LoRusso Patricia M, Jones Suzanne F, Koch Kevin M, Arya Nikita, Fleming Ronald A, Loftiss Jill, Pandite Lini, Gadgeel Shirish, Weber Barbara L, Burris Howard A
Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
J Clin Oncol. 2008 Jun 20;26(18):3051-6. doi: 10.1200/JCO.2007.14.9633.
This 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.
Doses 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.
Fifty-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 (>or= 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.
The 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.
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、药效学及初步临床活性。
根据首个治疗周期中的剂量限制性毒性，以至少三名患者为一组逐步增加拉帕替尼（每日口服一次，持续给药）和多西他赛（静脉注射，每3周一次）的剂量，直至达到最佳耐受方案。由于剂量限制性毒性（中性粒细胞减少），方案进行了修订，纳入了培非格司亭，并进行了第二个剂量递增阶段以确定多西他赛、拉帕替尼和培非格司亭联合用药的最佳耐受方案。确定最佳耐受方案后，测定拉帕替尼和多西他赛的药代动力学，以评估在最佳耐受方案剂量水平下多西他赛与拉帕替尼之间相互作用的可能性。
入组了52例晚期实体瘤患者。拉帕替尼、多西他赛与培非格司亭联合用药的最佳耐受方案剂量水平分别为1250 mg（每日一次）和75 mg/m²（每3周一次）。总体而言，不良事件的严重程度为轻度至中度。大多数患者（≥25%）报告的与药物相关的不良事件为腹泻（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，有2例患者确认部分缓解。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）联合用药时的药代动力学与单独给药时无显著差异。
多西他赛、拉帕替尼与培非格司亭联合用药耐受性良好。未观察到药代动力学相互作用。在该I期药物联合试验中观察到了临床活性。
