Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.
Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers.
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DOI：
10.1158/2159-8290.cd-16-1250
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发表时间：
2017-06
期刊：
影响因子：
28.2
通讯作者：
Wainberg ZA
中科院分区：
文献类型：
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作者：
de Bono J;Ramanathan RK;Mina L;Chugh R;Glaspy J;Rafii S;Kaye S;Sachdev J;Heymach J;Smith DC;Henshaw JW;Herriott A;Patterson M;Curtin NJ;Byers LA;Wainberg ZA
Talazoparib抑制PARP的催化活性，将PARP1捕获在受损的DNA上，导致brca1 /2突变细胞的细胞死亡。我们在这个分两部分的I期首次人体试验中评估了talazoparib治疗。一项开放标签、多中心、剂量递增研究（NCT01286987）确定了每日一次talazoparib的抗肿瘤活性、MTD、药代动力学和药理学。MTD为1.0 mg/天，消除半衰期为50小时。治疗相关不良事件包括疲劳（26/71例，37%）和贫血（25/71例，35%）。3 - 4级不良事件包括贫血（17/71例，24%）和血小板减少（13/71例，18%）。剂量≥0.60 mg/天时，观察到持续的PARP抑制作用。在1.0 mg/天的剂量下，14例BRCA突变相关乳腺癌和卵巢癌患者中有7例（50%）和12例（42%）患者以及胰腺癌和小细胞肺癌患者中分别观察到证实的应答。Talazoparib显示出单药抗肿瘤活性，并且在推荐剂量为1.0 mg/天的患者中耐受性良好。
Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation– associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.