固定剂量）：5×10^8个CAR T细胞。
AIC100 CAR T细胞剂量水平2.5（固定剂量）：2.5×10^8个CAR T细胞。根据持续收集的安全性和疗效数据，必要时可评估队列2.5这一中间降阶剂量。
AIC100 CAR T细胞剂量水平4（固定剂量）：7.5×10^8个CAR T细胞。根据持续收集的安全性和疗效数据，必要时可评估拟定的队列4递增剂量。
AIC100 CAR T细胞剂量水平5（固定剂量）：1×10^9个CAR T细胞。根据持续收集的安全性和疗效数据，必要时可评估拟定的队列5递增剂量。
本研究旨在评估AIC100嵌合抗原受体（CAR）T细胞治疗复发/难治性低分化甲状腺癌及未分化甲状腺癌（包括新诊断患者）的安全性和耐受性，并确定II期推荐剂量。
The purpose of this study is to assess the safety and tolerability and determine the recommended Phase 2 dose of AIC100 Chimeric Antigen Receptor (CAR) T cells in patients with relapsed/refractory poorly differentiated thyroid cancer and anaplastic thyroid cancer, including newly diagnosed.
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