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|Ref Type||Journal Article|
|Authors||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|
|Title||Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors.|
|Journal||OncoTargets and therapy|
|Abstract Text||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.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.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.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.|
|Molecular Profile||Treatment Approach|
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|Unknown unknown||Advanced Solid Tumor||not applicable||Omaveloxolone||Phase I||Actionable||In a Phase I trial, treatment with Omaveloxolone (RTA 408) in patients with an advanced solid tumor led to a median progression-free survival of 1.5 months, an overall survival of 5.8 months, and one patient with lung cancer experienced stable disease for greater than 12 months (PMID: 28919776).||28919776|