肿瘤细胞治疗研究
英文原题：Phase 1 Dose Escalation and Expansion Study of PRAME T Cell Receptor (TCR) Engineered NK Cells in Participants With Recurrent and/or Refractory Melanoma (PRAMETIME-Mel)
Phase 1 Dose Escalation and Expansion Study of PRAME T Cell Receptor (TCR) Engineered NK Cells in Participants With Recurrent and/or Refractory Melanoma (PRAMETIME-Mel)
这是一项 I 期注册临床试验，评估细胞治疗用于黑色素瘤的安全性、可行性及初步疗效。当前状态：招募中。计划入组 39 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT06660420。
不限性别 · ≥ 18 Years
纳入标准：
1. 受试者必须年满18岁。
2. 受试者必须愿意且能够提供知情同意。
3. 受试者必须具有HLA A*02:01。
4. 受试者必须具有组织学记录的局部晚期、不可切除或转移性黑色素瘤，且对免疫检查点抑制剂（ICI）治疗复发和/或难治，包括抗PD-1单药或联合抗CTLA-4阻断抗体和/或抗LAG-3抗体。
在剂量递增阶段，将入组皮肤、黏膜或原发灶不明的黑色素瘤受试者。葡萄膜黑色素瘤受试者可能在剂量确认阶段有资格入组未来的不同队列。受试者应按照标准临床实践指南接受过标准治疗（SOC）。受试者在转移阶段接受的含抗PD-1抗体治疗方案不得超过3线。
5. 受试者的东部肿瘤协作组（ECOG）体能状态必须为0或1。
6. 预期寿命3个月。
7. 接受过一种或多种既往全身治疗的受试者允许入组
8. 女性受试者符合以下至少一项条件即可参与：非育龄期女性（WOCBP）或同意在研究治疗期间及PRAME-TCR-NK细胞输注后6个月内遵循避孕指南的WOCBP。怀孕或怀疑怀孕的女性受试者必须立即通知其医生。
怀孕的女性受试者将被退出研究。
9. 男性受试者必须同意在研究治疗期间及PRAME-TCR-NK细胞输注后6个月内遵循避孕指南。使伴侣怀孕或怀疑自己已使伴侣怀孕的男性受试者必须立即通知其医生。
10. 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。
11. 受试者必须具有根据实体瘤疗效评价标准（RECIST）可测量的疾病。
12. 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：
13. 左心室射血分数>50%。
14. 充分的呼吸储备定义为呼吸困难0级或1级，且室内空气下基线血氧饱和度>92%。
15. 愿意按研究要求接受强制性血液采集和活检。
16. 受试者必须同意在输注后至少24个月内不接种活疫苗。
17. 愿意签署方案PA17-0483的长期随访同意书，该同意书将与临床试验入组知情同意书同时签署。
排除标准：
1. 怀孕、哺乳，或在研究预计期间内（从筛选访视开始至PRAME-TCR-NK细胞输注后6个月）计划怀孕。
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。已进入一项研究性研究随访阶段的受试者，只要距上次研究性药物末次给药已过3周，即可参加。
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、脱发或其他非相关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。如果受试者接受了重大手术，他们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周内接受过既往放疗。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（2周放疗），允许1周洗脱期。
5. 在PRAME-TCR-NK输注前6周内接种过活疫苗。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（鸡痘）、黄热病、狂犬病、卡介苗和伤寒疫苗。季节性流感和COVID-19注射疫苗一般为灭活病毒疫苗，允许使用；然而，鼻内流感疫苗为减毒活疫苗，不允许使用。
6. 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）。
7. 有第二种恶性肿瘤病史，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受试者。
8. 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，且在入组研究前至少2周内不需要类固醇治疗，则可参加。
9. 过去2年内需要系统性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）。
10. 需要系统性免疫抑制治疗或其他生理性皮质类固醇替代治疗。
11. 有症状或可能干扰疑似药物相关肺毒性检测或管理的间质性肺病。
12. 活动性感染（例如，COVID-19、流感、严重急性呼吸综合征[SARS]、近期脓毒症）。对于已从感染中恢复的受试者，可在完全恢复后开始淋巴细胞清除。
13. 已知人类免疫缺陷病毒（HIV）感染、活动性或慢性乙型肝炎或丙型肝炎病毒感染。
14. 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、干扰受试者在整个研究期间的参与、或不符合受试者参与研究最佳利益的状况、治疗或实验室异常。
15. 已知会干扰配合研究要求的精神疾病或物质滥用障碍。
16. 曾接受过同种异体组织/实体器官移植。
17. 在开始淋巴细胞清除性化疗前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。
18. 使用Fridericia公式校正的QT间期延长至>480毫秒。
19. 有出血或血栓性疾病或存在严重出血风险的受试者。有已知深静脉血栓形成/肺栓塞病史且正在接受适当抗凝治疗的受试者符合条件。
20. LDH > 2.5倍ULN的受试者。评估应在筛选时进行。
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Inclusion Criteria:
1. Participants must be 18 years or older.
2. Participants must be willing and able to provide informed consent.
3. Participants must have HLA A\*02:01.
4. Participants must have histologically documented locally advanced, unrespectable, or metastatic melanoma that is relapsed and/or refractory to immune checkpoint inhibitor (ICI) therapy including either anti-PD-1 either with or without anti-CTLA-4 blocking antibody and/or anti-LAG-3 antibody.
