肿瘤细胞治疗研究
英文原题：Phase 1 Dose Escalation and Expansion Study of TROP2 CAR Engineered IL15-transduced Cord Blood-derived NK Cells in Patients With Advanced Solid Tumors (TROPIKANA)
这是一项 I 期注册临床试验，评估 NK 细胞治疗实体瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 54 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT06066424。
不限性别 · ≥ 18 Years
纳入标准：
患者必须符合以下标准才能进入研究：
1. 参与者必须年满18岁。
2. 参与者必须愿意且能够提供知情同意。
3. 在剂量递增阶段，参与者必须具有组织学记录的局部晚期、不可切除或转移性实体瘤，且在接受已知可延长生存的局部标准治疗后复发或进展，或没有可用的标准治疗，或拒绝此类治疗。
4. 在剂量扩展队列1中，患者必须具有组织学记录的局部晚期、不可切除或转移性NSCLC。参与者应在晚期阶段接受过至少两线治疗。患有转移性PD-L1阳性疾病的参与者预计应接受过既往免疫治疗，除非有禁忌症。具有可操作改变（例如EGFR、ALK、BRAF V600E、RET、ROS1、MET、NTRK）的参与者应接受过既往FDA批准的靶向治疗。
5. 在剂量扩展队列2中，患者必须具有组织学记录的局部晚期或转移性HER2阴性/HER2低表达乳腺癌（IHC 0、IHC 1或IHC 2+/原位杂交阴性）乳腺癌。参与者应在晚期阶段接受过至少一线治疗。患有转移性TNBC且PD-L1阳性的参与者预计应接受过既往免疫治疗，除非有禁忌症。患有HR阳性疾病的参与者预计应在转移或辅助阶段接受过既往细胞周期蛋白依赖性激酶4/6抑制剂。
6. 参与者肿瘤必须通过MDACC临床实验室改进（CLIA）实验室（临床实验室或临床转化单元；附录8）的IHC检测显示TROP2表达为2+或3+。
7. 参与者必须具有东部肿瘤协作组（ECOG）体能状态评分为0或1（附录3）。
8. 预期寿命≥3个月。
9. 女性参与者如果符合以下至少一项条件，则有资格参与：
1. 不是附录2中定义的育龄女性（WOCBP）或
2. 同意在研究治疗期间及TROP2-CAR-NK细胞输注后6个月内遵循附录2中避孕指南的WOCBP。
怀孕或怀疑怀孕的女性参与者必须立即通知其医生。怀孕的女性参与者将被退出研究。
10. 男性参与者必须同意在研究治疗期间及TROP2-CAR-NK细胞输注后6个月内遵循附录2中避孕指南。使伴侣怀孕或怀疑自己已使伴侣怀孕的男性参与者必须立即通知其医生。
11. 有生育能力的女性（WOCBP）必须在开始淋巴细胞清除性化疗前72小时内尿妊娠试验阴性。如果WOCBP的尿妊娠试验结果无法确认为阴性，则需要进行血清（β-人绒毛膜促性腺激素[β-hCG]）妊娠试验。
12. 根据实体瘤疗效评价标准（RECIST）v1.1（附录3），受试者必须具有可测量病灶。
13. 受试者在开始淋巴细胞清除性化疗前10天内必须具有以下定义的充分器官功能：
表1. 充分器官功能实验室值 系统功能 检测 实验室值 血液学 ANC ≥1500/µL 血小板 ≥100,000/µL 血红蛋白 ≥9.0 g/dLa 肾脏 肌酐 或 按Cockcroft-Gault公式计算的CrCl ≤1.5 × ULNb
肌酐 >1.5 × ULNb 的患者 ≥45 mL/min 肝脏 总胆红素 ≤1.5 × ULN 或 总胆红素水平 >1.5 × ULN 的患者直接胆红素 ≤ ULN AST和ALT ≤2.5 × ULN（肝转移患者 ≤5 × ULN） 凝血 PT/INR aPTT ≤1.5 × ULN，除非受试者正在接受抗凝治疗，只要PT或aPTT在抗凝剂预期用途的治疗范围内
ALT=丙氨酸氨基转移酶；ANC=中性粒细胞绝对计数；aPTT=活化部分凝血活酶时间；AST=天冬氨酸氨基转移酶；CrCl=肌酐清除率；INR=国际标准化比值；PT=凝血酶原时间；ULN=正常值上限。
