肿瘤细胞治疗研究
英文原题：CART-PSMA-TGFβRDN Cells for Castrate-Resistant Prostate Cancer
这是一项 I 期注册临床试验，评估细胞治疗用于前列腺癌的安全性、可行性及初步疗效。当前状态：进行中（不再招募）。计划入组 23 例。试验地点：美国 · 费城（共 1 个中心）。登记号：NCT03089203。
仅男性 · ≥ 18 Years
纳入标准
1. 转移性去势抵抗性前列腺癌。
2. 已随方案版本15修订而删除。
3. 影像学显示骨转移和／或可测量的非骨转移病灶（淋巴结或内脏）。
4. 年龄≥18岁。
5. ECOG体能状态评分0～1。
6. 器官功能符合以下标准：
1）血清肌酐≤1.5 mg/dL，或肌酐清除率≥60 mL/min；
2）血清总胆红素<正常上限（ULN）的1.5倍；
3）血清ALT／AST<ULN的2倍。
7. 经医生研究者确认，入组资格确认前4周内血液学储备充足，定义如下：
1）血红蛋白>10 g/dL；
2）血小板>100,000/μL；
3）ANC>1,500/μL。注：受试者不得依赖输血。
8. 有去势抵抗性前列腺腺癌进展证据，定义如下：
1）睾酮处于去势水平（<50 ng/mL），可接受或未接受雄激素剥夺治疗；并且
2）医生确认入组资格前12周内出现以下至少一项疾病进展指标：
i）按RECIST 1.1标准判定软组织进展；
ii）按PCWG2标准，骨扫描出现≥2个新病灶，提示骨病变进展；
iii）按PCWG2标准，血清PSA较最低值升高≥25%，且绝对升幅≥2 ng/mL。
9. 既往至少接受一种转移性去势抵抗性前列腺癌标准初始治疗（如多西他赛化疗、17α-裂解酶抑制剂或第二代抗雄激素治疗）。
10. 提供书面知情同意。
11. 有生育能力的受试者须同意使用可接受的避孕方法。
排除标准
1. 已随方案版本16修订而删除。
2. 过去3年内曾患活动性、非根治性治疗的非前列腺原发恶性肿瘤。
3. 已随方案版本6修订而删除。
4. 需要长期使用全身糖皮质激素治疗者。患者可使用低剂量激素（泼尼松等效剂量≤10 mg）。
5. 已随方案版本13修订而删除。
6. 按纽约心脏协会分级为Ⅲ／Ⅳ级心血管功能障碍。
7. 存在有症状的椎体转移并影响脊髓功能（根据病史、体格检查或MRI判定）。
8. 活动性自身免疫病，包括结缔组织病、葡萄膜炎、炎症性肠病或多发性硬化；或有严重自身免疫病史（由医生研究者判定），且曾需长期免疫抑制治疗。
9. 存在持续性或活动性感染。
10. 对研究产品辅料（人血清白蛋白、DMSO和右旋糖酐40）有过敏或超敏反应史。
11. 活动性乙肝、丙肝或HIV感染。
12. 医生研究者认为会显著增加发生不可控细胞因子释放综合征（CRS）或CAR相关神经毒性风险的活动性疾病。
Inclusion Criteria: 1. Metastatic castrate resistant prostate cancer 2. RETIRED WITH PROTOCOL VERSION 15 3. Radiographic evidence of osseous metastatic disease and/or measurable, non-osseous metastatic disease (nodal or visceral) 4. Patients ≥ 18 years of age 5. ECOG performance status of 0 - 1 6. Adequate organ function, as defined by: 1. Serum creatinine ≤ 1.5 mg/dl or creatinine clearance ≥ 60 cc/min 2. Serum total bilirubin \< 1.5x ULN 3. Serum ALT/AST \< 2x ULN 7. Adequate hematologic reserve within 4 weeks of eligibility confirmation by physician-investigator as defined by: 1. Hgb \> 10 g/dl 2. PLT \> 100 k/ul 3. ANC \> 1.5 k/ul Note: Subjects must not be transfusion dependent 8. Evidence of progressive castrate resistant prostate adenocarcinoma, as defined by: 1. Castrate levels of testosterone (\< 50 ng/ml) with or without the use of androgen-deprivation therapy AND 2. Evidence of one of the following measures of progressive disease in the 12 weeks preceding eligibility confirmation by physician: i. soft tissue progression by RECIST 1.1 criteria ii. osseous disease progression with 2 or more new lesions on bone scan (as per PCWG2 criteria) iii. increase in serum PSA of at least 25% and an absolute increase of 2 ng/ml or more from nadir (as per PCWG2 criteria) 9. Prior therapy with at least one standard initial therapy for the treatment of metastatic castrate resistant prostate cancer (i.e. docetaxel chemotherapy, 17α lyase inhibitor, or second-generation anti-androgen therapy) 10. Provides written informed consent 11. Subjects of reproductive potential must agree to use acceptable birth control methods Exclusion Criteria: 1. RETIRED WITH PROTOCOL V16 2. History of an active non-curative non-prostate primary malignancy within the prior 3 years 3. RETIRED WITH PROTOCOL VERSION 6 4. Subjects who require the chronic use of systemic corticosteroid therapy. Patients may be on a low dose of steroids (≤10mg equivalent of prednisone). 