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美国马里兰州国家癌症研究院的科学家发现了一种可以有效治疗进展期癌症的新药。他们的研究结果报道在4月13日出版的《临床肿瘤学杂志》上，文章中说，多（ADP核糖酶）多聚酶（PARP）抑制剂ABT-888治疗进展期难治性肿瘤的单剂量实验性研究结果表明，这种药物对靶位有药代动力学调节作用，并且研究方法也是有效的。 美国马里兰州国家癌症研究院的James H. Doroshow博士及其同事说，为了明确药物研发过程，美国食品和药物管理局(FDA)已经同意进行临床前实验，在有限数量的患者中进行短期实验，评价可以应用但不会引起毒性的剂量。 研究者选取13名患者，让他们一次口服ABT-888，10毫克，25毫克或者50毫克以便建立时间过程，以及促进PARP活性抑制所需要的剂量。9名患者在25毫克和50毫克剂量水平的时候，外周血单个核细胞出现多（ADP核糖酶）抑制，这种效果通过肿瘤活检确定。总之，药物显示良好的口服生物活性，并且可以被很好的耐受。五个月就得到了上述结果，已经为随后的I期实验设计提供指导。 Doroshow博士对路透社记者说：“我们最近的0期实验结果表明可以进行先导性研究，帮助在少数患者中确定癌症治疗新药的作用机制。”他说：“这些需要关注分子研究的发展。分子学技术可以帮助我们了解如何最有效地使用新的癌症药物。” 在相关评论中，美国密执安州底特律市韦恩州立大学的Patricia M. LoRusso博士说：“近十年内，有五百多种癌症药物有希望进入临床研发，我们进行临床研究的人已经意识到，需要有一个更加明智的研发计划。” 他说：“只有时间可以告诉我们，是否临床前研究会成为一个研究工具，最终帮助我们发现产生明显疗效，延长生存的药物。” 推荐原始出处： Journal of Clinical Oncology, 10.1200/JCO.2008.19.7681 Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies Shivaani Kummar, Robert Kinders, Martin E. Gutierrez, Larry Rubinstein, Ralph E. Parchment, Lawrence R. Phillips, Jiuping Ji, Anne Monks, Jennifer A. Low, Alice Chen, Anthony J. Murgo, Jerry Collins, Seth M. Steinberg, Helen Eliopoulos, Vincent L. Giranda, Gary Gordon, Lee Helman, Robert Wiltrout, Joseph E. Tomaszewski, and James H. Doroshow* From the Center for Cancer Research and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda; Laboratory of Human Toxicology and Pharmacology, Applied/Developmental Research Support Directorate, Science Applications International Corporation Frederick Inc, National Cancer Institute Frederick, Frederick; and Abbott Laboratories, Abbott Park, IL. Purpose: We 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. Results: Thirteen 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. Conclusion: Within 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. (责任编辑：Doctor001) |
