Multicenter phase II trial of the historic deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma
Multicenter phase II trial of the historic deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma
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DOI：
10.1097/cmr.0b013e328307c248
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发表时间：
2008-08-01
影响因子：
2.2
通讯作者：
Schadendorf, Dirk
中科院分区：
文献类型：
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作者：
Hauschild, Axel;Trefzer, Uwe;Schadendorf, Dirk
转移性黑色素瘤的全身治疗疗效低，需要新的治疗策略。组蛋白去乙酰化酶抑制剂被认为可以恢复肿瘤抑制基因的表达，诱导肿瘤细胞分化、生长停滞和凋亡。本研究旨在评价组蛋白去乙酰化酶抑制剂吡啶甲基-N-{4-[（2-氨基苯基）-氨基甲酰基]-苄基}-氨基甲酸酯（MS-275）在转移性黑色素瘤患者中的疗效、安全性和药代动力学。患有对至少一种早期全身治疗难治的不可切除的AJCC IV期黑色素瘤的患者被随机分配接受MS-275 3 mg每两周一次（第1 + 15天，A组）或7 mg每周一次（第1 + 8 + 15天，13组），以4周为周期。主要研究终点为客观肿瘤缓解，次要终点为安全性和至进展时间。根据Simon的两阶段设计，该研究最初允许每组14名患者入组;如果至少有1名应答者，则额外入组33名患者。在入组的28例患者中，未检测到客观缓解。A组4例（29%）患者和B组3例（21%）患者显示疾病稳定。两组的中位至进展时间相当，分别为55.5天和51.5天;中位总生存期为8.84个月。毒性为轻度至中度，恶心（39%）和低磷血症（29%）是最常报告的事件。未发生治疗相关严重不良事件。MS-275单药治疗耐受性良好，显示长期肿瘤稳定，但在预治疗的转移性黑色素瘤中无客观缓解。需要进一步评价MS-275联合用药方案。
Systemic treatment of metastatic melanoma is of low efficacy, and new therapeutic strategies are needed. Histone deacetylase inhibitors are supposed to restore the expression of tumor suppressor genes and induce tumor cell differentiation, growth arrest, and apoptosis. This study was aimed to evaluate the efficacy, safety, and pharmacokinetics of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate (MS-275) in patients with pretreated metastatic melanoma. Patients with unresectable AJCC stage IV melanoma refractory to at least one earlier systemic therapy were randomized to receive MS-275 3 mg biweekly (days 1 + 15, arm A) or 7 mg weekly (days 1 + 8 + 15, arm 13), in 4-week cycles. The primary study endpoint was objective tumor response, secondary endpoints were safety and time-to-progression. On the basis of Simon's two-stage design, the study initially allowed an entry of 14 patients per arm; if there was at least one responder, additional 33 patients were to be enrolled. Among 28 patients enrolled, no objective response was detected. Four (29%) patients in arm A and three (21%) patients in arm B showed disease stabilizations. Median time-to-progression was comparable in both arms with 55.5 versus 51.5 days, respectively; median overall survival was 8.84 months. Toxicity was mild to moderate with nausea (39%) and hypophosphatemia (29%) as the most frequently reported events. No treatment-related serious adverse events occurred. Single-agent treatment with MS-275 was well-tolerated and showed long-term tumor stabilizations, but no objective responses in pretreated metastatic melanoma. Further evaluation of MS-275 in combination schedules is warranted.