Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies.
We carried out a multicenter dose-escalation phase I study of oral OPB-51602, a signal transducer and activator of transcription 3 phosphorylation inhibitor, in patients with relapsed or refractory hematological malignancies to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity. Twenty patients were treated with OPB-51602 at doses of 1, 2, 3, 4, and 6 mg in the "3 + 3" dose escalation design. The most common treatment-related adverse events included nausea (55%), peripheral sensory neuropathy (45%), and diarrhea (40%). The most frequently observed grade 3 or 4 drug-related adverse events were neutropenia (20%), leukopenia (15%), lymphopenia (10%), and thrombocytopenia (10%). The MTD was 6 mg, with dose-limiting toxicities of grade 3 lactic acidosis and increased blood lactic acid levels observed in one of three patients and grade 1-2 peripheral neuropathy in three of three patients. The recommended dose was determined to be 4 mg. OPB-51602 was rapidly absorbed, and exposure tended to increase in a dose-dependent manner. Accumulation of OPB-51602 was seen with 4 weeks of multiple treatments. No clear therapeutic response was observed. Durable stable disease was observed in two patients with acute myeloid leukemia and one with myeloma. In conclusion, the MTD of OPB-51602 was 6 mg. OPB-51602 was safe and well tolerated in a dose range of 1-4 mg. However, long-term administration at higher doses was difficult with the daily dosing schedule, and no response was seen. Therefore, further clinical development of OPB-51602 for hematological malignancies with a daily dosing schedule was terminated.
Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
Michinori
M
Ogura
Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.
Toshiki
T
Uchida
Department of Hematology and Oncology, Cancer Institute Hospital, Japanese Foundation For Cancer Research, Tokyo, Japan.
Yasuhito
Y
Terui
Department of Hematology, Nagoya University Hospital, Nagoya, Japan.
Fumihiko
F
Hayakawa
Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
Yukio
Y
Kobayashi
Division of Hematology and Oncology, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Masafumi
M
Taniwaki
Division of Medical Oncology, Hematology and Infectious Disease, Fukuoka University Hospital, Fukuoka, Japan.
Yasushi
Y
Takamatsu
Nagoya Medical Center, Nagoya, Japan.
Tomoki
T
Naoe
Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
Kensei
K
Tobinai
Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
Wataru
W
Munakata
Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan.
Takeshi
T
Yamauchi
Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan.
Akiko
A
Kageyama
Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan.
Miyuki
M
Yuasa
Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan.
Masaaki
M
Motoyama
Otsuka Pharmaceutical Co., Ltd, Tokyo, Japan.
Takeshi
T
Tsunoda
Department of Hematology and Oncology, Cancer Institute Hospital, Japanese Foundation For Cancer Research, Tokyo, Japan.
Kiyohiko
K
Hatake
D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009325:Nausea / Q000139:chemically induced; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
Daily dosing schedule; OPB-51602; STAT3 inhibitor; hematological malignancy; phase I study