A phase I first-in-human trial of bardoxolone methyl in patients with advanced solid tumors and lymphomas.
OBJECTIVE
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.


METHODS
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.
Department ofInvestigational Cancer Therapeutics, Phase I Clinical Trials Program, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. dshong@mdanderson.org
David S
DS
Hong
Razelle
R
Kurzrock
Jeffrey G
JG
Supko
Xiaoying
X
He
Aung
A
Naing
Jennifer
J
Wheler
Donald
D
Lawrence
Joseph Paul
JP
Eder
Colin J
CJ
Meyer
Deborah A
DA
Ferguson
James
J
Mier
Marina
M
Konopleva
Sergej
S
Konoplev
Michael
M
Andreeff
Donald
D
Kufe
Hillard
H
Lazarus
Geoffrey I
GI
Shapiro
Bruce J
BJ
Dezube
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019938:Cyclin D1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D007680:Kidney Neoplasms / Q000188:drug therapy; D008223:Lymphoma / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D009828:Oleanolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors; D013964:Thyroid Neoplasms / Q000188:drug therapy; D055815:Young Adult
D000970:Antineoplastic Agents; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D019938:Cyclin D1; D009828:Oleanolic Acid; C445068:bardoxolone methyl; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D053612:Janus Kinases