1. 必须在筛选检测前2周内不依赖促红细胞生成素且未输注浓缩红细胞的情况下满足标准。受试者可正在接受稳定剂量的促红细胞生成素（≥约3个月）。
2. 血清肌酐和CrCl应按机构标准进行解读和计算。
14. 左心室射血分数 >50%。
15. 充分的呼吸储备，定义为呼吸困难0级或1级，且室内空气中血氧饱和度 >92%。
16. 允许既往接受过TROP2靶向治疗。
17. 愿意按研究要求接受强制性血液采集和活检。
18. 愿意签署方案PA17-0483长期随访的知情同意书。
19. 愿意在TROP2-NK细胞输注后的前2周内停留在研究机构2小时车程内（约100英里半径范围内）。
排除标准
符合以下任一标准的受试者将不符合资格：
1. 妊娠、哺乳，或预期在研究预计期间内（从筛选访视开始至TROP2-CAR-NK细胞输注后6个月）怀孕。
2. 在开始淋巴细胞清除性化疗前2周或5个半衰期内（以较短者为准）接受过全身性抗癌治疗。对于接受单克隆抗体治疗的受试者，必须在开始淋巴细胞清除性化疗前至少已过3周。已进入研究性研究随访阶段的受试者可以参加，只要距上次研究性药物末次给药后已过3周。
3. 受试者必须已从既往治疗导致的所有AE中恢复至≤1级或基线水平。患有≤2级神经病变、脱发或其他不相关AE的受试者，可由主要研究者（PI）/共同主要研究者（co-PIs）酌情判定为合格。如果受试者接受过大手术，则必须在开始淋巴细胞清除性化疗前从干预措施的毒性和/或并发症中充分恢复。
4. 在开始淋巴细胞清除性化疗前2周内接受过放疗。受试者必须已从所有放疗相关毒性中恢复，不需要皮质类固醇，且未发生过放射性肺炎。对于非CNS疾病的姑息性放疗（放疗≤2周），允许1周洗脱期。
5. 在TROP2-CAR-NK输注前6周内以及输注后至少24个月内接受过活疫苗。活疫苗的例子包括但不限于以下：麻疹、腮腺炎、风疹、水痘/带状疱疹（水痘）、黄热病、狂犬病、卡介苗和伤寒疫苗。季节性流感和COVID-19注射疫苗通常为灭活病毒疫苗，允许使用；然而，鼻内流感疫苗（如FluMist®）为减毒活疫苗，不允许使用。
6. 既往接受过CAR T或NK细胞或其他基因修饰T或NK细胞治疗。
7. 诊断为免疫缺陷或正在接受慢性全身性类固醇治疗（剂量超过每日10 mg泼尼松等效剂量）。
8. 有第二恶性肿瘤病史，除非已完成潜在治愈性治疗且2年内无恶性肿瘤证据。该时间要求不适用于成功接受皮肤基底细胞癌、皮肤鳞状细胞癌、浅表性膀胱癌、宫颈原位癌或其他原位癌根治性切除术的患者。
9. 已知活动性CNS转移和/或癌性脑膜炎。既往接受过脑转移治疗的患者如果已完成放疗、临床稳定，且在研究入组前至少2周内不需要类固醇治疗，则可以参加。
10. 在过去2年内需要全身治疗的活跃性自身免疫性疾病（即使用疾病修饰药物、皮质类固醇或免疫抑制药物）。允许进行替代治疗（例如，甲状腺素、胰岛素或针对肾上腺或垂体功能不全的生理性皮质类固醇替代治疗等）。
11. 有需要类固醇治疗的间质性肺病（ILD）病史，或当前患有肺炎/ILD。
12. 需要全身治疗的活跃性感染。
13. 已知的人类免疫缺陷病毒（HIV）感染。
14. 已知的活跃性或慢性乙型或丙型肝炎病毒感染。
15. 已知的活跃性结核病（结核分枝杆菌）病史。
16. 根据治疗研究者的意见，存在或当前有证据表明的任何可能混淆研究结果、干扰参与者在整个研究期间的参与、或不符合患者最佳利益的状况、治疗或实验室异常。
17. 已知的精神疾病或物质滥用障碍，会干扰对研究要求的配合。
18. 曾接受过同种异体组织/实体器官移植。
19. 在开始淋巴细胞清除化疗前12个月内有临床显著的心血管疾病，包括纽约心脏协会III级或IV级充血性心力衰竭、不稳定型心绞痛、心肌梗死、脑血管事件或与血流动力学不稳定相关的心律失常。注意：允许药物控制的心律失常。
20. 使用Fridericia公式校正的QT间期延长至>480毫秒。
21. 有出血或血栓性疾病或存在严重出血风险的参与者。已知深静脉血栓/肺栓塞但正在接受适当抗凝治疗的参与者符合条件。
22. 既往治疗中有≥3级口腔炎或黏膜炎病史的参与者。
Inclusion Criteria:
Patients must meet the following criteria for study entry:
