FILGRASTIM SD/01 IN NONSMALL CELL LUNG CANCER

目的：此第一阶段研究的主要目标是比较 阿司匹林的安全性、剂量效应、药效学和药代动力学 FILEGRATIM-SD/01到FILEGRATIM。Filgratim-SD/01尚未经过测试 在人类身上。FILGRATIM-SD/01是FILGRATIM(G-CSF，Neupogen)的共价体 在N-末端与聚乙二醇分子结合。 蛋白质的聚乙二醇化减少了清除量并增加了一半- 化合物的寿命，从而产生持续的持续效应。文件抓取时间 是一种谱系特异性的造血生长因子，优先于 刺激中性粒细胞的生长、分化和功能。它有 已被FDA批准用于化疗引起的中性粒细胞减少症，骨髓 移植、严重慢性中性粒细胞减少症和干细胞动员。 FILEGRATIM-SD/01提供了类似的药理作用 与重复注射非格列西汀相同，可从 单次注射。潜在的好处将包括减少注射， 提高患者的依从性，在一段时间内不间断治疗 当患者不能就诊时，减轻了医疗负担 支持人员。 方法：本研究针对非小细胞肺癌患者。 需要化疗的癌症。这项研究将分两部分进行，剂量 卡铂/紫杉醇一周期前后用药研究 化疗。研究的总持续时间为五周。病人 将随机(3：1)接受Filgratim-SD/01或Neupogen 在整个研究过程中。在A部分，化疗前，患者随机 接受研究药物将按剂量接受一次注射 第一天的任务。随机接受G-CSF治疗的患者将收到 皮下注射5微克/公斤/天，连续5天或直到ANC 达到75,000人。患者将连续12天每天抽血 用于常规血细胞计数和化验、药代动力学和CD34 分析。化疗将包括卡铂(AUC为6，30分钟 加紫杉醇(24小时静脉滴注，225 mg/m2)。二十四小时 化疗结束后，患者将接受研究药物或G- 使用G-CSF的患者将在5点给药。 在ANC&GT；10,000之前，每天每公斤。每天抽血15天 在B部分期间连续进行类似于A部分的分析。 药效学方法将用于比较G-CSF和非格列西汀- SD/01号文件A部分和B部分。描述性统计将用于 描述A部分的中性粒细胞和CD34计数。 将使用线性模型来估计Filgratim-SD/01的关联性 B部分中性粒细胞反应的剂量。这种中性粒细胞反应将是 通过G-CSF抢救的需要以及严重的 中性粒细胞减少症。在每个剂量组中，患者需要 G-CSF抢救将描述性地与患者比例进行比较 G-CSF组中符合抢救标准者。

PURPOSE: The primary objectives of this phase I study are to compare the safety, dose response, pharmacodynamic and pharmcokinetic properties of filgrastim-SD/01 to filgrastim. Filgrastim-SD/01 has not yet been tested in humans. Filgrastim-SD/01 is filgrastim (G-CSF, Neupogen) covalently bound at the N-terminus with a polyethylene glycol (PEG) molecule. Pegylation of a protein decreases the clearance and increases the half- life of compounds, resulting in a sustained duration effect. Filgrastim is a lineage-specific hematopoietic growth factor that preferentially stimulates the growth, differentiation and function of neutrophils. It has been approved by the FDA for chemotherapy-induced neutropenia, bone marrow transplantation, severe chronic neutropenic and stem cell mobilization. Filgrastim-SD/01 offers the advantage that similar pharmacologic effects identical to repeat injections of filgrastim can be obtained from a single injection. Potential benefits would include fewer injections, increased patient compliance, uninterrupted therapy over periods of time when the patient cannot visit clinics, and reduced burden on medical support staff. METHODS: This study is directed at patients with non-small cell lung cancer requiring chemotherapy. The study will be done in two parts, dosing with study drug pre and post one cycle of carboplatin/paclitaxel chemotherapy. The total duration of the study is five weeks. Patients will be randomized (3:1) to receive either filgrastim-SD/01 or Neupogen throughout the study. During part A, pre-chemotherapy, patients randomized to receive study drug will receive one injection according to dose assignment on day 1. Patients randomized to G-CSF will receive subcutaneous injections at 5 ug/kg/day for five days or until the ANC reaches 75,000. Patients will have daily blood draws for 12 days in a row for routine blood counts and chemistries, pharmacokinetics, and CD34 analysis. The chemotherapy will consist of carboplatin (AUC of 6, 30 min infusion) plus paclitaxel (24 hour infusion, 225 mg/M2). Twenty-four hours after completion of chemotherapy, patients will receive study drug or G- CSF at the dose given in part A. Patients on G-CSF will be dosed at 5 ug/kg/day until ANC > l0,000. There will be daily blood draws for 15 days in a row during part B for analyses similar to part A. Pharmacokinetic and pharmacodynamic methods will be used to compare G-CSF and filgrastim- SD/01 in parts A and B. Descriptive statistics will be used to characterize the neutrophil and CD34 counts during part A. Generalized linear models will be used to estimate the association of filgrastim-SD/01 dose on neutrophil responses in part B. This neutrophil response will be measured by the need for G-CSF rescue as well as duration of severe neutropenia. The proportion of patients in each dosing group who require G-CSF rescue will be descriptively compared to the proportion of patients in the G-CSF group who met the criteria for rescue.