A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas

• Published in: Clinical cancer research Vol. 18; no. 12; pp. 3396 - 3406
• Main Authors: HONG, David S, KURZROCK, Razelle, MIER, James, KONOPLEVA, Marina, KONOPLEV, Sergej, ANDREEFF, Michael, KUFE, Donald, LAZARUS, Hillard, SHAPIRO, Geoffrey I, DEZUBE, Bruce J, SUPKO, Jeffrey G, XIAOYING HE, NAING, Aung, WHELER, Jennifer, LAWRENCE, Donald, EDER, Joseph Paul, MEYER, Colin J, FERGUSON, Deborah A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.06.2012
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Colorectal Neoplasms - drug therapy; Cyclin D1 - metabolism; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Hematologic and hematopoietic diseases; Humans; Janus Kinases - antagonists & inhibitors; Kidney Neoplasms - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma - drug therapy; Male; Maximum Tolerated Dose; Medical sciences; Melanoma - drug therapy; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; Neoplasms - drug therapy; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Oleanolic Acid - adverse effects; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacokinetics; Oleanolic Acid - therapeutic use; Pharmacology. Drug treatments; RNA, Messenger - genetics; RNA, Messenger - metabolism; STAT Transcription Factors - antagonists & inhibitors; Thyroid Neoplasms - drug therapy; Tumors; Young Adult; Antineoplastic agent; Human; Solid tumor; Patient; Malignant hemopathy; Malignant tumor; Lymphoid neoplasm; Lymphoma; Bardoxolone; Lymphoproliferative syndrome; Clinical trial; Advanced stage; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-2703

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. 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. 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. 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.