1. Participants must be 18 years or older.
2. Participants must be willing and able to provide informed consent.
3. In the dose escalation, participants must have histologically documented locally advanced, unresectable, or metastatic solid tumor that has relapsed or progressed following local standard treatments that are known to prolong survival, or for which no standard treatment is available, or refused such therapy.
4. In dose expansion Cohort 1, patients must have histologically documented locally advanced, unresectable, or metastatic NSCLC. Participants should have received at least two prior lines of therapy in the advanced setting. Participants with metastatic PD-L1-positive disease will be expected to have prior immunotherapy unless contraindicated. Participants with actionable alterations (e.g., EGFR, ALK, BRAF V600E, RET, ROS1, MET, NTRK) should have received prior FDA-approved targeted therapy.
5. In dose expansion Cohort 2, patients must have histology documented locally advanced or metastatic HER2-negative/HER2-low breast cancer (IHC 0, IHC 1, or IHC 2+/ in situ hybridization negative) breast cancer. Participants should have received at least one prior line of therapy in the advanced setting. Participants with metastatic TNBC that is PD-L1 positive will be expected to have prior immunotherapy unless contraindicated. Participants with HR-positive disease will be expected to have received a prior cyclin- dependent kinase 4/6 inhibitor in the metastatic or adjuvant setting.
6. Participant tumors must demonstrate TROP2 expression of 2+ or 3+ as determined by IHC test at the MDACC Clinical Laboratory Improvements (CLIA) Laboratories (Clinical Lab or Clinical Translational Unit; Appendix 8).
7. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 3).
8. Life expectancy ≥3 months.
9. A female participant is eligible to participate if at least one of the following conditions applies:
1. Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 OR
2. A WOCBP who agrees to follow the contraceptive guidelines in Appendix 2 during the study treatment period and for 6 months post TROP2-CAR-NK cell infusion.
Female participants who become pregnant or suspect pregnancy must immediately notify their doctor. Females participants who become pregnant will be taken off study.
10. Male participants must agree to follow the contraceptive guidelines in Appendix 2 during the study treatment period and for 6 months post TROP2-CAR-NK cell infusion. Male participants who father a child or suspect that they have fathered a child must immediately notify their doctor.
11. WOCBP must have a negative urine pregnancy test within 72 hours prior to the start of lymphodepleting chemotherapy. If a WOCBP has a urine pregnancy test that cannot be confirmed as negative, a serum (beta-human chorionic gonadotropin \[β-hCG\]) pregnancy test will be required.
12. Participants must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 3).
13. Participants must have adequate organ function as defined below within 10 days prior to the start of lymphodepleting chemotherapy:
Table 1. Adequate Organ Function Laboratory Values Systemic Function Test Laboratory Value Hematologic ANC ≥1500/µL Platelets ≥100,000/µL Hemoglobin ≥9.0 g/dLa Renal Creatinine OR CrCl by Cockcroft-Gault formula ≤1.5 × ULNb
≥45 mL/min for patients with creatinine \>1.5 × ULNb Hepatic Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels \>1.5 × ULN AST and ALT ≤2.5 × ULN (≤5 × ULN for patients with liver metastases) Coagulation PT/INR aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
ALT=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; CrCl=creatinine clearance; INR=international normalized ratio; PT=prothrombin time; ULN=upper limit of normal.
1. Criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within last 2 weeks of the screening test. Participants may be on a stable dose of erythropoietin (≥ approximately 3 months).
2. Serum creatinine and CrCl should be interpreted and calculated per institutional standard.
14. Left ventricular ejection fraction \>50%.
15. Adequate respiratory reserve defined as dyspnea Grade 0 or 1 and saturated oxygen \>92% in room air.
16. Prior treatment with TROP2-targeted therapy will be allowed.
17. Willing to undergo mandatory blood collections and biopsies as required by the study.
18. Willing to sign consent for long-term follow-up on protocol PA17-0483.
19. Willing to stay within a 2-hour drive (approximately 100-mile radius) of the study site during the first 2 weeks after the TROP2-NK cell infusion.
