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

Ben C Creelan,1 Dmitry I Gabrilovich,2 Jhanelle E Gray,1 Charles C Williams,1 Tawee Tanvetyanon,1 Eric B Haura,1 Jeffrey S Weber,3 Geoffrey T Gibney,4 Joseph Markowitz,5 Joel W Proksch,6 Scott A Reisman,6 Mark D McKee,7 Melanie P Chin,6 Colin J Meyer,6 Scott J Antonia11Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Drive, Tampa, FL, USA; 2The Wistar Institute, Philadelphia, PA, USA; 3Laura and Isaac Perlmutter Cancer Center, New York, NY, USA; 4Department of Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA; 5Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Magnolia Drive, Tampa, FL, USA; 6Reata Pharmaceuticals, Inc., Irving, TX, USA; 7AbbVie, Inc., North Chicago, IL, USABackground: Omaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. Weconducted 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, nitrotyrosine, nitric oxide synthase, melanoma, non-small cell lung cancer, immuno-oncology, myeloid-derived suppressor cells, bardoxolone methyl