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.

Figure 1

Pharmacokinetics of bardoxolone methyl. A, mean plasma concentration-time profiles for the first (circles) and last (squares) dose of bardoxolone methyl in the cohort of patients receiving 900 mg/d. Error bars depict the SD of the mean concentration of bardoxolone methyl in plasma for the day 21 dose. B, relationship between the apparent oral clearance (CL/F) of bardoxolone methyl and dose. C, relationship between the biological half-life (t_1/2,z) of bardoxolone methyl and dose. B and C, data points are the observed values in individual patients and the solid lines were generated by linear regression analysis of the data.

Figure 2

Pharmacodynamics of bardoxolone methyl. A, levels of NF-κB, cyclin D1, and TUNEL activity were monitored by immunohistochemistry in core biopsies from consenting patients. The average number of positively staining tumor cells per hpf at baseline and after 1 cycle of treatment is shown for 5 patients. The dose of bardoxolone methyl each patient received is indicated. B, representative images of NF-κB and cyclin D1 staining in tumor biopsies from 3 patients. C, NQO1 transcript levels were monitored using qPCR in PBMCs isolated from patients at baseline (BL), day 2 (D2), and day 22 (D22). P-values were determined using the Student’s t-test and indicate statistical significance relative to baseline (BL).

Figure 3

A, waterfall plot of best response of 44 patients who received bardoxolone methyl. Best overall response was categorized as progressive disease (black bars), stable disease (blue bars), partial response or complete response (both red bars). “c” represents patients who exhibited clinical progression but were not restaged by RECIST/WHO. B, images of a patient with anaplastic thyroid cancer who responded to bardoxolone methyl after cycle 2 (best response −69%) and stayed on protocol for 18 months. Left panel is the image taken at baseline; right panel is the image of the same patient taken after two cycles of treatment.