FILGRASTIM SD/01 IN NONSMALL CELL LUNG CANCER

目得：本I期研究的主要目的是比较非格司亭-SD/01与非格司亭的安全性、剂量反应、药效学和药代动力学特性。非格司亭-SD/01尚未在人体中进行测试。非格司亭-SD/01是在N-末端与聚乙二醇（PEG）分子共价结合的非格司亭（G-CSF，Neupogen）。蛋白质的聚乙二醇化降低了清除率并增加了化合物的半衰期，导致持续的持续效应。非格司亭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、严重慢性血小板减少症和干细胞动员。非格司亭-SD/01的优点是，单次注射可获得与重复注射非格司亭相同的相似药理学作用。潜在的好处将包括减少注射，提高患者的依从性，在患者无法访问诊所的时间段内不间断治疗，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。本研究将分两部分进行，在一个周期的卡铂/紫杉醇化疗前后给予研究药物。研究的总持续时间为五周。在整个研究期间，患者将随机（3：1）接受非格司亭-SD/01或Neupogen。在A部分化疗前，随机接受研究药物的患者将根据第1天的剂量分配接受一次注射。随机分配至G-CSF组的患者将接受5 ug/kg/天的皮下注射，持续5天或直至ANC达到75，000。患者将连续12天每天抽血，用于常规血细胞计数和化学、药代动力学和CD 34分析。化疗将包括卡铂（AUC 6，30分钟输注）加紫杉醇（24小时输注，225 mg/M2）。化疗完成后24小时，患者将接受研究药物或G-CSF，剂量与A部分相同。使用G-CSF的患者将以5 ug/kg/天给药直至ANC > 10，000。在B部分期间，将连续15天每天采血，进行与A部分相似的分析。将使用药代动力学和药效学方法比较A部分和B部分中的G-CSF和非格司亭-SD/01。描述性统计量将用于描述A部分的中性粒细胞和CD 34计数。在B部分，将使用广义线性模型估计非格司亭-SD/01剂量与中性粒细胞应答的相关性。该中性粒细胞应答将通过G-CSF急救的需要以及重度中性粒细胞减少的持续时间来测量。将每个给药组中需要G-CSF补救治疗的患者比例与G-CSF组中符合补救治疗标准的患者比例进行连续比较。预计这种药物的副作用特征将与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G-CSF相关的骨痛更严重和/或持续时间更长。结果：13例入组患者中有12例完成了研究。副作用仅限于轻度至中度的骨痛，与所有剂量水平的标准非格司亭相似。中性粒细胞升高的程度及其持续时间和动员的祖细胞数量方面存在剂量反应效应。这项研究于1998年5月在美国临床肿瘤学会上以摘要的形式发表。手稿正在制作中。意义：这项研究可能有助于改善化疗诱导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.