Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 1; pp. 125 - 130
• Main Authors: Bendell, Johanna C., Hong, David S., Burris, Howard A., Naing, Aung, Jones, Suzanne F., Falchook, Gerald, Bricmont, Patricia, Elekes, Agnes, Rock, Edwin P., Kurzrock, Razelle
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2014; Springer; Springer Nature B.V
• Subjects: Acidosis, Lactic - chemically induced; Acidosis, Lactic - physiopathology; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Biological Availability; Cancer Research; Cohort Studies; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Diarrhea - chemically induced; Diarrhea - physiopathology; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Investigational - administration & dosage; Drugs, Investigational - adverse effects; Drugs, Investigational - pharmacokinetics; Drugs, Investigational - therapeutic use; Feasibility Studies; Female; Half-Life; Humans; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nausea - chemically induced; Nausea - physiopathology; Neoplasms - blood; Neoplasms - drug therapy; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Severity of Illness Index; STAT3 Transcription Factor - antagonists & inhibitors; Tumors; OPB-31121; Solid tumors; Dose escalation; STAT3; Human; Solid tumor; Malignant tumor; Increasing dose; Transcription factor STAT3; Advanced stage; Inhibitor; Pharmacokinetics; Cancer
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-014-2480-2

Purpose 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. Methods .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. Results 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. Conclusions 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.