ArticleClinical cancer research : an official journal of the American Association for Cancer Research2009
A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
40 citing papers in PubMed, 93 citations in OpenAlex.
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- Aurora B Inhibitors as Cancer Therapeutics.Molecules (Basel, Switzerland) · 2023Review
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- Aurora Kinase B Inhibition: A Potential Therapeutic Strategy for Cancer.Molecules (Basel, Switzerland) · 2021Review
- Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy.Molecular cancer · 2021Review
- Aurora kinases in ovarian cancer.ESMO open · 2020Review
- Wise Management of Ovarian Cancer: On the Cutting Edge.Journal of personalized medicine · 2020Review
- The role of Aurora-A in human cancers and future therapeutics.American journal of cancer research · 2020Review
- A Ploidy Increase Promotes Sensitivity of Glioma Stem Cells to Aurora Kinases Inhibition.Journal of oncology · 2019Article
- A quantitative proteomic response of hepatocellular carcinoma Hep3B cells to danusertib, a pan-Aurora kinase inhibitor.Journal of Cancer · 2018Article
- Multi-kinase inhibitors, AURKs and cancer.Medical oncology (Northwood, London, England) · 2016Review
- Aurora Kinases and Potential Medical Applications of Aurora Kinase Inhibitors: A Review.Journal of clinical medicine research · 2015Review
- Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications.Cancer metastasis reviews · 2015Review
- Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies.Investigational new drugs · 2015Article
- Article
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeThis 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
designIn part 1, patients received escalating doses of danusertib (24-hour 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).
resultsFifty-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 >or=360 mg/m(2) with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m(2). The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m(2). Danusertib showed dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at >or=500 mg/m(2). One patient with refractory small cell lung cancer (1,000 mg/m(2) with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.
conclusionsDanusertib was well tolerated with target inhibition in skin at >or=500 mg/m(2). 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.
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