title: Preclinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with insulin-like growth factor receptor-1/insulin receptor selectivity.
abstract: Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously; dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer.
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA, USA.
authors: Gary K
authors: GK
authors: Schwartz
authors: Memorial Sloan-Kettering Cancer Center, New York, NY, USA, USA.|Weill Cornell Medical College, New York, NY, USA, USA.
authors: Mark A
authors: MA
authors: Dickson
authors: Yale Cancer Center, Yale University, New Haven, CT, USA, USA.
authors: Patricia M
authors: PM
authors: LoRusso
authors: Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors: Edward A
authors: EA
authors: Sausville
authors: Fuji Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors: Yoshimi
authors: Y
authors: Maekawa
authors: Fuji Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors: Yasuo
authors: Y
authors: Watanabe
authors: Fuji Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors: Naomi
authors: N
authors: Kashima
authors: Planning Department, Kyowa Hakko Kirin Pharma Inc., Princeton, NJ, USA.
authors: Daisuke
authors: D
authors: Nakashima
authors: Tokyo Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan.
authors: Shiro
authors: S
authors: Akinaga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics*; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C508053:ERBB2 protein, human
keywords: Insulin receptor; KW-2450; insulin-like growth factor receptor-1; phase I; pre-clinical