Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors
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To determine the maximum tolerated dose (MTD) and biologic activity of OPB-31121, an oral inhibitor of STAT3, administered twice daily (BID) to subjects with advanced solid tumors.
.Subjects received escalating doses of OPB-31121 BID for the first 21 days of each 28-day cycle in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), safety, pharmacokinetics, and antitumor activity were assessed.
Thirty subjects were treated twice daily with OPB-31121 at 6 dose levels: 50 mg (n = 4); 70 mg (n = 3); 140 mg (n = 3); 200 mg (n = 4); 300 mg (n = 9); 350 mg (n = 7). There were no DLTs observed until 300 mg BID (Grade 3 lactic acidosis). At the next dose level (350 mg BID), two subjects had DLTs (Grade 3 vomiting and Grade 3 diarrhea). Thus, 300 mg BID was declared the MTD. OPB-31121-related adverse events included nausea (80 %), vomiting (73 %), diarrhea (63 %), and fatigue (33 %), all of which were primarily grade 1/2. Pharmacokinetics demonstrated high inter-subject variability with exposures 146- to 4,788-fold lower than target concentrations from tumor-bearing mouse models. No objective responses were observed, and all subjects who completed two cycles of treatment had disease progression at their first assessment.
Twice-daily administration of OPB-31121 was feasible up to doses of 300 mg. The pharmacokinetic profile was unfavorable, and no objective responses were observed.
- Calvisi, DF, Ladu, S, Gorden, A (2006) Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130: pp. 1117-1128 CrossRef
- Li, WC, Ye, SL, Sun, RX (2006) Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin Cancer Res 12: pp. 7140-7148 CrossRef
- Brambilla, L, Genini, D, Laurini, E (2013) Abstract C180: Novel small molecule inhibitors of signal transducer and activator of transcription (STAT3) for cancer treatment. Mol Cancer Ther 12: pp. C180
- Declaration of Helsinki. In: www.wma.net/e/ethicsunit/helsinki.htm. World Medical Association, Ethics Unit 2007
- Englund, G, Rorsman, F, Ronnblom, A (2006) Regional levels of drug transporters along human intestinal tract: co-expression of ABC and SLC transporters and comparison with Caco-2 cells. Eur J Phar Sci 29: pp. 269-277 CrossRef
- Siegmund, W, Ludwig, K, Engel, G (2003) Variability of intestinal expression of p-glycoprotein in healthy volunteers as described by absorption of talinonol from four bioequivalent tablets. J Pharm Sci 92: pp. 604-610 CrossRef
- Verstovsek, S, Kantarjian, H, Mesa, RA (2010) Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363: pp. 1117-1127 CrossRef
- Harrison, C, Kiladjian, J-J, Al-Ali, HK (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366: pp. 787-798 CrossRef
- Verstovsek, S, Mesa, RA, Gotlib, J (2012) A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366: pp. 799-807 CrossRef
- Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors
Cancer Chemotherapy and Pharmacology
Volume 74, Issue 1 , pp 125-130
- Cover Date
- Print ISSN
- Online ISSN
- Springer Berlin Heidelberg
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- Dose escalation
- Solid tumors
- Industry Sectors
- Author Affiliations
- 1. Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA
- 2. MD Anderson Cancer Center, Houston, TX, USA
- 3. Otsuka Pharmaceutical Development and Commercialization, Inc, Princeton, NJ, USA
- 4. Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, San Diego, CA, USA