A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas

Abstract

Purpose Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Experimental Design Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. Results The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Conclusions Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Daily oral administration of fumaric acid esters over 12 weeks was associated with the increased expression of NRF2 target genes in the skin of patients with psoriasis (Onderdijk et al, 2014). Similarly, a fivefold increase in the mRNA level of NQO1 has been reported in peripheral blood mononuclear cells obtained from cancer patients that received a daily dose of CDDO-Me for 3 weeks (Hong et al, 2012).…”

Genetic and Pharmacologic Targeting of Glycogen Synthase Kinase 3β Reinforces the Nrf2 Antioxidant Defense against Podocytopathy

“…10 The benefits of Nrf2 signaling in human kidney disease were initially recognized in patients with cancer treated with bardoxolone, a potent Nrf2 inducer. 41 Subsequent clinical trials demonstrated that bardoxolone is effective in improving kidney function in patients with diabetes and advanced-stage CKD. 12 However, this effect was lately found to be associated with elevated albuminuria, excess serious adverse effects, and mortality caused by heart failure and cardiovascular events, which prematurely terminated the phase 3 large-scale, longterm, randomized controlled trial of bardoxolone (Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: the Occurrence of Renal Events) in patients with diabetic kidney disease.…”

Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

“…Of 30 assessable patients in the second study, 40% achieved disease stabilization and two objective responses were seen (Hong et al, 2008). The results of this phase 1 study have been published (Hong et al, 2012). …”