FILGRASTIM SD/01 IN NONSMALL CELL LUNG CANCER

目的：本I期研究的主要目的是比较非格司汀- sd /01与非格司汀的安全性、剂量反应、药效学和药代动力学特性。非格司汀- sd /01尚未在人体中进行测试。filgrastim - sd /01是在n端与聚乙二醇（PEG）分子共价结合的filgrastim （G-CSF, Neupogen）。聚乙二醇化的蛋白质减少清除率和增加半衰期的化合物，导致持续的持续效应。Filgrastim是一种谱系特异性造血生长因子，优先刺激中性粒细胞的生长、分化和功能。它已被FDA批准用于化疗诱导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。非格司汀- sd /01的优点是，单次注射可获得与重复注射非格司汀相同的类似药理作用。潜在的好处包括减少注射，提高病人的依从性，在病人不能去诊所的一段时间内不间断的治疗，以及减轻医疗支助人员的负担。方法：本研究针对需要化疗的非小细胞肺癌患者。该研究将分两部分进行，分别在卡铂/紫杉醇化疗一个周期前和一个周期后给药。研究的总持续时间为五周。在整个研究过程中，患者将被随机分配（3:1）接受非格司汀- sd /01或Neupogen。在A部分化疗前，随机分配接受研究药物的患者将在第1天根据剂量分配接受一次注射。随机分配到G-CSF组的患者将接受5 ug/kg/天的皮下注射，持续5天或直到ANC达到75000。患者将连续12天每天抽血，进行常规血液计数、化学、药代动力学和CD34分析。化疗将由卡铂（AUC为6,30 min输注）加紫杉醇（24小时输注，225 mg/M2）组成。化疗结束24小时后，患者接受a部分剂量的研究药物或G-CSF， G-CSF剂量为5 ug/kg/天，直至ANC 10万。每天会有血了连续15天在B部分分析类似于部分a .药代动力学和药效学方法将被用于比较g - csf和filgrastim-SD / 01在a和B部分将使用描述性统计描述中中性粒细胞和CD34计数部分a .广义线性模型将被用来估计filgrastim-SD协会/ 01剂量中性粒细胞反应本中性粒细胞反应B部分将被测量的g - csf的必要性抢救以及严重中性粒细胞减少的持续时间。将每个给药组中需要G-CSF抢救的患者比例与G-CSF组中符合抢救标准的患者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，骨痛可能比与G-CSF相关的疼痛更严重和/或持续时间更长。结果：13名入组患者中有12名完成了研究。副作用仅限于轻度至中度强度的骨痛，与所有剂量水平的标准非格昔汀相似。在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方面存在剂量反应效应。该研究于1998年5月作为摘要发表在美国临床肿瘤学会上。一份手稿正在进行中。意义：本研究可能有助于改善化疗引起的中性粒细胞减少症的治疗形式。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.