Wong AL1, Soo RA1, Tan DS2, Lee SC1, Lim JS3, Marban PC4, Kong LR5, Lee YJ5, Wang LZ6, Thuya WL5, Soong R5, Yee MQ5, Chin TM1, Cordero MT4, Asuncion BR5, Pang B5, Pervaiz S7, Hirpara JL5, Sinha A8, Xu WW9, Yuasa M10, Tsunoda T10, Motoyama M10, Yamauchi T11, Goh BC12
1Department of Haematology-Oncology, National University Health System Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System Cancer Science Institute.
2Department of Medical Oncology, National Cancer Centre.
3Department of Haematology-Oncology, National University Health System Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System.
4Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System.
5Cancer Science Institute.
6Cancer Science Institute Departments of Pharmacology.
7Physiology, Yong Loo Lin School of Medicine.
8Department of Diagnostic Imaging, National University Health System, Singapore.
9Otsuka Beijing Research Institute, Beijing, China.
10Otsuka Pharmaceutical Co., Ltd, Chiyoda-ku.
11Fuji Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd, Chiyoda-ku, Japan.
12Department of Haematology-Oncology, National University Health System Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System Cancer Science Institute Departments of Pharmacology email@example.com.
BACKGROUND: The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors.
PATIENTS AND METHODS: Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing.
RESULTS: Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr(705)) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure.
CONCLUSION: OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored.
CLINICALTRIALSGOV IDENTIFIER: NCT01184807.