Faculty Collaboration Database

A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas. Clin Cancer Res 2012 Jun 15;18(12):3396-406

Date

05/29/2012

Pubmed ID

22634319

Pubmed Central ID

PMC4494099

DOI

10.1158/1078-0432.CCR-11-2703

Scopus ID

2-s2.0-84862557429 (requires institutional sign-in at Scopus site)   190 Citations

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.

Author List

Hong DS, Kurzrock R, Supko JG, He X, Naing A, Wheler J, Lawrence D, Eder JP, Meyer CJ, Ferguson DA, Mier J, Konopleva M, Konoplev S, Andreeff M, Kufe D, Lazarus H, Shapiro GI, Dezube BJ

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Agents
Carcinoma, Renal Cell
Colorectal Neoplasms
Cyclin D1
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Janus Kinases
Kidney Neoplasms
Lymphoma
Male
Maximum Tolerated Dose
Melanoma
Middle Aged
NAD(P)H Dehydrogenase (Quinone)
NF-E2-Related Factor 2
NF-kappa B
Neoplasms
Oleanolic Acid
RNA, Messenger
STAT Transcription Factors
Thyroid Neoplasms
Young Adult