Millward M J, House C, Bowtell D, Webster L, Olver I N, Gore M, Copeman M, Lynch K, Yap A, Wang Y, Cohen P S, Zalcberg J
Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
Br J Cancer. 2006 Oct 9;95(7):829-34. doi: 10.1038/sj.bjc.6603331. Epub 2006 Sep 12.
Midostaurin (PKC412A), N-benzoyl-staurosporine, potently inhibits protein kinase C alpha (PKCalpha), VEGFR2, KIT, PDGFR and FLT3 tyrosine kinases. In mice, midostaurin slows growth and delays lung metastasis of melanoma cell lines. We aimed to test midostaurin's safety, efficacy and biologic activity in a Phase IIA clinical trial in patients with metastatic melanoma. Seventeen patients with advanced metastatic melanoma received midostaurin 75 mg p.o. t.i.d., unless toxicity or disease progression supervened. Patient safety was assessed weekly, and tumour response was assessed clinically or by CT. Tumour biopsies and plasma samples obtained at entry and after 4 weeks were analysed for midostaurin concentration, PKC activity and multidrug resistance. No tumour responses were seen. Two (12%) patients had stable disease for 50 and 85 days, with minor response in one. The median overall survival was 43 days. Seven (41%) discontinued treatment with potential toxicity, including nausea, vomiting, diarrhoea and/or fatigue. One patient had >50% reduction in PKC activity. Tumour biopsies showed two PKC isoforms relatively insensitive to midostaurin, out of three patients tested. No modulation of multidrug resistance was demonstrated. At this dose schedule, midostaurin did not show clinical or biologic activity against metastatic melanoma. This negative trial reinforces the importance of correlating biologic and clinical responses in early clinical trials of targeted therapies.
米哚妥林（PKC412A），N-苯甲酰-星孢菌素，能有效抑制蛋白激酶Cα（PKCα）、血管内皮生长因子受体2（VEGFR2）、干细胞生长因子受体（KIT）、血小板衍生生长因子受体（PDGFR）和FMS样酪氨酸激酶3（FLT3）酪氨酸激酶。在小鼠中，米哚妥林可减缓黑色素瘤细胞系的生长并延缓其肺转移。我们旨在通过一项IIA期临床试验来测试米哚妥林对转移性黑色素瘤患者的安全性、疗效和生物学活性。17例晚期转移性黑色素瘤患者口服米哚妥林75毫克，每日3次，除非出现毒性反应或疾病进展。每周评估患者安全性，通过临床检查或CT评估肿瘤反应。对入组时及4周后获取的肿瘤活检组织和血浆样本进行米哚妥林浓度、PKC活性和多药耐药性分析。未观察到肿瘤缓解。2例（12%）患者疾病稳定50天和85天，其中1例有轻微反应。中位总生存期为43天。7例（41%）患者因潜在毒性反应停药，包括恶心、呕吐、腹泻和/或疲劳。1例患者PKC活性降低>50%。在3例接受检测的患者中，肿瘤活检显示有两种PKC同工型对米哚妥林相对不敏感。未显示多药耐药性的调节。在此剂量方案下，米哚妥林对转移性黑色素瘤未显示出临床或生物学活性。这项阴性试验强化了在靶向治疗的早期临床试验中关联生物学反应和临床反应的重要性。
