Cairo M S, Krailo M D, Weinthal J A, Secola R, Bergeron S, van de Ven C, Blazar B R, Garrison L, Reaman G H
Georgetown University Medical Center, Washington, DC, USA.
Cancer. 1998 Oct 1;83(7):1449-60.
This Phase I trial was developed to determine the safety, biologic activity, and effects on hematopoietic recovery of PIXY321 following ifosfamide, carboplatin, and etoposide chemotherapy for children with recurrent or refractory solid tumors.
Children (age < 22 years at diagnosis) received ifosfamide 1800 mg/m2/day x 5 days, carboplatin 400 mg/m2/day x 2 days, and etoposide 100 mg/m2/day x 5 days, followed by daily subcutaneous administration of PIXY321. Dose-limiting toxicity was defined as Grade IV toxicity related to PIXY321. Pharmacokinetic and endogenous cytokine production studies were conducted during Course 1, and peripheral blood (PB) progenitor cell and receptor expression studies were conducted during Course 1 when the white blood cell count recovered to > or=1000/mm3.
Twenty-four children received ifosfamide, carboplatin, and etoposide chemotherapy plus PIXY321, the latter at doses of 500 /g/m2/day (n=3), 750 microg/m2/day (n=6), 1000 microg/m2/day (n=9), or 500 microg/m2/twice a day (n=6). PIXY321 was well tolerated, with only 1 dose-limiting toxicity (chills, occurring at a dose of 750 microg/m2/day). The maximum tolerated dose was not reached in this study. The median days to absolute neutrophil count recovery (> or =1000/mm3) and platelet recovery (>100,000/mm3) during Course 1 following PIXY321 (1000 microg/ m2/day) were 22 days (range, 5-33 days) and 20 days (range, 5-31 days), respectively. There was a 2500, 5000, 3000, and 390% increase in PB granulocyte-macrophage colony-forming units, erythrocyte blast-forming units, granulocyte erythrocyte macrophage and megakaryocyte colony-forming units, and CD34+ cells, respectively.
In summary, this pediatric Phase I trial demonstrated that PIXY321 was well tolerated by children and resulted in platelet recovery a median of 20 days after ICE chemotherapy and an increase in the number of PB progenitor cells above baseline. However, based on recent negative results with PIXY321 in randomized Phase II/III trials involving adult subjects, PIXY321 is not currently available for future trials involving children.
本I期试验旨在确定对于复发或难治性实体瘤患儿，在接受异环磷酰胺、卡铂和依托泊苷化疗后使用PIXY321的安全性、生物学活性及对造血恢复的影响。
儿童（诊断时年龄<22岁）接受异环磷酰胺1800mg/m²/天×5天、卡铂400mg/m²/天×2天、依托泊苷100mg/m²/天×5天，随后每日皮下注射PIXY321。剂量限制性毒性定义为与PIXY321相关的IV级毒性。在第1疗程期间进行药代动力学和内源性细胞因子产生研究，在第1疗程白细胞计数恢复至≥1000/mm³时进行外周血（PB）祖细胞和受体表达研究。
24名儿童接受了异环磷酰胺、卡铂和依托泊苷化疗加PIXY321，后者的剂量分别为500μg/m²/天（n = 3）、750μg/m²/天（n = 6）、1000μg/m²/天（n = 9）或500μg/m²/天，每日2次（n = 6）。PIXY321耐受性良好，仅出现1例剂量限制性毒性（寒战，发生于750μg/m²/天的剂量）。本研究未达到最大耐受剂量。在PIXY321（1000μg/m²/天）治疗后的第1疗程期间，绝对中性粒细胞计数恢复（≥1000/mm³）和血小板恢复（>100,000/mm³）的中位天数分别为22天（范围5 - 33天）和20天（范围5 - 31天）。PB粒细胞 - 巨噬细胞集落形成单位、红细胞爆式集落形成单位、粒细胞红细胞巨噬细胞和巨核细胞集落形成单位以及CD34 +细胞分别增加了2500%、5000%、3000%和390%。
总之，这项儿科I期试验表明，儿童对PIXY321耐受性良好，在ICE化疗后血小板恢复的中位时间为20天，且PB祖细胞数量比基线增加。然而，基于近期PIXY321在涉及成年受试者的随机II/III期试验中的阴性结果，PIXY321目前不可用于未来涉及儿童的试验。
