A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors.
A phase I trial of docetaxel and pulse-dose 17-allylamino-17-demethoxygeldanamycin in adult patients with solid tumors.
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DOI：
10.1007/s00280-011-1789-3
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发表时间：
2012-04
影响因子：
3
通讯作者：
Solit, David B.
中科院分区：
文献类型：
--
作者：
Iyer, Gopa;Morris, Michael J.;Rathkopf, Dana;Slovin, Susan F.;Steers, Macaulay;Larson, Steven M.;Schwartz, Lawrence H.;Curley, Tracy;DeLaCruz, Anthony;Ye, Qing;Heller, Glenn;Egorin, Merrill J.;Ivy, S. Percy;Rosen, Neal;Scher, Howard I.;Solit, David B.
旨在确定 17-烯丙氨基-17-去甲氧基格尔德霉素 (17-AAG) 与多西紫杉醇联合用药每 21 天一次在晚期实体瘤恶性肿瘤患者中的最大耐受剂量 (MTD)、临床毒性和药代动力学。多西紫杉醇给药时间超过 1 小时，剂量为 55、70 和 75 mg/m2。多西紫杉醇输注完成后，17-AAG 在 1-2 小时内以 80 至 650 mg/m2 的剂量递增，在 12 个患者队列中进行。在第 1 周期期间收集血清用于药代动力学和药效学研究。通过高效液相色谱法测定多西紫杉醇、17-AAG 和 17-AG 水平。通过免疫印迹监测外周血单核细胞中 17-AAG 的生物学效应。 49 名患者接受了多西紫杉醇和 17-AAG 治疗。最常见的 3 级和 4 级全因毒性是白细胞减少症、淋巴细胞减少症和中性粒细胞减少症。未定义 MTD；然而，观察到三种剂量限制性毒性，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，剂量从多西他赛 75 mg/m2-17-AAG 650 mg/m2 停止。在 46 名可评估患者中，1 名肺癌患者出现部分缓解。在肺癌、前列腺癌、黑色素瘤和膀胱癌患者中观察到轻微反应。观察到多西紫杉醇清除率降低与 17-AAG 剂量水平之间存在相关性。多西紫杉醇和 17-AAG 的组合在患有实体瘤的成年患者中具有良好的耐受性，尽管患者对 DMSO 制剂的不耐受阻碍了剂量的进一步增加。推荐的 II 期剂量为多西紫杉醇 70 mg/m2 和 17-AAG 500 mg/m2。
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/m2. 17-AAG was administered over 1–2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m2 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/m2-17-AAG 650 mg/m2 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/m2 and 17-AAG 500 mg/m2.
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影响因子：
8
作者：
Chandarlapaty, S.;Scaltriti, M.;Angelini, P.;Ye, Q.;Guzman, M.;Hudis, C. A.;Norton, L.;Solit, D. B.;Arribas, J.;Baselga, J.;Rosen, N.
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ROSEN, N
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45.3
作者：
Grem, JL;Morrison, G;Wilson, RH
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Wilson, RH
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作者：
Ramanathan, RK;Trump, DL;Egorin, MJ
通讯作者：
Egorin, MJ
影响因子：
45.3
作者：
Sequist, Lecia V.;Gettinger, Scott;Natale, Ronald
通讯作者：
Natale, Ronald