Prados Michael D, Lamborn Kathleen R, Chang Susan, Burton Eric, Butowski Nicholas, Malec Mary, Kapadia Ami, Rabbitt Jane, Page Margaretta S, Fedoroff Ann, Xie Dong, Kelley Sean K
Department of Neurosurgery, University of California, San Francisco, CA 94143-0372, USA.
Neuro Oncol. 2006 Jan;8(1):67-78. doi: 10.1215/S1522851705000451.
The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmaco-kinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eightythree patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%-71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted.
本研究旨在确定厄洛替尼的最大耐受剂量,并单独或与替莫唑胺联合使用时,在有或没有酶诱导抗癫痫药物(EIAEDs)的情况下,对患有恶性胶质瘤的患者其药代动力学和安全性进行特征描述。在这项剂量递增研究中,患有稳定或进展性恶性原发性胶质瘤的患者单独接受厄洛替尼治疗或与替莫唑胺联合治疗。在每个治疗组中,患者根据是否同时服用EIAEDs进行分层。厄洛替尼以每日口服100mg开始,作为28天的治疗周期,剂量以每天50mg递增,直至500mg/天。替莫唑胺每28天连续5天以150mg/m²给药,在第二个周期剂量递增至200mg/m²。对83名患者进行了评估。皮疹、疲劳和腹泻是最常见的不良事件,通常为轻度至中度。对于多形性胶质母细胞瘤且未接受EIAEDs的患者,厄洛替尼的推荐2期剂量为200mg/天;对于接受替莫唑胺加厄洛替尼并同时服用EIAEDs的患者,为450mg/天;对于单独接受厄洛替尼并同时服用EIAEDs的患者,至少为500mg/天。在可评估反应的57名患者中,8名有部分缓解(PR)。57名患者中有6名无进展生存期超过6个月,其中4名患者有PR。与单独使用厄洛替尼相比,同时服用EIAEDs会降低厄洛替尼的暴露量(降低33%-71%)。厄洛替尼和替莫唑胺之间存在适度的药代动力学相互作用。良好的耐受性和抗肿瘤活性证据表明,有必要对厄洛替尼进行进一步研究。