A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors

Carolyn D. Britten, Elizabeth Garrett-Mayer, Steven H. Chin, Keisuke Shirai, Besim Ogretmen, Tricia A. Bentz, Alan Brisendine, Kate Anderton, Susan L. Cusack, Lynn W. Maines, Yan Zhuang, Charles D. Smith, Melanie B. Thomas

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Abstract

Purpose: Sphingosine kinases (SK1 and SK2) regulate tumor growth by generating the mitogenic and proinflammatory lipid sphingosine 1-phosphate (S1P). This phase I study investigated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABC294640, a first-in-class orally available inhibitor of SK2. Experimental Design: Escalating doses of ABC294640 were administered orally to patients with advanced solid tumors in sequential cohorts at the following dose levels: 250 mg qd, 250 mg bid, 500 mg bid, and 750 mg bid, continuously in cycles of 28 days. Serial blood samples were obtained to measure ABC294640 concentrations and sphingolipid profiles. Results: Twenty-two patients were enrolled, and 21 received ABC294640. The most common drug-related toxicities were nausea, vomiting, and fatigue. Among the 4 patients at 750 mg bid, one had dose-limiting grade 3 nausea and vomiting, and 2 were unable to complete cycle 1 due to diverse drug-related toxicities. The 500 mg bid dose level was established as the recommended phase II dose. ABC294640 administration resulted in decreases in S1P levels over the first 12 hours, with return to baseline at 24 hours. The best response was a partial response in a patient with cholangiocarcinoma at 250 mg qd, and stable disease was observed in 6 patients with various solid tumors across dose levels. Conclusions: At 500 mg bid, ABC294640 is well tolerated and achieves biologically relevant plasma concentrations. Changes in plasma sphingolipid levels may provide a useful pharmacodynamic biomarker for ABC294640.

Original languageEnglish (US)
Pages (from-to)4642-4650
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
StatePublished - Aug 15 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Britten, C. D., Garrett-Mayer, E., Chin, S. H., Shirai, K., Ogretmen, B., Bentz, T. A., Brisendine, A., Anderton, K., Cusack, S. L., Maines, L. W., Zhuang, Y., Smith, C. D., & Thomas, M. B. (2017). A phase I study of ABC294640, a first-in-class sphingosine kinase-2 inhibitor, in patients with advanced solid tumors. Clinical Cancer Research, 23(16), 4642-4650. https://doi.org/10.1158/1078-0432.CCR-16-2363