Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer
Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer
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DOI：
10.1200/jco.2007.14.9633
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发表时间：
2008-06-20
影响因子：
45.3
通讯作者：
Burris, Howard A., III
中科院分区：
文献类型：
--
作者：
LoRusso, Patricia M.;Jones, Suzanne F.;Burris, Howard A., III
目的：本I期研究评估了拉帕替尼和多西他赛在晚期实体瘤患者中的安全性、最佳耐受方案（OTR）、药代动力学、药效学和初步临床活性。患者和方法拉帕替尼（每天口服一次，连续）和多西他赛（静脉注射，每3周一次）的剂量在至少3名患者的队列中根据第一个治疗周期的剂量限制性毒性增加，直到达到OTR。由于剂量限制性毒性（中性粒细胞减少），该方案进行了修订，纳入了pegfilgrastim，并进行了第二个剂量递增阶段，以确定多西他赛、拉帕替尼和pegfilgrastim联合使用的OTR。在确定OTR后，测定拉帕替尼和多西他赛的药代动力学，以估计在OTR剂量水平上多西他赛和拉帕替尼之间相互作用的可能性。结果共纳入52例晚期实体瘤患者。拉帕替尼和多西他赛联合pegfilgrastim的OTR剂量水平分别为1,250 mg（每日1次）和75 mg/m(2)（每3周1次）。总体而言，不良事件（ae）的严重程度为轻度至中度。大多数患者报告的药物相关不良反应（>= 25%）为腹泻（56%）、皮疹（52%）、疲劳（27%）和恶心（25%）。在43例可评估临床反应的患者中，2例患者证实部分反应。拉帕替尼（曲线下面积，最大血清浓度）和多西他赛（曲线下面积，清除率）合用时药代动力学与单独给药时无显著差异。结论多西他赛、拉帕替尼联合培非格拉西汀耐受性良好。未观察到药代动力学相互作用。在这个I期药物联合试验中可以看到临床活性。
PurposeThis phase I study assessed the safety, optimally tolerated regimen (OTR), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of lapatinib and docetaxel in patients with advanced solid tumors.Patients and MethodsDoses of lapatinib (oral once daily, continuous) and docetaxel (intravenous, every 3 weeks) were escalated in cohorts of at least three patients based on dose-limiting toxicities in the first treatment cycle until the OTR was reached. The protocol was amended to include pegfilgrastim because of dose-limiting toxicity (neutropenia), and a second dose-escalation phase was conducted to determine the OTR for the combination of docetaxel, lapatinib, and pegfilgrastim. After the determination of the OTR, the pharmacokinetics of lapatinib and docetaxel were determined to estimate the potential for an interaction between docetaxel and lapatinib at the OTR dose level.ResultsFifty-two patients with advanced solid tumors were enrolled. The OTR dose level for lapatinib and docetaxel with pegfilgrastim was 1,250 mg (once daily) and 75 mg/m(2) (once every 3 weeks), respectively. Overall, adverse events (AEs) were mild to moderate in severity. The drug-related AEs reported by most patients (>= 25%) were diarrhea (56%), rash (52%), fatigue (27%), and nausea (25%). Of 43 patients assessable for clinical response, two patients had confirmed partial responses. The pharmacokinetics of lapatinib (area under the curve, maximum serum concentration) and docetaxel (area under the curve, clearance) in combination were not significantly different than when the drugs are administered separately.ConclusionThe combination of docetaxel and lapatinib with pegfilgrastim was well tolerated. No pharmacokinetic interaction was observed. Clinical activity was seen in this phase I drug combination trial.