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A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas.
MedLine Citation:
PMID:  22634319     Owner:  NLM     Status:  Publisher    
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. Clin Cancer Res; 18(12); 1-11. ©2012 AACR.
David S Hong; Razelle Kurzrock; Jeffrey G Supko; Xiaoying He; Aung Naing; Jennifer Wheler; Donald Lawrence; Joseph Paul Eder; Colin J Meyer; Deborah A Ferguson; James Mier; Marina Konopleva; Sergej Konoplev; Michael Andreeff; Donald Kufe; Hillard Lazarus; Geoffrey I Shapiro; Bruce J Dezube
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-25
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  -     ISSN:  1078-0432     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Authors' Affiliations: Departments ofInvestigational Cancer Therapeutics (Phase I Clinical Trials Program), Leukemia, Division of Cancer Medicine, and Hematopathology, and Molecular Hematology and Therapy Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; Reata Pharmaceuticals, Inc., Irving, Texas; Massachusetts General Hospital; Beth Israel Deaconess Medical Center, Dana-Farber/Harvard Cancer Center, Harvard Medical School; Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute; Dana-Farber Cancer Institute; Division of Hematology/Oncology, Massachusetts General Hospital; Department of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Medicine, University Hospitals Case Medical Center, Cleveland, Ohio.
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