Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Eur J Cancer. 2010 Jan;46(2):340-7. doi: 10.1016/j.ejca.2009.10.026. Epub 2009 Nov 27.
Phase I dose-escalation study to determine the toxicity and maximum tolerated dose (MTD) of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, administered on a twice weekly schedule in patients with advanced cancer.
17-DMAG was administered as a 1- to 2-h infusion twice weekly in 4-week cycles. An accelerated titration design was followed until toxicity was observed, at which point standard dose-escalation proceeded. MTD was defined as the dose at which no more than one of the six patients experienced a dose-limiting toxicity (DLT). Pharmacokinetics were assessed, and Hsp70 mRNA, whose gene product is a chaperone previously shown to be upregulated following the inhibition of Hsp90, was measured in peripheral blood mononuclear cells (PBMCs).
A total of 31 patients received 92 courses of treatment. The MTD was 21mg/m(2)/d; 20 patients were enrolled at this dose level. Nine patients had stable disease for a median of 4 (range 2-22) months. Both C(max) and AUC increased proportionally with dose. The most common toxicities were grade 1 or 2 fatigue, anorexia, nausea, blurred vision and musculoskeletal pain. DLTs were peripheral neuropathy and renal dysfunction. Expression of Hsp70 mRNA in PBMCs was highly variable.
Twice-weekly i.v. infusion of 17-DMAG is well tolerated, and combination phase I studies are warranted.
采用每周 2 次的给药方案，对晚期癌症患者进行 17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素（17-DMAG）的 I 期剂量递增研究，以确定其毒性和最大耐受剂量（MTD）。17-DMAG 是一种热休克蛋白 90（Hsp90）抑制剂，给药方式为 1-2 小时静脉输注，每 4 周为一个周期。采用加速滴定设计，直至观察到毒性，此时进行标准剂量递增。MTD 定义为 6 名患者中不超过 1 名发生剂量限制性毒性（DLT）的剂量。评估了药代动力学，测量了外周血单核细胞（PBMC）中 Hsp70mRNA 的表达，Hsp70mRNA 的基因产物是一种伴侣蛋白，先前的研究表明，在 Hsp90 抑制后其表达上调。
共 31 例患者接受了 92 个疗程的治疗。MTD 为 21mg/m2/d；20 例患者在此剂量水平入组。9 例患者疾病稳定，中位数为 4（范围 2-22）个月。Cmax 和 AUC 均与剂量成比例增加。最常见的毒性反应是 1 或 2 级疲劳、厌食、恶心、视力模糊和肌肉骨骼疼痛。DLT 为周围神经病变和肾功能障碍。PBMC 中 Hsp70mRNA 的表达高度可变。
每周 2 次静脉输注 17-DMAG 耐受性良好，值得开展联合 I 期研究。
