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Creelan BC, Gabrilovich DI, Gray JE, et al. Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors. Onco Targets Ther. 2017;10:4239-4250doi: 10.2147/OTT.S136992.
Creelan, B. C., Gabrilovich, D. I., Gray, J. E., Williams, C. C., Tanvetyanon, T., Haura, E. B., Weber, J. S., Gibney, G. T., Markowitz, J., Proksch, J. W., Reisman, S. A., McKee, M. D., Chin, M. P., Meyer, C. J., & Antonia, S. J. (2017). Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors. OncoTargets and therapy, 104239-4250. https://doi.org/10.2147/OTT.S136992
Creelan, Ben C, et al. "Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors." OncoTargets and therapy vol. 10 (2017): 4239-4250. doi: https://doi.org/10.2147/OTT.S136992
Creelan BC, Gabrilovich DI, Gray JE, Williams CC, Tanvetyanon T, Haura EB, Weber JS, Gibney GT, Markowitz J, Proksch JW, Reisman SA, McKee MD, Chin MP, Meyer CJ, Antonia SJ. Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors. Onco Targets Ther. 2017 Aug 29;10:4239-4250. doi: 10.2147/OTT.S136992. eCollection 2017. PMID: 28919776; PMCID: PMC5587199.
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Onco Targets Ther. 2017 Aug 29;10:4239-4250. doi: 10.2147/OTT.S136992. eCollection 2017.

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.

OncoTargets and therapy

Ben C Creelan, Dmitry I Gabrilovich, Jhanelle E Gray, Charles C Williams, Tawee Tanvetyanon, Eric B Haura, Jeffrey S Weber, Geoffrey T Gibney, Joseph Markowitz, Joel W Proksch, Scott A Reisman, Mark D McKee, Melanie P Chin, Colin J Meyer, Scott J Antonia

Affiliations

  1. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Drive, Tampa, FL, USA.
  2. The Wistar Institute, Philadelphia, PA, USA.
  3. Laura and Isaac Perlmutter Cancer Center, New York, NY, USA.
  4. Department of Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA.
  5. Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Drive, Tampa, FL, USA.
  6. Reata Pharmaceuticals, Inc., Irving, TX, USA.
  7. AbbVie, Inc., North Chicago, IL, USA.

PMID: 28919776 PMCID: PMC5587199 DOI: 10.2147/OTT.S136992

Abstract

BACKGROUND: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity.

METHODS: Omaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression.

RESULTS: Omaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year.

CONCLUSIONS: Omaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

Keywords: antioxidant inflammation modulator; bardoxolone methyl; immuno-oncology; melanoma; myeloid-derived suppressor cells; nitric oxide synthase; nitrotyrosine; non-small cell lung cancer

Conflict of interest statement

Disclosure The authors MPC, SAR, JWP, and CJM are employed by, and have a financial interest in, Reata Pharmaceuticals. DIG has served as a paid consultant with Reata Pharmaceuticals. MDM is employed

References

  1. Biochim Biophys Acta. 2016 Nov;1860(11 Pt A):2537-2552 - PubMed
  2. Arch Dermatol Res. 2014 Jul;306(5):447-54 - PubMed
  3. Nat Med. 2007 Jul;13(7):828-35 - PubMed
  4. Clin Cancer Res. 2016 Aug 1;22(15):3849-59 - PubMed
  5. PLoS One. 2015 Apr 21;10(4):e0122942 - PubMed
  6. Cancer Immunol Res. 2016 Apr;4(4):345-53 - PubMed
  7. Clin Cancer Res. 2013 Jul 1;19(13):3439-49 - PubMed
  8. Clin Cancer Res. 2010 Mar 15;16(6):1812-23 - PubMed
  9. Redox Biol. 2016 Aug;8:98-109 - PubMed
  10. Cancer Immunol Res. 2015 Feb;3(2):136-48 - PubMed
  11. Cancer Immunol Res. 2015 Nov;3(11):1236-47 - PubMed
  12. Radiat Res. 2014 May;181(5):512-20 - PubMed
  13. Pharmacol Rev. 2012 Oct;64(4):972-1003 - PubMed
  14. Arch Toxicol. 2011 Apr;85(4):239 - PubMed
  15. Science. 2011 Mar 25;331(6024):1612-6 - PubMed
  16. Cancer Res. 2013 Nov 15;73(22):6609-20 - PubMed
  17. Clin Cancer Res. 2012 Jun 15;18(12):3396-406 - PubMed
  18. Eur J Cancer. 2009 Jan;45(2):228-47 - PubMed
  19. Biochem Soc Trans. 2015 Aug;43(4):602-10 - PubMed
  20. Clin Cancer Res. 2015 Dec 15;21(24):5453-9 - PubMed
  21. Cancer Res. 2010 Jun 15;70(12):4949-60 - PubMed
  22. BMC Dermatol. 2015 Jul 14;15:10 - PubMed
  23. Am J Nephrol. 2014;39(6):499-508 - PubMed
  24. Cancer Prev Res (Phila). 2014 Aug;7(8):835-44 - PubMed
  25. PLoS One. 2014 Jun 04;9(6):e98896 - PubMed
  26. Mol Cancer Ther. 2014 Dec;13(12):2968-77 - PubMed
  27. Radiat Res. 2015 Mar;183(3):338-44 - PubMed
  28. Am J Nephrol. 2013;37(3):208-11 - PubMed
  29. Front Immunol. 2015 Jan 30;6:12 - PubMed
  30. Cancer Cell. 2016 Jun 13;29(6):820-831 - PubMed
  31. Cancer Chemother Pharmacol. 2012 Feb;69(2):431-8 - PubMed

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