肿瘤细胞治疗研究
英文原题：Phase I/II Study: Allogeneic NK-cell Therapy With Chemotherapy for Post-Surgery PDA or Cholangiocarcinoma Patients
这是一项 I/II 期注册临床试验，评估异体 NK 细胞治疗胰腺癌、胆管癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 42 例。试验地点：中国 · 台南（共 1 个中心，其中中国 1 个）。登记号：NCT06730009。
不限性别 · ≥ 18 Years
纳入标准：
1. 已签署并注明日期的知情同意书。
2. 性别不限，在签署知情同意书之日年龄大于18岁（含18岁）。
3. 根据国际抗癌联盟（UICC）组织病理学分期系统，受试者已接受原发肿瘤肉眼切除术且残留原发肿瘤符合以下所有项目：
* 在手术时或手术前，为II期或III期。
* 局部残留肿瘤分类为R0或R1。
* 术中腹腔灌洗细胞学检查阴性。
4. 组织学确诊的PDA或胆管癌。
5. 在筛选访视前12周内接受过根治性切除术，并将接受辅助SLOG化疗。注：将招募接受过手术且既往接受或未接受过新辅助治疗的癌症受试者。
6. 东部肿瘤协作组（ECOG）体能状态（PS）0-1。
7. 第1次访视时血液学功能充分的受试者：
* 总白细胞（WBC）≥ 3,000 cells/mm3。
* 绝对中性粒细胞计数（ANC）≥ 1,500 cells/mm3。
* 血小板 ≥ 100,000 counts/mm3。
* 血红蛋白 ≥ 9 g/dL。
* 凝血酶原时间国际标准化比值（INR）在正常范围内。注：筛选期间允许复测以确认合格性。
8. 第1次访视时肝肾功能充分的受试者：
* 血清肌酐 ≤ 1.5× 正常值上限（ULN）。
* 血尿素氮（BUN）≤ 1.5× ULN。
* 总胆红素 ≤ 1.5× ULN。
* 丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）≤ 2.5× ULN。
* 碱性磷酸酶（ALP）≤ 5× ULN。
* 白蛋白 ≥ 3.0 g/dL。注：筛选期间允许复测以确认合格性。
9. 人类免疫缺陷病毒（HIV）和梅毒螺旋体（快速血浆反应素[RPR]/性病研究实验室[VDRL]和梅毒螺旋体血凝试验[TPHA]）检测阴性。
10. 受试者经巨细胞病毒免疫球蛋白G（CMV IgG）阳性确认既往有巨细胞病毒（CMV）感染。
11. 有生育能力的受试者必须同意采取至少两种避孕措施，其中一种必须是避孕套或其他充分的屏障法，从
* 签署知情同意书至研究产品（IP）给药末次剂量后28天。
* 开始奥沙利铂治疗至末次剂量后至少15个月（女性）或12个月（男性）。
* 开始吉西他滨治疗至末次剂量后至少6个月（女性）或3个月（男性）。
12. 同意遵守临床方案计划的治疗。注：如果存在活动性乙型肝炎，允许进行抗病毒治疗。
排除标准：
1. 在筛选访视前28天内接受过任何其他研究性、抗肿瘤药物或免疫细胞治疗。
2. 有任何既往恶性肿瘤病史，但以下情况除外：
1. 非侵袭性、非黑色素瘤性皮肤癌（包括鳞状细胞癌、基底细胞癌或原位癌），仅通过冷冻手术或手术切除治愈。
2. 其他原发性恶性肿瘤，诊断为无病生存超过5年。
3. 免疫缺陷，目前正在接受针对自身免疫性疾病的免疫抑制治疗，或在第1天前14天内接受过相当于泼尼松龙30毫克/天以上剂量的全身性类固醇治疗超过7天。
4. 已知有转移。
5. 在筛选前2年内有持续存在的急性疾病，或严重的医疗状况，如心血管（例如，纽约心脏协会III级或IV级）、肝脏（例如，Child-Pugh C级）、精神状况（例如，酗酒、药物滥用）、病史、体检发现或实验室异常，研究者认为可能干扰试验结果或对受试者的安全产生不利影响。
6. 可能导致临床明显血栓形成的高凝状态。
7. 已知对氨基糖苷类（例如，链霉素、庆大霉素）或杆菌肽过敏。
8. 已知对Allogeneic Magicell-NK的任何成分过敏，包括人血清白蛋白。
9. 已知对S-1、亚叶酸、奥沙利铂或吉西他滨的任何成分过敏。
10. 对S-1、亚叶酸、奥沙利铂或吉西他滨有任何禁忌症，包括：
- 严重骨髓抑制或可能加剧的骨髓抑制。
11. 有症状的CMV疾病。
12. 有任何诊断或怀疑的心律失常或QT间期延长史。
13. 筛选时心电图（ECG）检查确定男性受试者校正QT间期（QTc）≥ 450 ms，女性受试者QTc ≥ 470 ms。
14. 在筛选访视前28天内接受过任何与QT延长相关的药物（参见附录3. 与QT延长相关的药物，包括但不限于其中列出的药物）。
15. 在筛选访视前28天内接受过溴夫定或其类似物（例如，索立夫定）或任何活疫苗。
16. 筛选时哺乳或血清或尿液妊娠试验阳性的女性受试者。
Inclusion Criteria:
