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首页> 外文OA文献 >ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.
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ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.

机译：ZD1839是一种选择性的口服表皮生长因子受体酪氨酸激酶抑制剂，在实体瘤患者中具有良好的耐受性和活性：I期试验的结果。

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PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.
机译：目的：研究口服，选择性表皮生长因子受体酪氨酸激酶抑制剂ZD1839在实体恶性肿瘤患者中的耐受性，药代动力学和抗肿瘤活性。患者和方法：这是一个开放的，第一阶段，逐步提高的多剂量耐受性和药代动力学试验。 ZD1839每天给药一次，连续14天，然后停药14天。剂量递增从50 mg / d开始，一直持续到925 mg或直到观察到一致的剂量限制毒性（DLT）。结果：64名患者进入了八个剂量水平。与剂量相关的最常见的1级和2级不良事件是痤疮样（或毛囊炎）皮疹，恶心和腹泻。接受700 mg / d治疗的9名患者中有3名出现了DLT（可逆3级腹泻）。三年级和四年级的事件很少见。 ZD1839的暴露与剂量成正比，平均终末半衰期为48小时（范围为37至65）。 16例非小细胞肺癌（NSCLC）患者中有4例从ZD1839 300到700 mg / d观察到客观的部分反应。总体而言，有16名患者继续研究≥3个月，其中有7名患者（5名NSCLC，包括其中3名部分缓解的患者）继续研究≥6个月。结论：ZD1839具有良好的耐受性，DLT的剂量远高于观察到的抗肿瘤活性。药代动力学分析证实，ZD1839适合作为每日一次的口服片剂制剂给药。正在对NSCLC进行II期单药治疗和III期联合试验，以进一步研究ZD1839的疗效，耐受性和最佳每日剂量。

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