Abstract B56: A phase 1, open-label, dose escalation, nonrandomized study to assess the maximum tolerated dose, dose limiting toxicity, and pharmacokinetics of OPB-31121 in subjects with advanced solid tumors.
Authors: Kurzrock Razelle , Naing Aung , Falchook Gerald S. , Hong David S. , Elekes Agnes , Sumida Takumi , Bricmont Patricia , Kodama Takeshi , Motoyama Masaaki , Patil Shiva , Lee Jennifer , Jones Suzanne , Infante Jeffrey , Burris Howard , Bendell Johanna 
Published: June 2012

Abstract
Background: OPB-31121 is a novel compound exhibiting potent growth inhibition of cancer cell lines in vitro and xenografts in vivo. The exact mechanism of action of OPB-31121 has not been fully characterized, but studies indicate that a major effect is inhibition of STAT3 phosphorylation. STAT3 is frequently activated in a variety of solid and hematologic malignancies and may present an important target for antitumor therapy.
Methods: Open-label, non-randomized, multi-center study in subjects with advanced solid tumors, using a 3+3 dose escalation design. OPB-31121 was administered orally for 21 days followed by 7 days rest per cycle (28-day cycle). The starting dose was 50 mg BID with escalations planned until the dose-limiting toxicity (DLT) was reached. The primary endpoint was determination of maximum tolerated dose (MTD). Additional endpoints included safety, pharmacokinetics, and anti-tumor effect of OPB-31121.
Results: 30 subjects received treatment with OPB-31121. Most common tumor types were colorectal cancer (15), breast (3) and thyroid (2). Mean age was 55.9 (range 35–80) years and 17 of the patients were female. Most common adverse events (AEs) potentially attributed to treatment were gastrointestinal: nausea (80%), vomiting (73%), diarrhea (63%), anorexia (20%), and constipation (17%). Most AEs were CTCAE grades 1–2 and manageable with supportive treatment. Three DLTs were observed: one at 300 mg BID (grade 3 lactic acidosis), and two at 350 mg BID (a grade 3 diarrhea and a grade 3 vomiting); the MTD was 300 mg BID. All patients recovered from DLTs after discontinuing the drug. Six additional (9 total) subjects discontinued during the first cycle. Eight subjects completed only one cycle and 13 completed two cycles. No objective responses were observed. Disease progression was observed in all evaluable patients at first restaging. Pharmacokinetic measurements showed low and transient plasma levels of OPB-31121. Inter-patient variability was high. Exposure was low - area-under-the-curve (AUC) values were 2–3 orders of magnitude lower than those measured at active doses in mouse models. Analysis of metabolites in plasma samples indicates extensive CYP3A4 metabolism and suggests a large first-pass effect in humans, which had not been observed in rodents.
Conclusions: OPB-31121 does not show potential as a therapeutic option for most malignancies. The extensive first-pass metabolism and dose-limiting gastrointestinal AEs limit the level of systemic exposure that can be achieved with this agent. Further studies may be warranted in cancers of organs where local concentrations of the compound may be higher (e.g., liver) and an exploratory study in hepatocellular carcinoma is ongoing in Asia. Because STAT3 remains an attractive antitumor target, chemically related compounds with similar pharmacologic activities are currently being evaluated preclinically.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B56.