Open-Label, Exploratory Phase II Trial of Oral Itraconazole for the Treatment of Basal Cell Carcinoma
Open-Label, Exploratory Phase II Trial of Oral Itraconazole for the Treatment of Basal Cell Carcinoma
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DOI：
10.1200/jco.2013.49.9525
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发表时间：
2014-03-10
影响因子：
45.3
通讯作者：
Tang, Jean Y.
中科院分区：
文献类型：
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作者：
Kim, Daniel J.;Kim, James;Tang, Jean Y.
目的
伊曲康唑是一种经美国食品药品监督管理局批准的抗真菌药物，它可抑制刺猬（HH）信号通路，而该通路是基底细胞癌（BCC）肿瘤发生的关键驱动因素，并能减少小鼠体内BCC的生长。我们评估了伊曲康唑对人类BCC肿瘤中HH通路以及肿瘤大小的影响。
患者与方法
将患有直径>4mm的单个BCC肿瘤的患者纳入两个队列，分别接受口服伊曲康唑治疗，队列A为每天两次，每次200mg，持续1个月；队列B为每天两次，每次100mg，平均持续2.3个月。主要终点是生物标志物的变化：Ki67肿瘤增殖和HH活性（GLI1 mRNA）。次要终点包括患有多个肿瘤的部分患者的肿瘤大小变化。
结果
共纳入29例患者，其中19例接受伊曲康唑治疗。伊曲康唑治疗与两例不良事件相关（2级疲劳和4级充血性心力衰竭）。伊曲康唑使细胞增殖减少45%（P = 0.04），HH通路活性降低65%（P = 0.03），肿瘤面积减少24%（95%置信区间，18.2% - 30.0%）。在8例患有多个未经活检肿瘤的患者中，4例达到部分缓解，4例病情稳定。未接受治疗的对照患者以及先前接受维莫德吉治疗的患者的肿瘤在增殖或肿瘤大小方面无显著变化。
结论
伊曲康唑在人类中具有抗BCC活性。这些结果为更大规模、更长时间的试验以评估伊曲康唑的临床疗效提供了依据，尤其是相对于其他HH通路抑制剂而言。
Purpose Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors.Patients and Methods Patients with one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors.Results A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size.Conclusion Itraconazole has anti-BCC activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other HH pathway inhibitors.