Exclusion Criteria
Participants who meet any of the following criteria will not be eligible:
1. Pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 6 months post TROP2-CAR-NK cell infusion.
2. Has received systemic anticancer therapy within 2 weeks or 5 half-lives, whichever is shorter, prior to the start of lymphodepleting chemotherapy. For participants treated with monoclonal antibodies, at least 3 weeks must have elapsed prior to the start of lymphodepleting chemotherapy. Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 3 weeks after the last dose of the previous investigational agent.
3. Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants with ≤ Grade 2 neuropathy, alopecia, or other non-relevant AEs may be deemed eligible at the discretion of the principal investigator (PI)/co-PIs. If a participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to the start of lymphodepleting chemotherapy.
4. Has received prior radiotherapy within 2 weeks of the start of lymphodepleting chemotherapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
5. Has received a live vaccine within 6 weeks prior to TROP2-CAR-NK infusion and for at least 24 months post infusion. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza and COVID- 19 vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
6. Prior CAR T or NK cell or other genetically modified T or NK cell therapy.
7. Has diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in doses exceeding 10 mg daily of prednisone equivalent).
8. History of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years. The time requirement does not apply to patients who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers.
9. Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate if they completed radiation therapy, are clinically stable, and without requirement of steroid treatment for at least 2 weeks prior to study enrollment.
10. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed.
11. History of interstitial lung disease (ILD) that required steroids or has current pneumonitis/ILD.
12. Active infection requiring systemic therapy.
13. Known human immunodeficiency virus (HIV) infection.
14. Known active or chronic hepatitis B or hepatitis C virus infection.
15. Known history of active tuberculosis (Mycobacterium Tuberculosis).
16. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
17. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
18. Has had an allogenic tissue/solid organ transplant.
19. Clinically significant cardiovascular disease within 12 months prior to the start of lymphodepleting chemotherapy, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular event, or cardiac arrhythmia associated with hemodynamic instability. NOTE: medically controlled arrhythmia would be permitted.
20. Prolongation of corrected QT interval using Fridericia's formula to \>480 milliseconds.
21. Participants with bleeding or thrombotic disorders or at risk for severe hemorrhage. Participants with known deep vein thrombosis/pulmonary embolism who are on appropriate anti-coagulation treatment are eligible.
22. Participants with history of ≥ Grade 3 stomatitis or mucositis with prior therapy.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 Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 · through study completion; an average of 1 year
入组剂量递增阶段的受试者将根据加入本研究的时间被分配至 TROP2-CAR-NK 细胞的某一剂量水平。将测试最多 5 个剂量水平的 TROP2-CAR-NK 细胞。每个剂量水平至少入组 3 名受试者。 第一组受试者将接受最低剂量水平。如果未观察到不可耐受的不良反应，每个新组将接受比前一组更高的剂量。这一过程将持续进行，直至确定 TROP2-CAR-NK 细胞的最高可耐受剂量。 入组剂量扩展阶段的受试者将接受在剂量递增阶段确定的推荐剂量的 TROP2-CAR-NK 细胞。
入组剂量递增阶段的受试者将根据加入本研究的时间被分配至 TROP2-CAR-NK 细胞的某一剂量水平。将测试最多 5 个剂量水平的 TROP2-CAR-NK 细胞。每个剂量水平至少入组 3 名受试者。 第一组受试者将接受最低剂量水平。如果未观察到不可耐受的不良反应，每个新组将接受比前一组更高的剂量。这一过程将持续进行，直至确定 TROP2-CAR-NK 细胞的最高可耐受剂量。 入组剂量扩展阶段的受试者将接受在剂量递增阶段确定的推荐剂量的 TROP2-CAR-NK 细胞。
入组剂量递增阶段的受试者将根据加入本研究的时间被分配至 TROP2-CAR-NK 细胞的某一剂量水平。将测试最多 5 个剂量水平的 TROP2-CAR-NK 细胞。每个剂量水平至少入组 3 名受试者。 第一组受试者将接受最低剂量水平。如果未观察到不可耐受的不良反应，每个新组将接受比前一组更高的剂量。这一过程将持续进行，直至确定 TROP2-CAR-NK 细胞的最高可耐受剂量。 入组剂量扩展阶段的受试者将接受在剂量递增阶段确定的推荐剂量的 TROP2-CAR-NK 细胞。
确定可给予晚期实体瘤受试者的TROP2-CAR-NK细胞的推荐剂量。
To find the recommended dose of TROP2- CAR-NK cells that can be given to participants with advanced forms of solid tumors.
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