Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers
Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers
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DOI：
10.1158/1078-0432.ccr-06-2233
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发表时间：
2007-03-15
影响因子：
11.5
通讯作者：
Belani, Chandra P.
中科院分区：
文献类型：
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作者：
Ramanathan, Ramesh K.;Egorin, Merrill J.;Belani, Chandra P.
目的：主要目的是确定17-（烯丙胺）-17-去甲氧基格尔达霉素（17AAG）的剂量限制性毒性（DLT）和推荐的II期剂量，每周给药两次。实验设计：递增剂量的17AAG静脉注射给3 - 6名患者。方案A（每周两次x 3周，每4周）的剂量水平为100、125、150、175和200 mg/m(2)，方案B（每周两次x 2周，每3周）的剂量水平为150、200和250 mg/m(2)。采集外周血单个核细胞（PBMC）检测热休克蛋白（HSP） 90和客户蛋白（HSP90）。结果：44例患者入组，32例A组，12例b组。在200 mg/m(2)的A组，6例患者中有2例出现了dlt（1例3级血小板减少症和1例3级腹痛）。在方案B中，两名接受250 mg/m剂量治疗的患者均出现DLT（3级头痛伴恶心/呕吐）。bbb5 %的患者出现3/4级毒性反应，包括可逆性肝酶升高（47%）、恶心（9%）、呕吐（9%）和头痛（5%）。未观察到客观的肿瘤反应。监测到的PBMC蛋白中唯一一致的变化是HSP70浓度增加0.8- 30倍，但这些不是剂量依赖性的。PBMC HSP70的增加在整个治疗周期中持续存在，但在第1周期最后一次17AAG剂量和第2周期第一次17AAG剂量之间恢复到基线水平。结论：推荐的17AAG II期剂量为175 ~ 200mg /m2，每周给药两次，并持续引起PBMC HSP70升高。
Purpose: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week.Experimental Design: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly x 3 weeks, every 4 weeks) were 100, 125, 150,175, and 200 mg/m(2) and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m(2). Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins.Results: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m(2), DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m(2) developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2.Conclusions: The recommended phase II doses of 17AAG are 175 to 200 mg/m2 when given twice a week and consistently cause elevations in PBMC HSP70.