Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors
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Purpose OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phaseI dose-escalation study of OPB-31121 was conducted to determine maximum-tolerateddose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients withadvanced solid tumors. Materials and MethodsPatients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluatedby the National Cancer Institute–Common Terminology Criteria for Adverse Events (NCICTCAE)ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively. ResultsTwenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinuedtreatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs wereobserved: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse eventswere gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea(72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eightpatients had stable disease and 10 patients had disease progression. Two patients (1 coloncancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continuedtreatment up to cycle 13 before disease progression. ConclusionThis study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has apreliminary antitumor activity.
Abstract
Purpose OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phaseI dose-escalation study of OPB-31121 was conducted to determine maximum-tolerateddose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients withadvanced solid tumors. Materials and MethodsPatients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluatedby the National Cancer Institute–Common Terminology Criteria for Adverse Events (NCICTCAE)ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively. ResultsTwenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinuedtreatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs wereobserved: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse eventswere gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea(72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eightpatients had stable disease and 10 patients had disease progression. Two patients (1 coloncancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continuedtreatment up to cycle 13 before disease progression. ConclusionThis study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has apreliminary antitumor activity.
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