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: CONCLUSIONS:
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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 |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 18
Issue 12
Pg. 3396-406
(Jun 15 2012)
ISSN: 1557-3265 [Electronic] United States |
PMID | 22634319
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2012 AACR. |
Chemical References |
- Antineoplastic Agents
- NF-E2-Related Factor 2
- NF-kappa B
- NFE2L2 protein, human
- RNA, Messenger
- STAT Transcription Factors
- Cyclin D1
- Oleanolic Acid
- bardoxolone methyl
- NAD(P)H Dehydrogenase (Quinone)
- NQO1 protein, human
- Janus Kinases
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Topics |
- 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
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