1. Dated and signed informed consent.
2. Either sex, aged older than 18 years old (inclusive) at date of consent.
3. Subject with a macroscopic resection of the primary tumor and residual primary tumor that satisfies all of the items below according to the Union for International Cancer Control (UICC) histopathologic staging system:
* At or before the surgery, stage II or stage III.
* Local residual tumor classified as R0 or R1.
* Cytologic examination negative upon intraoperative peritoneal lavage.
4. Histologically confirmed PDA or cholangiocarcinoma.
5. Received curative resection within 12 weeks prior to screening visit and will receive adjuvant SLOG chemotherapy. Note: Subjects with cancer who had undergone surgery with or without prior neo-adjuvant therapy will be recruited.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
7. Subject with adequate hematology function at Visit 1:
* Total white blood cell (WBC) ≥ 3,000 cells/mm3.
* Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3.
* Platelets ≥ 100,000 counts/mm3.
* Hemoglobin ≥ 9 g/dL.
* International normalized ratio (INR) of prothrombin time within normal range. Note: Re-test for eligibility is allowed during the screening period.
8. Subject with adequate hepatic and renal function at Visit 1:
* Serum creatinine ≤ 1.5× Upper Limit of Normal (ULN).
* Blood urea nitrogen (BUN) ≤ 1.5× ULN.
* Total bilirubin ≤ 1.5× ULN.
* Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5× ULN.
* Alkaline phosphatase (ALP) ≤ 5× ULN.
* Albumin ≥ 3.0 g/dL. Note: Re-test for eligibility is allowed during the screening period.
9. Negative response in human immunodeficiency virus (HIV) and treponema pallidum (rapid plasma reagin \[RPR\]/venereal disease research laboratory \[VDRL\] and treponema pallidum hemagglutination \[TPHA\]).
10. Subject confirmed with past cytomegalovirus (CMV) infection in terms of having positive CMV immunoglobin G (CMV IgG).
11. Subject with childbearing potential must agree to use at least two contraceptive precautions, one of which must be a condom or other adequate barrier method, from
* signing informed consent until 28 days after the last dose of investigational product (IP) administration.
* initiation of oxaliplatin treatment until at least 15 months (female) or 12 months (male) following the last dose.
* initiation of gemcitabine treatment until at least 6 months (female) or 3 months (male) following the last dose.
12. Agree to be in compliance with clinical protocol-planned treatment. Note: Anti-virus treatment is allowed if active hepatitis B is presented.
Exclusion Criteria:
1. Received any other investigational, anti-neoplastic medications, or immune cell therapy within 28 days prior to screening visit.
2. Any prior history of malignant neoplasm, except:
1. Non-invasive, non-melanomatous skin cancer (including squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ), curatively treated with cryosurgery or surgical excision only.
2. Other primary malignant neoplasm diagnosed as disease free for more than 5 years.
3. Immunocompromized, currently under immunosuppressive treatment for autoimmune disease, or have received systemic steroid of equivalent dosage higher than prednisolone 30 mg/day for more than 7 days within 14 days prior to Day 1.
4. With known metastases.
5. With ongoing acute diseases, or serious medical conditions within the past 2 years prior to screening, such as cardiovascular (e.g., New York Heart Association grade III or IV), hepatic (e.g., Child-Pugh Class C), psychiatric condition (e.g., alcoholism, drug abuse), medical history, physical findings, or laboratory abnormality that in the investigators' opinion could interfere with the results of the trial or adversely affect the safety of the subject.
6. Hypercoagulable state that may lead to clinically apparent thrombosis.
7. With known hypersensitivity to aminoglycoside (e.g., streptomycin, gentamicin) or bacitracin.
8. With known hypersensitivity to any of the components of Allogeneic Magicell-NK, including human serum albumin.
9. With known hypersensitivity to any of the components of S-1, leucovorin, oxaliplatin, or gemcitabine.
10. With any contraindication to S-1, leucovorin, oxaliplatin, or gemcitabine, including:
\- Severe myelosuppression or myelosuppression that probably exacerbates.
