|
美國馬里蘭州國家癌癥研究院的科學家發現了一種可以有效治療進展期癌癥的新藥。他們的研究結果報道在4月13日出版的《臨床腫瘤學雜志》上，文章中說，多（ADP核糖酶）多聚酶（PARP）抑制劑ABT-888治療進展期難治性腫瘤的單劑量實驗性研究結果表明，這種藥物對靶位有藥代動力學調節作用，并且研究方法也是有效的。 美國馬里蘭州國家癌癥研究院的James H. Doroshow博士及其同事說，為了明確藥物研發過程，美國食品和藥物管理局(FDA)已經同意進行臨床前實驗，在有限數量的患者中進行短期實驗，評價可以應用但不會引起毒性的劑量。 研究者選取13名患者，讓他們一次口服ABT-888，10毫克，25毫克或者50毫克以便建立時間過程，以及促進PARP活性抑制所需要的劑量。9名患者在25毫克和50毫克劑量水平的時候，外周血單個核細胞出現多（ADP核糖酶）抑制，這種效果通過腫瘤活檢確定。總之，藥物顯示良好的口服生物活性，并且可以被很好的耐受。五個月就得到了上述結果，已經為隨后的I期實驗設計提供指導。 Doroshow博士對路透社記者說：“我們最近的0期實驗結果表明可以進行先導性研究，幫助在少數患者中確定癌癥治療新藥的作用機制。”他說：“這些需要關注分子研究的發展。分子學技術可以幫助我們了解如何最有效地使用新的癌癥藥物。” 在相關評論中，美國密執安州底特律市韋恩州立大學的Patricia M. LoRusso博士說：“近十年內，有五百多種癌癥藥物有希望進入臨床研發，我們進行臨床研究的人已經意識到，需要有一個更加明智的研發計劃。” 他說：“只有時間可以告訴我們，是否臨床前研究會成為一個研究工具，最終幫助我們發現產生明顯療效，延長生存的藥物。” 推薦原始出處： 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. (責任編輯：Doctor001) |
