A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-r

StephenW

http://www.ncbi.nlm.nih.gov/pubmed/22426640
Invest New Drugs. 2012 Mar 17. [Epub ahead of print]
A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma.Yau T, Cheng PN, Chan P, Chan W, Chen L, Yuen J, Pang R, Fan ST, Poon RT.
SourceDepartment of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.

AbstractBackground Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. Methods Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. Results Fifteen patients were enrolled at weekly doses of 500 U/kg (n = 3), 1000 U/kg (n = 3), 1600 U/kg (n = 3) and 2500 U/kg (n = 6). The median age was 57 years (33-74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600-2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients. Conclusion Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.

StephenW

投资的新药物。 2012年3月17日。 [出处提前打印]
第一阶段升级剂量研究中晚期肝癌患者的聚乙二醇重组人精氨酸酶1（PEG-rhArg1的）。
，陈，陈带够成的PN油T，W，陈林根，袁家宁，ŕ庞，范ST，潘RT。
源

医学系，香港大学玛丽医院，薄扶林，香港，中国。
抽象

背景肝细胞癌（HCC）细胞精氨酸营养缺陷，其中枯竭导致肿瘤消退。目前的研究评估安全性，药代动力学（PK）/药效学（PD）的参数，和潜在的抗肿瘤活性聚乙二醇重组人精氨酸酶1（PEG-rhArg1）的晚期肝癌患者。方法的资格准则，包括可测量病灶的晚期肝癌，Child-Pugh分级A或B，和足够的器官功能。最初的单一静脉推注，随后由每周PEG-rhArgI的剂量，在3 + 3设计升级从500U /公斤至2500单位/公斤。结果15例患者，每周剂量500U /公斤（N = 3），000 U /公斤（N = 3），1600的U /公斤（N = 3）和2500ü/公斤（N = 6）。年龄中位数为57岁（33-74），87％是乙肝病毒携带者，47％曾经接受过全身治疗。最常报告的与毒品有关的非血液学不良事件（AES），腹泻（13.3％），腹部不适（6.7％）和恶心（6.7％）。没有与毒品有关的血液学不良事件被发现。只有六个病人接受，2500U/kg挂-rhArg1经验丰富的DLT（4级胆红素升高），从而最大耐受剂量为2500单位/公斤1。 PK和PD分析表明，PEG-rhArg1的剂量依赖的方式诱导精氨酸耗竭有效。在1,600-2,500的U / kg范围内取得了足够的精氨酸耗竭剂量，因此，最优生物剂量1600单位/公斤，这是作为推荐剂量选择。最好的回应是8周的26.7％的患者病情稳定。结论PEG-rhArg1的有管理的安全性和活动中晚期肝癌患者的初步证据。