A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation
A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation
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DOI：
10.1007/s00280-013-2113-1
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发表时间：
2013-05-01
影响因子：
3
通讯作者：
Calvert, Hilary
中科院分区：
文献类型：
--
作者：
Plummer, Ruth;Lorigan, Paul;Calvert, Hilary
聚（ADP核糖）聚合酶抑制已被证明可以增强DNA损伤剂的细胞毒性。一项鲁卡帕尼和替莫唑胺的I期研究表明，在PARP抑制期间可以给予全剂量的替莫唑胺。我们报告了一项II期研究的结果，在晚期转移性黑色素瘤患者中，静脉注射鲁卡帕尼12mg /m(2)和口服替莫唑胺200mg /m(2)，每28天1-5天。接受化疗的患者中没有可测量的转移性黑色素瘤，表现状态为千分之一货币信号2，终末器官功能良好。治疗一直持续到病情进展。采用两阶段II期设计，以反应率为主要终点。研究了群体药代动力学和药效学。纳入46例患者，其中37例患者至少接受2个周期治疗，17例患者至少接受6个周期治疗。25例（54%）患者出现骨髓抑制，需要减少25%的替莫唑胺剂量。缓解率为17.4%，中位进展时间为3.5个月，中位总生存期为9.9个月，36%的患者在6个月时无进展。这项研究表明替莫唑胺（150- 200mg /m(2)/天）可以安全地与鲁卡帕尼的PARP抑制剂量一起给予，比历史对照组增加转移性黑色素瘤患者的无进展生存期。
poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma.Patients with chemotherapy na < ve measurable metastatic melanoma, performance status a parts per thousand currency sign2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored.Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months.This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.