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: Gary K Schwartz, Mark A Dickson, Patricia M LoRusso, Edward A Sausville, Yoshimi Maekawa, Yasuo Watanabe, Naomi Kashima, Daisuke Nakashima, Shiro Akinaga
• Journal: Cancer science (Cancer Sci) Vol. 107 Issue 4 Pg. 499-506 (Apr 2016) ISSN: 1349-7006 [Electronic] England
• PMID: 26850678 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Protein Kinase Inhibitors
• ERBB2 protein, human
• Receptor, ErbB-2
• Receptor, IGF Type 1
• Receptor, Insulin

Topics

• Adult
• Aged
• Animals
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, genetics, pathology)
• Female
• Humans
• Maximum Tolerated Dose
• Mice
• Protein Kinase Inhibitors (administration & dosage)
• Receptor, ErbB-2 (genetics)
• Receptor, IGF Type 1 (biosynthesis, genetics)
• Receptor, Insulin (biosynthesis, genetics)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays