First study of the safety, tolerability, and pharmacokinetics of CP-724,714 in patients with advanced malignant solid HER2-expressing tumors
First study of the safety, tolerability, and pharmacokinetics of CP-724,714 in patients with advanced malignant solid HER2-expressing tumors
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DOI：
10.1158/1078-0432.ccr-06-1539
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发表时间：
2007-02-15
影响因子：
11.5
通讯作者：
Tolcher, Anthony W.
中科院分区：
文献类型：
--
作者：
Munster, Pamela N.;Britten, Carolyn D.;Tolcher, Anthony W.
目的：测试CP-724,714的耐受性、安全性和推荐的II期剂量，CP-724,714是一种可逆的、高选择性的口服HER2酪氨酸激酶抑制剂，用于治疗表达HER2的晚期实体肿瘤患者。实验设计：I期试验评估CP-724,714每天递增剂量，21天为一个周期。结果：30例女性患者[中位年龄51岁(37-71岁)；中位表现状态1例(0-1)]接受CP-724,714四种剂量水平的治疗：250 mg 1次/d(4例)，250 mg/d 2次(15例)，250 mg/d 3次(6例)，400 mg/d(5例)。由于可逆性的淤胆性肝功能障碍，每天两次400毫克和每天三次250毫克的剂量是不可行的。与治疗相关的不良反应有恶心(58%)、乏力(23%)、高胆红素血症(27%)、转氨酶升高(30%)和皮疹(30%)；没有观察到腹泻和心肌病。在28名可评估的患者中没有观察到客观反应；8名(29%)患者病情稳定。27名患者(96%)以前接受曲妥珠单抗治疗，并接受了大量的预治疗(化疗前中位数为6；范围为1-11)。结论：剂量限制毒性包括高胆红素血症、丙氨酸氨基转移酶升高、血小板减少和肺血栓形成。尽管方案规定的CP-724,714的最大耐受量为每天三次250毫克，但由于过多的晚期肝毒性，建议的第11期剂量为每天两次250毫克。尽管之前接受了广泛的治疗，但29%的患者病情稳定。一项针对乳腺癌患者的II期试验已经启动。
Purpose: To test the tolerability, safety, and recommended phase II dose of CP-724,714, a reversible, highly selective, oral HER2 tyrosine kinase inhibitor in patients with advanced solid tumor malignancies that express HER2.Experimental Design: A phase I trial evaluated escalating doses of CP-724,714, administered daily in 21-day cycles. Pharmacokinetics/pharmacodynamics were evaluated in serial blood samples and in pretreatment and posttreatment tumor and skin biopsies.Results: Thirty female patients [median age, 51 years (range, 37-71); median performance status, 1 (range, 0-1)] received CP-724,714 at four dose levels: 250 mg once daily (4 patients), 250 mg twice daily (15 patients), 250 mg thrice daily (6 patients), and 400 mg twice daily (5 patients). Dosing at 400 mg twice daily and 250 mg thrice daily was not feasible due to reversible, cholestatic liver dysfunction. Treatment-related adverse events were nausea (58%), asthenia (23%), hyperbilirubinemia (27%), elevated transaminases (30%), and skin rash (30%); neither diarrhea nor cardiomyopathy was observed. No objective responses were observed in 28 evaluable patients; 8 (29%) patients had stable disease. Twenty-seven (96%) patients received prior trastuzumab and were heavily pretreated (median prior chemotherapy, 6; range, 1-11). Systemic exposure exceeded the in vivo efficacy threshold required in preclinical studies.Conclusions: Dose-limiting toxicities included hyperbilrubinemia, elevated alanine aminotransferase, thrombocytopenia and pulmonary embolus. Although the protocol-specified maximum tolerated dose of CP-724,714 was 250 mg thrice daily, the recommended phase 11 dose was 250 mg twice daily due to excessive late-cycle hepatotoxicity. Despite extensive prior treatment, 29% of patients had stable disease. A phase II trial has been initiated in patients with breast cancer.