Modi Shanu, Stopeck Alison T, Gordon Michael S, Mendelson David, Solit David B, Bagatell Rochelle, Ma Weining, Wheler Jennifer, Rosen Neal, Norton Larry, Cropp Gillian F, Johnson Robert G, Hannah Alison L, Hudis Clifford A
Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
J Clin Oncol. 2007 Dec 1;25(34):5410-7. doi: 10.1200/JCO.2007.11.7960.
This phase I study examined whether a heat shock protein (Hsp) 90 inhibitor tanespimycin (17-AAG; KOS-953) could be administered safely in combination with trastuzumab at a dose that inhibits Hsp90 function in vivo in lymphocytes.
Patients with an advanced solid tumor progressing during standard therapy were eligible. Patients were treated with weekly trastuzumab followed by intravenous tanespimycin, assessed in escalating dose levels.
Twenty-five patients were enrolled onto four tanespimycin dose levels: 225 (n = 4), 300 (n = 3), 375 (n = 8), and 450 mg/m2 (n = 10). Dose-limiting toxicity (DLT) was observed at the third and fourth cohort (1 patient each): more than 2-week delay for grade 4 fatigue/grade 2 nausea and anorexia (375 mg/m2); more than 2-week delay for thrombocytopenia (450 mg/m2). Drug-related grade 3 toxicity included emesis, increased ALT, hypersensitivity reactions (two patients each), and drug-induced thrombocytopenia (n = 1). Common mild to moderate toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT, and anorexia. Pharmacokinetic analysis demonstrated no difference in tanespimycin kinetics with or without trastuzumab. Pharmacodynamic testing showed reactive induction of Hsp70 (a marker of Hsp90 inhibition) in lymphocytes at all dose levels. Antitumor activity was noted (partial response, n = 1; minor response, n = 4; stable disease > or = 4 months, n = 4). Tumor regressions were seen only in patients with human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer.
Tanespimycin plus trastuzumab is well tolerated and has antitumor activity in patients with HER-2+ breast cancer whose tumors have progressed during treatment with trastuzumab. These data suggest that Hsp90 function can be inhibited in vivo to a degree sufficient to cause inhibition of tumor growth.
本I期研究探讨了热休克蛋白（Hsp）90抑制剂坦螺旋霉素（17-AAG；KOS-953）与曲妥珠单抗联合使用时，能否在抑制淋巴细胞体内Hsp90功能的剂量下安全给药。
符合条件的患者为在标准治疗期间病情进展的晚期实体瘤患者。患者接受每周一次的曲妥珠单抗治疗，随后静脉注射坦螺旋霉素，并按剂量递增水平进行评估。
25名患者被纳入四个坦螺旋霉素剂量水平组：225（n = 4）、300（n = 3）、375（n = 8）和450 mg/m²（n = 10）。在第三和第四队列中观察到剂量限制毒性（DLT）（各1例患者）：4级疲劳/2级恶心和厌食延迟超过2周（375 mg/m²）；血小板减少延迟超过2周（450 mg/m²）。与药物相关的3级毒性包括呕吐、ALT升高、过敏反应（各2例患者）和药物性血小板减少（n = 1）。常见的轻度至中度毒性包括疲劳、恶心、腹泻、呕吐、头痛、皮疹/瘙痒、AST/ALT升高和厌食。药代动力学分析表明，无论是否使用曲妥珠单抗，坦螺旋霉素的动力学均无差异。药效学测试显示，在所有剂量水平下，淋巴细胞中均有Hsp70（Hsp90抑制的标志物）的反应性诱导。观察到抗肿瘤活性（部分缓解，n = 1；轻微缓解，n = 4；疾病稳定≥4个月，n = 4）。仅在人表皮生长因子受体2（HER-2）阳性转移性乳腺癌患者中观察到肿瘤退缩。
坦螺旋霉素加曲妥珠单抗耐受性良好，对曲妥珠单抗治疗期间肿瘤进展的HER-2+乳腺癌患者具有抗肿瘤活性。这些数据表明，Hsp90功能在体内可被抑制到足以抑制肿瘤生长的程度。
