Document Detail


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:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:  Clinical Trial, Phase I; Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-25
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  18     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-18     Completed Date:  2012-12-20     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3396-406     Citation Subset:  IM    
Copyright Information:
©2012 AACR.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Antineoplastic Agents / adverse effects,  pharmacokinetics,  therapeutic use*
Carcinoma, Renal Cell / drug therapy
Colorectal Neoplasms / drug therapy
Cyclin D1 / metabolism
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Janus Kinases / antagonists & inhibitors
Kidney Neoplasms / drug therapy
Lymphoma / drug therapy*
Male
Maximum Tolerated Dose
Melanoma / drug therapy
Middle Aged
NAD(P)H Dehydrogenase (Quinone) / genetics,  metabolism
NF-E2-Related Factor 2 / metabolism
NF-kappa B / metabolism
Neoplasms / drug therapy*
Oleanolic Acid / adverse effects,  analogs & derivatives*,  pharmacokinetics,  therapeutic use
RNA, Messenger / genetics,  metabolism
STAT Transcription Factors / antagonists & inhibitors
Thyroid Neoplasms / drug therapy
Young Adult
Grant Support
ID/Acronym/Agency:
P30 CA016672/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/NF-E2-Related Factor 2; 0/NF-kappa B; 0/NFE2L2 protein, human; 0/RNA, Messenger; 0/STAT Transcription Factors; 0/methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate; 136601-57-5/Cyclin D1; 6SMK8R7TGJ/Oleanolic Acid; EC 1.6.5.2/NAD(P)H Dehydrogenase (Quinone); EC 1.6.5.2/NQO1 protein, human; EC 2.7.10.2/Janus Kinases

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