A Phase I Study of Mistletoe Extract on PK, PD, and Safety of Gemcitabine in CA

槲寄生提取物对吉西他滨在 CA 中的 PK、PD 和安全性的 I 期研究

基本信息

批准号：
7732850
负责人：
Patrick J Mansky
金额：
$ 9.6万
依托单位：
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732850
关键词：
Acute Kidney Failure Antimetabolites Area Botanicals Cancer Patient Cellulitis Chemotherapy-Oncologic Procedure Clinical Colorectal Cancer Country Cytokine Gene Data Data Analyses Dose Drug Interactions Drug Kinetics Enrollment European Gemcitabine/Mistletoe Gene Expression Goals Immunologic Markers Intervention Investigation Malignant Neoplasms Malignant neoplasm of pancreas Medicine Metabolism Mistletoe Mistletoe preparation Neutropenia Non-Small-Cell Lung Carcinoma Patients Pharmacodynamics Phase Phase I Clinical Trials Plant Extracts Population Study Preparation Range Recovery Safety Serum Solid Neoplasm Standards of Weights and Measures Thrombocytopenia Toxic effect Treatment Protocols Viscum album cancer therapy chemotherapeutic agent clinical efficacy design experience gemcitabine malignant breast neoplasm neutrophil pre-clinical

项目摘要

During the past 80 years, plant extracts of the European mistletoe Viscum album L. have been widely used for cancer treatment in European countries. Preclinical data suggest immunostimulatory and other immunomodulatory effects of this plant extract. In clinical practice, mistletoe extracts have been used in cancer patients as sole intervention or as adjunct to conventional cancer therapies. Clinical efficacy in the treatment of cancer is an area of active investigation, with inconclusive results to date, due in large part to the use of varying preparations, concentrations, study populations and regimens. Moreover, little is known about the toxicity of mistletoe and the potential for botanical and drug interactions between mistletoe extract and standard chemotherapeutic agents. Gemcitabine is an approved antimetabolite chemotherapeutic agent with demonstrated single agent efficacy in the treatment of a wide range of solid tumors. Because the metabolism and pharmacokinetics of gemcitabine are well characterized, it is a chemotherapeutic agent well suited for the study of botanical/drug interactions in cancer therapy. The goals of this study are to investigate in a two-step phase I dose escalation design the effect of a highly purified mistletoe extract on the pharmacokinetics, pharmacodynamics, and safety of gemcitabine. Pharmacokinetic toxicity profiles of gemcitabine in combination with mistletoe, neutrophil recovery, cytokine gene expression, and serum levels of markers of immune activation will be investigated in 40-50 patients with advanced solid tumors. The study aims at establishing a paradigm for the investigation of botanicals used in conjunction with standard cancer chemotherapy in complementary cancer medicine. The study completed accrual in July 2007 after enrolling 44 patients: 17 patients had colorectal cancer, 12 breast cancer, 8 pancreatic cancer and 4 NSCLC, respectively. Patients experienced 4 DLTs, including grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 acute renal failure and grade 3 cellulitis . The MTD for the combination regimen of mistletoe and gemcitabine was established at gemcitabine dose level 8: 1300 mg/ m2 and mistletoe 250 mg s.c. The study is now closed to accrual and data analysis is ongoing.

过去80年来，欧洲槲寄生Viscum album L.的植物提取物已在欧洲国家广泛用于癌症治疗。临床前数据表明这种植物提取物具有免疫刺激和其他免疫调节作用。在临床实践中，槲寄生提取物已被用于癌症患者作为单独的干预措施或作为传统癌症治疗的辅助手段。癌症治疗的临床疗效是一个正在积极研究的领域，迄今为止尚未得出结论，这在很大程度上是由于使用了不同的制剂、浓度、研究人群和治疗方案。此外，人们对槲寄生的毒性以及槲寄生提取物与标准化疗药物之间的植物和药物相互作用的可能性知之甚少。吉西他滨是一种经批准的抗代谢化疗药物，在治疗多种实体瘤方面已证明单药疗效。由于吉西他滨的代谢和药代动力学已得到充分表征，因此它是一种非常适合研究癌症治疗中植物/药物相互作用的化疗药物。本研究的目的是在两步 I 期剂量递增设计中研究高度纯化的槲寄生提取物对吉西他滨药代动力学、药效学和安全性的影响。将在 40-50 名晚期实体瘤患者中研究吉西他滨与槲寄生联合用药的药代动力学毒性特征、中性粒细胞恢复、细胞因子基因表达和免疫激活标记物的血清水平。该研究旨在建立一个范例，用于研究在补充癌症医学中与标准癌症化疗结合使用的植物药。该研究于 2007 年 7 月完成了招募，招募了 44 名患者：其中 17 名患者患有结直肠癌，12 名乳腺癌患者，8 名胰腺癌患者和 4 名非小细胞肺癌患者。患者经历了 4 次 DLT，包括 4 级中性粒细胞减少症、4 级血小板减少症、4 级急性肾衰竭和 3 级蜂窝织炎。槲寄生和吉西他滨联合用药方案的 MTD 是在吉西他滨剂量水平 8：1300 mg/m2 和皮下注射槲寄生 250 mg 时确定的。该研究现已结束应计，数据分析正在进行中。