11. With symptomatic CMV disease.
12. With any history of diagnosed or suspected cardiac arrhythmia or QT interval prolongation.
13. Male subject with a corrected QT interval (QTc) ≥ 450 ms and female subject with a QTc ≥ 470 ms as determined by electrocardiogram (ECG) examination at screening.
14. Received any drugs associated with QT prolongation within 28 days prior to the Screening Visit (refer to Appendix 3. Drugs Associated with QT Prolongation, including but not limited to the drug listed therein).
15. Received brivudine or its analogs (e.g., sorivudine) or any live vaccines within 28 days prior to the Screening Visit.
16. Female subject who is lactating or has positive serum or urine pregnancy test 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：Ph I Evaluation of safety parameters, numbers of participants with Treatment-Emergent Adverse Events (TEAEs). · The number of participants with Treatment-Emergent Adverse Events (TEAEs) was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0) to assess the tolerability of Magicell-NK treatment. · 15 months；Ph I Laboratory tests · Number of participants with abnormal laboratory test results. · 15 months；Ph I Body weight · Body weight (KG) will be measured at baseline, treatment, and F1 visits. The number of participants with abnormal body weight change. · 5 months；Ph I Vital signs · Number of participants with abnormal vital signs. · 15 months；Ph I Dose-limiting toxicities · Adverse events were assessed according to NCI-CTCAE v5.0 criteria. · 4 months；Ph I Maximum Tolerated Dose (MTD) and Recommended Phase II Dose · MTD is defined as the highest dose level at which ≤ 1/6 of subjects experienced DLT. · 4 months
次要终点：Ph I Disease-free survival (DFS)；Ph II Evaluation of safety parameters, numbers of participants with Treatment-Emergent Adverse Events (TEAEs)；Ph II Laboratory tests；Ph II Body weight；Ph II Vital signs；Ph I/II Tumor recurrence rate (TRR)；Ph I/II Changes in Frequency and Duration of ctDNA；Ph I/II Changes in Frequency and Duration of Circulating Tumor Count (CTC)
Ph I SLOG + 异体NK细胞剂量递增（队列1：10 × 10^8 细胞；队列2：20 × 10^8 细胞）Ph II 第1组 SLOG + 异体NK细胞
Ph II 第2组
这是一项I/II期研究，旨在表征Allogeneic Magicell-NK输注在PDA或胆管癌患者术后中的安全性、耐受性和初步疗效。受试者将在每个化疗周期的第11天接受总共6次IP静脉（IV）输注。计划总共进行6个周期的IP输注。 研究的I期部分是一项Allogeneic Magicell-NK的首次人体I期试验，因此采用开放标签、剂量递增的方式设计。将采用标准的3+3设计来评估Allogeneic Magicell-NK的安全性特征，并确定MTD/MFD。计划设两个剂量队列：起始剂量为10 × 10^8个细胞（队列1），并递增至20 × 10^8个细胞（队列2）。 研究的II期部分设计为一项开放标签、双臂、随机临床试验，比较SLOG联合Allogeneic Magicell-NK与单用SLOG在PDA或胆管癌切除术后作为辅助治疗的效果。约30名受试者将按2:1的比例随机分配至两个组：第1组：SLOG联合Allogeneic Magicell-NK（20名受试者）；第2组：单用SLOG（10名受试者）。随后，受试者将接受12周的SLOG化疗，联合或不联合Allogeneic Magicell-NK输注。
This is a phase I/II study which intends to characterize the safety, tolerability, and preliminary efficacy of Allogeneic Magicell-NK infusion in PDA or cholangiocarcinoma patients after surgery. Subjects will receive a total of 6 intravenous (IV) infusions of the IP on the 11th day of each chemotherapy cycle. A total of 6 cycles of IP infusions are planned. The phase I part of the study is a first-in-human phase I trial of Allogeneic Magicell-NK and is therefore designed in an open-label, dose-escalation manner. A standard 3+3 design will be employed to assess the safety profile of Allogeneic Magicell-NK and to determine the MTD/MFD. Two dose cohorts are planned: the starting dose is 10 × 10\^8 cells (Cohort 1), and escalates to 20 × 10\^8 cells (Cohort 2). The phase II part of the study is designed as an open-label, two-arm, randomized clinical trial comparing the combination of SLOG and Allogeneic Magicell-NK with SLOG alone when used as adjuvant therapy following resection for PDA or Cholangiocarcinoma. Approximately 30 subjects will be randomized at a 2:1 ratio between the two arms: Arm 1: SLOG and Allogeneic Magicell-NK (20 subjects); Arm 2: SLOG alone (10 subjects). Subjects will then receive 12 weeks of SLOG chemotherapy with or without Allogeneic Magicell-NK infusion.
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