5. RETIRED WITH PROTOCOL V13 6. Subjects with Class III/IV cardiovascular disability according to the New York Heart Association Classification 7. Subjects with symptomatic vertebral metastases affecting spinal cord function (as determined by clinical history, physical exam, or MRI imaging) 8. Active autoimmune disease, including connective tissue disease, uveitis, inflammatory bowel disease, or multiple sclerosis; or a history of severe (as judged by the physician-investigator) autoimmune disease requiring prolonged immunosuppressive therapy 9. Patients with ongoing or active infection. 10. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40) 11. Active hepatitis B, hepatitis C or HIV infection. 12. Active medical condition that, in the opinion of the physician-investigator, would substantially increase the risk of uncontrollable CRS or CAR Neurotoxicity.
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：Occurrence of study related adverse events, laboratory toxicities and clinical events that are possibly, likely, or definitely related to study participation. · using CTCAE v 4.03 · 15 years；Clinical feasibility is defined as the frequency of subjects enrolled on this protocol who do not receive CART-PSMA-TGFβRDN cells. · 30 days；Manufacturing feasibility is determined by the frequency of product release failures and the occurrence of dose failures (inability to meet target dose). · 30 days
次要终点：Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by RECIST；Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by PCWG2；Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by serum PSA measurement；Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by overal survival (OS).；Assess the clinical anti-tumor effect of CART-PSMA-TGFβRDN cells by number of subjects with progression free survival (PFS).
第0天给予1～3×10⁷个CART-PSMA-TGFβRDN细胞。
第0天给予1～3×10⁸个CART-PSMA-TGFβRDN细胞。
第0天给予1～3×10⁷个CART-PSMA-TGFβRDN细胞。
第0天给予0.70～1.00×10⁸个CART-PSMA-TGFβRDN细胞。
第0天给予根据队列1～2确定的MTD剂量CART-PSMA-TGFβRDN细胞。
这是一项单中心、单臂Ⅰ期研究，旨在确定通过慢病毒转导、静脉给予双靶点PSMA特异性且耐受TGFβ的自体CAR修饰T细胞（CART-PSMA-TGFβRDN细胞）治疗转移性去势抵抗性前列腺癌患者的安全性和可行性。
This is a single center, single arm Phase I study to establish the safety and feasibility of intravenously administered lentivirally transduced dual PSMA-specific/TGFβ-resistant CAR modified autologous T cells (CART-PSMA-TGFβRDN cells) in patients with metastatic castrate resistant prostate cancer.
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