Ramanathan Ramesh K, Egorin Merrill J, Eiseman Julie L, Ramalingam Suresh, Friedland David, Agarwala Sanjiv S, Ivy S Percy, Potter Douglas M, Chatta Gurkamal, Zuhowski Eleanor G, Stoller Ronald G, Naret Cynthia, Guo Jianxia, Belani Chandra P
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
Clin Cancer Res. 2007 Mar 15;13(6):1769-74. doi: 10.1158/1078-0432.CCR-06-2233.
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.
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.
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.
The recommended phase II doses of 17AAG are 175 to 200 mg/m(2) when given twice a week and consistently cause elevations in PBMC HSP70.
主要目的是确定每周给药两次的17 -（烯丙胺基）- 17 - 去甲氧基格尔德霉素（17AAG）的剂量限制性毒性（DLT）和推荐的II期剂量。
将递增剂量的17AAG静脉注射给3至6名患者组成的队列。方案A（每周两次，共3周，每4周重复）的剂量水平为100、125、150、175和200mg/m²，方案B（每周两次，共2周，每3周重复）的剂量水平为150、200和250mg/m²。采集外周血单个核细胞（PBMC）以评估热休克蛋白（HSP）90和HSP90客户蛋白。
共纳入44例患者，其中方案A组32例，方案B组12例。在方案A中，200mg/m²剂量时，6例患者中有2例出现DLT（1例3级血小板减少和1例3级腹痛）。在方案B中，接受250mg/m²治疗的2例患者均出现DLT（3级头痛伴恶心/呕吐）。超过5%的患者出现的3/4级毒性反应为肝酶可逆性升高（47%）、恶心（9%）、呕吐（9%）和头痛（5%）。未观察到客观肿瘤反应。监测的PBMC蛋白中唯一一致的变化是HSP70浓度增加0.8至30倍，但这些变化与剂量无关。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剂量与第2周期第一次17AAG剂量之间恢复到基线水平。
17AAG每周给药两次时，推荐的II期剂量为175至200mg/m²，且持续导致PBMC HSP70升高。
