Albanell Joan, Montagut Clara, Jones Eileen T, Pronk Linda, Mellado Begoña, Beech Janette, Gascon Pere, Zugmaier Gerhard, Brewster Michael, Saunders Mark P, Valle Juan W
Medical Oncology Department, Hospital Clinic, Barcelona, Spain.
Clin Cancer Res. 2008 May 1;14(9):2726-31. doi: 10.1158/1078-0432.CCR-07-1980.
To study the safety, pharmacokinetics, and recommended dose of the combination of pertuzumab, a humanized monoclonal antibody HER2-dimerization inhibitor, and capecitabine in patients with advanced malignancies.
Patients that had progressed to standard treatment were treated with pertuzumab at a fixed dose of 1,050 mg given i.v. on day 1 plus capecitabine at doses of 825-1,000-1,250 mg/m(2), twice daily orally on days 1 to 14 of each 21-day treatment cycle, in three sequential cohorts. The pharmacokinetics of capecitabine and pertuzumab were studied. Patients received a single dose of capecitabine in a pretreatment phase (day -7) followed by serum sampling for capecitabine and its metabolites.
Nineteen patients were accrued and 18 were assessable. The combination of capecitabine and pertuzumab was well tolerated at all dose levels and no dose-limiting toxicities were observed. The most frequent adverse event was asthenia, which was grade 3 in two patients. One asymptomatic pulmonary embolism occurred. No other grade 3 or 4 adverse events or cardiac or left ventricular ejection fraction events were reported. There was no apparent change in the pharmacokinetics of capecitabine and its metabolites when combined with pertuzumab. The pharmacokinetics of pertuzumab was apparently not modified when administered with capecitabine. Disease stabilization was observed in 11 patients.
Pertuzumab and capecitabine were well tolerated at all dose levels. Escalation beyond the highest dose level tested was not planned, as this included the recommended doses of monotherapy for both drugs. In conclusion, this combination is ready for phase II testing.
研究人源化单克隆抗体HER2二聚化抑制剂帕妥珠单抗与卡培他滨联合用药在晚期恶性肿瘤患者中的安全性、药代动力学及推荐剂量。
对标准治疗无效的患者接受帕妥珠单抗治疗，固定剂量为1050mg，静脉注射，第1天给药，联合卡培他滨，剂量为825 - 1000 - 1250mg/m²，在每21天治疗周期的第1至14天，每日口服两次，分三个连续队列进行。研究了卡培他滨和帕妥珠单抗的药代动力学。患者在预处理阶段（第-7天）接受单剂量卡培他滨，随后采集血清样本检测卡培他滨及其代谢产物。
共纳入19例患者，18例可评估。卡培他滨与帕妥珠单抗联合用药在所有剂量水平均耐受性良好，未观察到剂量限制性毒性。最常见的不良事件是乏力，2例患者为3级。发生1例无症状肺栓塞。未报告其他3级或4级不良事件或心脏或左心室射血分数事件。卡培他滨及其代谢产物与帕妥珠单抗联合使用时，药代动力学无明显变化。帕妥珠单抗与卡培他滨联合给药时，其药代动力学明显未改变。11例患者病情稳定。
帕妥珠单抗和卡培他滨在所有剂量水平均耐受性良好。未计划提高至所测试的最高剂量水平以上，因为这包括两种药物单药治疗的推荐剂量。总之，该联合用药方案已准备好进行II期试验。
