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A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas
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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. Clin Cancer Res; 18(12); 3396–406. ©2012 AACR.
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“In another Phase I trial of CDDO-Me in patients with advanced solid tumors and lymphomas, a complete tumor response occurred in one mantle cell lymphoma patient and a partial response was observed in an anaplastic thyroid carcinoma patient at a dose of 900 mg/day.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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“Overall, the data appeared encouraging enough to support continued development of other synthetic triterpenoids as anticancer agents (Hong et al., 2012).”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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In the citing paper
“Pharmacokinetic parameters suggest that CDDO-Me has a slow and saturable oral absorption, long terminal-phase half-life (39 hours at 900 mg/day), nonlinear dose-dependent exposures at high doses (600–1300 mg/day), and high interpatient variability.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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“Dose-limiting toxicities were grade 3 liver transaminase elevations that were reversible.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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“In clinical trials, CDDO-Me showed therapeutic activities against several types of cancers.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Hong et al., 2012
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Citations
Cites
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Oxidative Stress Is Progressively Enhanced With Advancing Stages of CKD
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Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide
Thimmulappa, R. K., Scollick, C., Traore, K., Yates, M. S., Trush, M. A., Liby, K. T., Sporn, M. B., Yamamoto, M. P., Kensler, T. W., & Biswal, S. S. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.102 · Cited by 360
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Molecular basis of the Keap1–Nrf2 system
Suzuki, T., & Yamamoto, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.006 · Cited by 995
Ruiz, S., Pérgola, P. E., Zager, R. A., & Vaziri, N. D. (2013) · Kidney International · doi:10.1038/ki.2012.439 · Cited by 730
Oxidant Mechanisms in Renal Injury and Disease
Ratliff, B. B., Abdulmahdi, W., Pawar, R. D., & Wolin, M. S. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6665 · Cited by 712
Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., Daiber, A., Ghezzi, P., León, R., López, M. G., Oliva, B., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014753 · Cited by 632
Metadata
- Authors
- Hong, D. S., Kurzrock, R., Supko, J. G., He, X., Naing, A., Wheler, J., Lawrence, D., Eder, J. P., Meyer, C. J., Ferguson, D. A., Mier, J., Konopleva, M., Konoplev, S., Andreeff, M., Kufe, D., Lazarus, H., Shapiro, G. I., & Dezube, B. J.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Hong, David S.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-06-14
- Volume
- 18
- Issue
- 12
- Pages
- 3396-3406
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4494099
- OpenAlex
- W2087928294
- Cited by
- 236
- References
- 43
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 17 · 2023: 14 · 2022: 21 · 2021: 18 · 2020: 17 · 2019: 20 · 2018: 14 · 2017: 18 · 2016: 15 · 2015: 23 · 2014: 17 · 2013: 13 · 2012: 3
- FWCI
- 7.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA166480, R01CA042802, P30CA016672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Physical Sciences › Chemistry › Organic Chemistry › Natural product bioactivities and synthesis
- Keywords
- bardoxolone methyl, synthetic triterpenoids, Nrf2 activation, NF-κB inhibition, dose-limiting toxicity, maximum tolerated dose, pharmacokinetics, pharmacodynamics, NQO1, mantle cell lymphoma, anaplastic thyroid carcinoma, advanced solid tumors, anticancer activity, liver transaminase elevation, estimated glomerular filtration rate, chronic kidney disease, oral administration
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Renal Cell, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Kidney Neoplasms, Lymphoma, Male, Melanoma, Middle Aged, Neoplasms, Oleanolic Acid, RNA, Messenger, Thyroid Neoplasms, Colorectal Neoplasms, NF-kappa B, NAD(P)H Dehydrogenase (Quinone), Cyclin D1, Maximum Tolerated Dose, STAT Transcription Factors, NF-E2-Related Factor 2, Janus Kinases, Young Adult
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