Rubin Eric H, Rothermel John, Tesfaye Fisseha, Chen Tianling, Hubert Martine, Ho Yu-Yun, Hsu Chyi-Hung, Oza Amit M
Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
J Clin Oncol. 2005 Dec 20;23(36):9120-9. doi: 10.1200/JCO.2005.03.0981. Epub 2005 Nov 21.
To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors.
Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration.
Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy.
Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.
评估天然埃坡霉素B——每周一次帕妥珠利在晚期实体瘤患者中的安全性和最大耐受剂量（MTD）。
患者接受帕妥珠利（0.3至3.6mg/m²）治疗，采用6周用药/3周停药或3周用药/1周停药方案。确定每种给药方案的剂量限制性毒性（DLT）、MTD和药代动力学。
入组91例患者。最常见的肿瘤类型包括卵巢癌、乳腺癌和结肠癌。采用6周用药/3周停药或3周用药/1周停药方案时，帕妥珠利剂量低于2.5mg/m²时耐受性良好。在更高剂量时，两种给药方案均观察到DLT，腹泻是最常见的DLT。两种治疗方案的MTD均为2.5mg/m²。短时间输注后，帕妥珠利血药浓度呈多相下降，终末半衰期为4天。药物清除不通过肾脏，且与体表面积无关。在所评估的剂量范围内，全身药物暴露大致与剂量成正比。3例患者获得部分缓解，31例患者病情稳定。2例获得部分缓解的患者之前接受过紫杉烷类治疗。
采用6周用药/3周停药或3周用药/1周停药方案，以2.5mg/m²的剂量给药时，帕妥珠利耐受性良好。与小鼠研究不同，帕妥珠利在人体内的终末半衰期相对较长。先前接受紫杉烷类治疗的患者出现部分缓解，这与有前景的临床前结果一致。
