Administered as a 24-Hour Infusion with and without Granulocyte Colony-Stimulating Factor in a 14-Day Cycle in Patients with Advanced Solid Tumors

Purpose: This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors. Experimental Design: In part 1, patients received escalating doses of danusertib (24hour infusion every 14 days) without filgrastim (granulocyte colony-stimulating factor, G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was done in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3). Results: Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose-limiting toxicity in part 1 without G-CSF. Most other adverse events were grade 1 to 2, occurring at doses ≥360 mg/m with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m. The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m. Danusertib showed doseproportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m. One patient with refractory small cell lung cancer (1,000 mg/m with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline. Conclusions: Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m. Preliminary evidence of antitumor activity, including a partial response and several occurrences of prolonged stable disease, was seen across a variety of advanced refractory cancers. Phase II studies are ongoing. (Clin Cancer Res 2009;15(21):6694–701) Danusertib is a small-molecule 3-aminopyrazole derivative that potently inhibits all Aurora kinase family members (A, B, and C). Aurora kinases are essential for mitosis (1) and cytokinesis with upregulation in many malignancies, including pancreatic (2), colorectal (3), ovarian (3), and esophageal cancer (4). Aurora A is required for spindle assembly and localizes to centrosomes. Aurora B is a chromosome passenger protein required for histone H3 phosphorylation (pH3), chromosome segregation, and cytokinesis (5–7). Several Aurora kinase inhibitors with diverse pharmacologic properties are in clinical trials (8–15). Danusertib is active in vitro against a wide range of cancer cell lines with submicromolar IC50 values for inhibition of proliferation. Danusertib shows dominant Aurora B kinase inhibition (16) with additional activity against bcr-abl, including the T315I mutation. In vitro studies have shown that danusertib causes a failure of cell division, resulting in polyploidy and reduction in viability. Danusertib inhibits Aurora B Authors' Affi l iat ions: Fox Chase Cancer Center, Philadelphia, Pennsylvania; Sarah Cannon Cancer Center, Nashville, Tennessee; and Nerviano Medical Sciences and Accelera, Nerviano, Italy Received 6/5/09; revised 7/16/09; accepted 7/16/09; published OnlineFirst 10/13/09. Grant support: The work was supported in part by National Cancer Institute grant P30 CA006927 to Fox Chase Cancer Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Presented in part at the 2006 American Association for Cancer ResearchNational Cancer Institute-European Organization for Research and Treatment of Cancer Annual Meeting (Abs. 343) and at the 2008 American Society of Clinical Oncology Annual Meeting (Abs. 2520). Requests for reprints: Roger B. Cohen, Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-214-1676; Fax: 215-728-3639; E-mail: rb_cohen@fccc.edu. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1445 6694 Clin Cancer Res 2009;15(21) November 1, 2009 www.aacrjournals. org Research. on July 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals. org Downloaded from Published OnlineFirst October 13, 2009; DOI: 10.1158/1078-0432.CCR-09-1445