FILGRASTIM SD/01 IN NONSMALL CELL LUNG CANCER

目的：这项第一阶段研究的主要目标是比较非格司替姆-SD/01和非格列格替姆的安全性、剂量反应、药效学和药代动力学特性。FILEGRATIM-SD/01尚未在人体上进行测试。FILEGRATIM-SD/01是FILGRATIM(G-CSF，Neupogen)，在N-末端与聚乙二醇分子共价结合。蛋白质的聚乙二醇化会减少化合物的清除量，延长化合物的半衰期，从而产生持续的持续效应。非格列西汀是一种谱系特异性的造血生长因子，优先刺激中性粒细胞的生长、分化和功能。它已被FDA批准用于化疗引起的中性粒细胞减少症、骨髓移植、严重的慢性中性粒细胞减少症和干细胞动员。FILEGRATIM-SD/01的优点在于，一次注射即可获得与重复注射FILGRATIM相同的类似药理作用。潜在的好处将包括减少注射，提高患者的依从性，在患者无法就诊的一段时间内不间断治疗，以及减轻医疗支持人员的负担。方法：本研究针对需要化疗的非小细胞肺癌患者。这项研究将分两部分进行，在卡铂/紫杉醇化疗前和一个周期后分别服用研究药物。研究的总持续时间为五周。在整个研究过程中，患者将被随机(3：1)接受Filgratim-SD/01或Neupogen治疗。在A部分，化疗前，随机接受研究药物的患者将在第一天根据剂量分配接受一次注射。随机接受G-CSF的患者将以每天5微克/公斤的速度皮下注射，持续5天或直到ANC达到75,000。患者将连续12天每天抽血进行常规血细胞计数和化学、药代动力学和CD34分析。化疗方案为卡铂(AUC，6，30min)加紫杉醇(24小时，225 mg/m2)。化疗完成24小时后，患者将接受研究药物或G-CSF，剂量为A部分。接受G-CSF的患者将以5微克/公斤/天的剂量服用，直到ANC&GT；10,000。在B部分期间，将连续15天每天抽血进行类似于A部分的分析。A部分和B部分将使用药代动力学和药效学方法来比较G-CSF和FILEGRIM-SD/01。描述性统计将用于描述A部分期间的中性粒细胞和CD34计数的特征。在B部分，将使用广义线性模型来估计FILGRGIM-SD/01剂量与中性粒细胞反应的相关性。这种中性粒细胞反应将通过G-CSF抢救的需要以及严重中性粒细胞减少的持续时间来衡量。每个剂量组中需要G-CSF抢救的患者的比例将与G-CSF组中符合抢救标准的患者的比例进行描述性比较。预计该药物的副作用将与G-CSF相似，最常见的不良反应是骨痛。由于研究药物的持续作用，骨疼痛可能比G-CSF更严重和/或持续更长时间。结果：13名入选患者中有12名完成了研究。副作用仅限于轻度到中度的骨痛，与所有剂量水平的标准非格列辛相似。中性粒细胞升高的程度和持续时间以及动员的祖细胞数量存在剂量反应效应。这项研究以摘要的形式在1998年5月的美国临床肿瘤学会上发表。一份手稿正在进行中。意义：这项研究可能有助于改进化疗引起的中性粒细胞减少症的治疗方式。未来的计划将取决于这次试验的结果。

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. It is expected that the side effect profile of this drug will mimic that of G-CSF, with the most common adverse reaction being bone pain. It is possible, because of the sustained action of the study drug, that bone pain may be more severe and/or of longer duration than that associated with G-CSF. RESULTS: Twelve of thirteen enrolled patients completed the study. Side effects were limited to bone pain which was mild to moderate in intensity, similar to standard filgrastim at all dose levels. There was a dose response effect with respect to the degree of neutrophil elevation and its duration and in terms of the number of progenitor cells mobilized. The study was presented as an abstract at the American Society of Clinical Oncology in May, 1998. A manuscript is in progress. SIGNIFICANCE: This study may contribute to an improved form of therapy for chemotherapy induced neutropenia. The future plans will depend on the results of this trial.