肿瘤细胞治疗研究
英文原题：iExosomes in Treating Participants With Metastatic Pancreas Cancer With KrasG12D Mutation
这是一项 I/II 期注册临床试验，评估间充质干细胞治疗胰腺癌的安全性、可行性及初步疗效。当前状态：招募中。计划入组 28 例。试验地点：美国 · 休斯顿（共 1 个中心）。登记号：NCT03608631。
不限性别 · ≥ 18 Years
纳入标准： • 组织学确诊转移性胰腺导管腺癌，且存在KRAS G12D突变。 • 有文件记录一线或多线全身治疗期间疾病进展或病情稳定。若疾病稳定，须已完成至少4个月细胞毒性化疗。 • KRAS G12D突变状态可依据既往常规分子分型结果确认（例如Foundation One、Caris、Oncomine等商业检测对组织或血液样本的检测）；也可在入组前通过组织活检或血液检测进一步确认。 • ECOG体能状态评分0–1。 • ANC≥1,500个/mm³。 • 血小板≥100,000/μL。 • 血红蛋白>9.0 g/dL。 • 总胆红素1–1.5 mg/dL。 • AST和ALT<ULN的2.5倍。 • 碱性磷酸酶<ULN的2.5倍。 • 肌酐<1.5 mg/dL。 • 已知Gilbert综合征患者的器官功能标准采用直接胆红素≤ULN的1.5倍，而非总胆红素。 • 有生育可能的女性（WOCBP；指未绝经至少12个月且未接受手术绝育者）须在治疗开始前1周内血清妊娠检测阴性，并在研究期间及末次研究药物给药后12周内使用适当避孕措施。原方案对WOCBP避孕要求重复说明。 • 有生育能力的男性受试者须在研究期间及末次研究药物给药后12周内采取适当避孕措施以避免受孕；若伴侣已妊娠或哺乳，受试者须使用避孕套。 • 患者须签署知情同意及授权书，确认其了解本研究的研究性质及相关已知风险。 排除标准： • 存在可能影响研究参与的严重和/或未控制合并症，如不稳定型心绞痛、6个月内心肌梗死、不稳定且有症状的心律失常、未控制的糖尿病、严重活动性感染或未控制感染。 • 妊娠（妊娠检测阳性）或哺乳。 • 已知中枢神经系统（CNS）疾病，但已治疗的脑转移除外。已治疗脑转移定义为治疗后无进展或出血证据、目前无需地塞米松，并在筛查期间通过临床检查和脑部影像（MRI或CT）确认；允许稳定剂量抗惊厥药。脑转移治疗可包括全脑放疗（WBRT）、立体定向放射外科（伽玛刀、直线加速器〔LINAC〕或等效技术）或其组合，由主治医生酌情决定。研究第1天前3个月内接受神经外科切除或脑活检的CNS转移患者排除。
Inclusion Criteria: * Patients with histologically confirmed metastatic pancreatic ductal adenocarcinoma harboring KrasG12D mutation * Patients must have documented progression or stable disease on one or more lines of systemic therapy. If stable disease, patient must have completed at least 4 months of chemotherapy with cytotoxic therapy * KrasG12D mutation status will be informed from any previous routine molecular profiling (using commercial assays such as Foundation One, Caris, Oncomine or other) of tissue or blood. Additional KrasG12D mutation status may be confirmed using tissue biopsy or blood prior to enrolling into the trial * ECOG (Eastern Cooperative Oncology Group) performance status of 0-1 * Absolute neutrophil count (ANC) more or equal to 1,500 cells/mm3 * Platelets more or equal to 100,000/ul * Hemoglobin more than 9.0 g/dL * Total bilirubin between 1 and 1.5 mg/dL * AST (aspartate aminotransferase) and ALT (alanine transaminase) less than 2.5 x ULN (upper limit of normal) * Alkaline phosphatase less than 2.5 x ULN * Creatinine less than 1.5 gm/dL * In patients with known Gilbert's syndrome, direct bilirubin less or equal to 1.5 x ULN will be used as organ function criteria, instead of total bilirubin * Negative serum pregnancy test in women with childbearing potential (WOCBP) defined as not post-menopausal for 12 months or no previous surgical sterilization, within one week prior to initiation of treatment. WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of study drug to minimize the risk of pregnancy. WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of study drug to minimize the risk of pregnancy * A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study and for up to 12 weeks after the last dose of study drug to minimize the risk of pregnancy. If the partner is pregnant or breastfeeding, the subject must use a condom * Patients must sign an informed consent and authorization indicating that they are aware of the investigational nature of this study and the known risks involved Exclusion Criteria: * Concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study such as unstable angina, myocardial infarction within 6 months, unstable symptomatic arrhythmia, uncontrolled diabetes, serious active or uncontrolled infection * Pregnancy (positive pregnancy test) or lactation * Known CNS (central nervous system) disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (magnetic resonance imaging-MRI or computerized tomography-CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; gamma knife, linear accelerator \[LINAC\], or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 will be excluded
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：Maximum Tolerated Dose Determined by Dose Limiting Toxicity · Dose limiting toxicity graded according to the NCI CTCAE, Version 4.0 · First 4 weeks of treatment；Minimal residual disease rate in high-risk patients · Will be modeled using logistic regression. · Up to 1 year；Overall survival (OS) · Estimated using the Kaplan-Meier product limit estimator. · Up to 1 year；Progression-free survival (PFS) · Estimated using Kaplan-Meier product limit estimator. · Up to 1 year
受试者在第1、4和10天接受间充质基质细胞来源外泌体负载KRAS G12D siRNA静脉输注，每次15–20分钟。每14天重复一个疗程；无疾病进展或不可接受毒性时最多进行3个疗程。出现治疗反应者可继续接受另外3个疗程。
这项I期试验研究间充质基质细胞来源外泌体负载KRAS G12D siRNA（iExosomes）用于治疗KRAS G12D突变且已发生远处转移的胰腺癌患者的最佳剂量和副作用。iExosomes可能有助于治疗胰腺癌。
This phase I trial studies the best dose and side effects of mesenchymal stromal cells-derived exosomes with KrasG12D siRNA (iExosomes) in treating participants with pancreatic cancer with KrasG12D mutation that has spread to other places in the body. iExosomes may work better at treating pancreatic cancer.
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