Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies
Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies
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DOI：
10.1200/jco.2008.19.7681
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发表时间：
2009-06-01
影响因子：
45.3
通讯作者：
Doroshow, James H.
中科院分区：
文献类型：
--
作者：
Kummar, Shivaani;Kinders, Robert;Doroshow, James H.
目的我们在美国食品和药物管理局的探索性研究新药指导下，进行了一种治疗剂的肿瘤学首个0期临床试验。首次在人类范围内研究了聚腺苷二磷酸核糖聚合酶(PARP)抑制剂ABT-888在晚期恶性肿瘤患者中的应用。患者和方法单次口服ABT-888 10、25和50 mg，以确定ABT-888抑制肿瘤标本和外周血单核细胞中PARP活性的剂量范围和时间过程，并评价ABT-888的药代动力学。在给药前和给药后采集血样和肿瘤活检组织以评估PARP活性和药代动力学。开发了一种新的统计学方法，并将其作为有限样本量试验的主要终点来研究药效调节。结果13名晚期恶性肿瘤患者接受了研究药物；9名患者接受了成对的肿瘤活检。ABT-888具有良好的口服生物利用度和耐受性。在25 mg和50 mg的剂量水平下，肿瘤活检组织和外周血单核细胞中的多聚ADP核糖水平受到统计学上的显著抑制。结论在研究激活的5个月内，我们获得了关键的生化和药代动力学数据，这些数据指导了ABT-888与DNA损伤剂联合使用的后续I期试验的设计。除了加速ABT-888的开发外，这项试验的快速结束表明，作为肿瘤学早期药物开发替代范例的一部分，进行原则证明阶段0试验是可行的。J Clin Oncol27：2705-2711(C)2009年美国临床肿瘤学会
PurposeWe conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.Patients and Methods ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size.ResultsThirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels.ConclusionWithin 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology. J Clin Oncol 27:2705-2711. (C) 2009 by American Society of Clinical Oncology