Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Cancer Chemother Pharmacol. 2012 Apr;69(4):1089-97. doi: 10.1007/s00280-011-1789-3. Epub 2011 Nov 29.
To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies.
Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m(2). 17-AAG was administered over 1-2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m(2) in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot.
Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m(2)-17-AAG 650 mg/m(2) due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed.
The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m(2) and 17-AAG 500 mg/m(2).
在每 21 天接受一次多西紫杉醇治疗的晚期实体瘤恶性肿瘤患者中，联合应用 17-烯丙氨基-17-去甲氧基格尔德霉素（17-AAG）时，确定最大耐受剂量（MTD）、临床毒性和药代动力学。
多西紫杉醇以 55、70 和 75mg/m²的剂量输注 1 小时。17-AAG 在多西紫杉醇输注完成后 1-2 小时内输注，剂量递增范围为 12 个患者队列的 80 至 650mg/m²。在第 1 周期期间收集血清进行药代动力学和药效学研究。多西紫杉醇、17-AAG 和 17-AG 通过高效液相色谱法测定。通过免疫印迹法监测外周血单核细胞中 17-AAG 的生物学效应。
49 例患者接受多西紫杉醇和 17-AAG 治疗。最常见的全因 3 级和 4 级毒性为白细胞减少、淋巴细胞减少和中性粒细胞减少。未定义 MTD；然而，观察到 3 种剂量限制毒性，包括 2 例中性粒细胞减少性发热和 1 例交界性心动过缓。由于患者对基于 DMSO 的 17-AAG 制剂不耐受，导致延迟毒性，因此在多西紫杉醇 75mg/m²-17-AAG 650mg/m² 时停止了剂量递增。在 46 例可评估患者中，1 例肺癌患者出现部分缓解。肺癌、前列腺癌、黑色素瘤和膀胱癌患者观察到轻微缓解。观察到减少的多西紫杉醇清除率与 17-AAG 剂量水平之间存在相关性。
多西紫杉醇与 17-AAG 联合应用于成人实体瘤患者耐受性良好，尽管患者对 DMSO 制剂不耐受，无法进一步增加剂量。推荐的 II 期剂量为多西紫杉醇 70mg/m²和 17-AAG 500mg/m²。