During dose escalation, participants with cutaneous, mucosal, or unknown primary melanoma will be enrolled. Participants with uveal melanoma may be eligible for future enrollment into distinct cohorts during the dose confirmation phase. Participants should have received standard-of-care (SOC) therapy per standard clinical practice guidelines. Participants must not have had exposure to more than 3 prior lines of anti-PD-1 antibody-containing therapeutic regimens administered in the metastatic setting.
5. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy 3 months.
7. Participants who received one or more prior systemic therapy are allowed for enrollment
8. A female participant is eligible to participate if at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive guidelines in during the study treatment period and for 6 months post PRAME-TCR-NK cell infusion. Female participants who become pregnant or suspect pregnancy must immediately notify their doctor.
Female participants who become pregnant will be taken off the study.
9. Male participants must agree to follow the contraceptive guidelines during the study treatment period and for 6 months post PRAME-TCR-NK cell infusion. Male participants who father a child or suspect that they have fathered a child must immediately notify their doctor.
10. WOCBP must have a negative urine pregnancy test within 72 hours before 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 \[£\]-hCG\]) pregnancy test will be required.
11. Participants must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST).
12. Participants must have adequate organ function as defined below within 10 days before the start of lymphodepleting chemotherapy:
13. Left ventricular ejection fraction \>50%.
14. Adequate respiratory reserve defined as dyspnea Grade 0 or 1 and baseline oxygen saturation \>92% in room air.
15. Willing to undergo mandatory blood collection and biopsies as required by the study.
16. Participants must agree not to receive a live vaccine for at least 24 months post-infusion.
17. Willing to sign consent for long-term follow-up on protocol PA17-0483 which will be signed at the same time with the clinical trial enrollment consent form.
Exclusion Criteria:
1. Pregnant, breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 6 months post PRAME-TCR-NK cell infusion.
2. Has received systemic anticancer therapy within 2 weeks or 5 half-lives, whichever is shorter, before the start of lymphodepleting chemotherapy. For participants treated with monoclonal antibodies, at least 3 weeks must have elapsed before 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 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 before 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 PRAME-TCR-NK 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 are live attenuated vaccines and are not allowed.
6. Has a diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in doses exceeding10 mg daily of prednisone equivalent).
7. 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 participants 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.
8. 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 the requirement of steroid treatment for at least 2 weeks prior to study enrollment.
9. Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with the 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) is allowed.
10. Need for systemic immunosuppressive therapy or other physiological replacement of corticosteroids.
11. Interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
12. Active infection (e.g., COVID-19, influenza, severe acute respiratory syndrome \[SARS\], recent sepsis). For participants recovered from infections, lymphodepletion may start after full recovery.
13. Known human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or hepatitis C virus infection.
14. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participants participation for the full duration of the study, or is not in the best interest of the participants to participate, in the opinion of the treating investigator.
15. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
16. Has had an allogeneic tissue/solid organ transplant.
17. Clinically significant cardiovascular disease within 12 months before 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: A medically controlled arrhythmia would be permitted.
18. Prolongation of corrected QT interval using Fridericia's formula to \>480 milliseconds.
19. Participants with bleeding or thrombotic disorders or at risk for severe hemorrhage. Participants with a known history of deep vein thrombosis/pulmonary embolism who are on appropriate anti-coagulation treatment are eligible.
20. Participants with LDH \> 2.5-fold ULN. The evaluation should be conducted at screening.
\-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：Safety and adverse events (AEs) · 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
您接受的 PRAME-TCR-NK 细胞剂量将取决于您加入本研究的时间。将测试最多 5 个研究产品剂量水平。第一组受试者将接受最低剂量水平的研究产品。如果未观察到不可耐受的副作用，每个新组将接受比前一组更高剂量的研究产品。这将持续进行，直至确定研究产品的最高可耐受剂量和推荐剂量。
受试者将接受推荐剂量的 PRAME-TCR-NK 细胞。所有受试者将接受相同剂量水平的 fludarabine 和 cyclophosphamide
寻找可给予复发和/或难治性黑色素瘤参与者的PRAME-TCR-NK细胞的最高耐受剂量和推荐剂量。还将研究PRAME-TCR-NK细胞的安全性和耐受性。
To find the highest tolerable dose and recommended dose of PRAME-TCR-NK cells that can be given to participants with recurrent and/or refractory melanoma. The safety and tolerability of PRAME-TCR-NK cells will also be studied.
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