A phase I, open-label, nonrandomized trial of OPB-31121, a STAT3 inhibitor, in patients with advanced solid tumors.

Abstract

e13056 Background: STAT pathway is activated in many solid tumors. OPB-31121 is an orally administered STAT3 inhibitor. We conducted a phase I study to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics of OPB-31121 in patients with advanced refractory solid tumors. Methods: A standard 3 + 3 dose-escalation design was used with a 28-day cycle. The tested dose level was 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg/day. Results: Twenty-one patients were enrolled. Median age was 58 (19-74) and 15 patients were male. The tumors of patients were gastric cancer (5), colorectal cancer (7), esophageal cancer (2), hepatocellular carcinoma (1), pancreatic cancer (1), lung cancer (1), neuroectodermal cancer (1), melanoma (1), parotid gland cancer (1), and cervix cancer (1). The patient number enrolled in each dose cohort was 100 mg (4), 200 mg (3), 400 mg (3), 600 mg (7), 800 mg (4), respectively. The most common toxicities of all grades were nausea (Gr 1:11, Gr 2: 5, Gr 3:0, Gr 4:0), vomiting (Gr 1: 9, Gr 2: 4, Gr 3: 1, Gr 4:0), diarrhea (Gr 1: 10, Gr 2: 3, Gr 3:2, Gr 4:0), fatigue (Gr 1:2, Gr 2: 1, Gr 3:0, Gr 4:0), anorexia (Gr 1:2, Gr 2: 2, Gr 3:0, Gr 4:0). These toxicities were predominantly grade 1 or grade 2. The dose-limiting toxicities (DLT) were grade 3 vomiting at 600 mg and grade 3 diarrhea at 800 mg. The MTD has not been determined yet. Cmax and AUC of OPB-31121 and metabolites increased with increasing doses of OPB-31121. Among 17 response-evaluable patients, 8 had the stable disease (disease control rate 47.1%). Disease stabilization more than 12 months was observed in a gastric cancer patient. Conclusions: OPB-31121 was well-tolerated and the DLT were grade 3 vomiting and diarrhea. The MTD has not been determined yet and the preliminary promising antitumor activity needs further validation in phase II studies. No significant financial relationships to disclose.