Munster Pamela N, Britten Carolyn D, Mita Monica, Gelmon Karen, Minton Susan E, Moulder Stacy, Slamon Dennis J, Guo Feng, Letrent Stephen P, Denis Louis, Tolcher Anthony W
Department of Interdisciplinary Oncology, Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Clin Cancer Res. 2007 Feb 15;13(4):1238-45. doi: 10.1158/1078-0432.CCR-06-1539.
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.
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.
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.
Dose-limiting toxicities included hyperbilirubinemia, 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 II 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.
在表达HER2的晚期实体瘤恶性肿瘤患者中，测试可逆、高度选择性口服HER2酪氨酸激酶抑制剂CP-724,714的耐受性、安全性及推荐的II期剂量。
一项I期试验评估了递增剂量的CP-724,714，以21天为周期每日给药。在系列血样以及治疗前和治疗后的肿瘤及皮肤活检样本中评估药代动力学/药效学。
30名女性患者[中位年龄51岁（范围37 - 71岁）；中位体能状态为1（范围0 - 1）]接受了四个剂量水平的CP-724,714：每日一次250mg（4例患者）、每日两次250mg（15例患者）、每日三次250mg（6例患者）以及每日两次400mg（5例患者）。由于可逆性胆汁淤积性肝功能障碍，每日两次400mg和每日三次250mg给药不可行。与治疗相关的不良事件包括恶心（58%）、乏力（23%）、高胆红素血症（27%）、转氨酶升高（30%）和皮疹（30%）；未观察到腹泻和心肌病。28例可评估患者中未观察到客观缓解；8例（29%）患者病情稳定。27例（96%）患者曾接受过曲妥珠单抗治疗且接受过大量预处理（中位既往化疗次数为6次；范围1 - 11次）。全身暴露超过了临床前研究所需的体内疗效阈值。
剂量限制性毒性包括高胆红素血症、丙氨酸转氨酶升高、血小板减少和肺栓塞。尽管方案规定的CP-724,714最大耐受剂量为每日三次250mg，但由于晚期周期肝毒性过大，推荐的II期剂量为每日两次250mg。尽管患者此前接受过广泛治疗，但29%的患者病情稳定。已启动针对乳腺癌患者的II期试验。
