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Cancer Sci. 2016 Apr;107(4):499-506. doi: 10.1111/cas.12906. Epub 2016 Mar 28.

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.

Author information

1
Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA, USA.
2
Memorial Sloan-Kettering Cancer Center, New York, NY, USA, USA.
3
Weill Cornell Medical College, New York, NY, USA, USA.
4
Yale Cancer Center, Yale University, New Haven, CT, USA, USA.
5
Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
6
Fuji Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
7
Planning Department, Kyowa Hakko Kirin Pharma Inc., Princeton, NJ, USA.
8
Tokyo Research Park, R&D Division, Kyowa Hakko Kirin Co., Ltd., Tokyo, Japan.

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.

KEYWORDS:

Insulin receptor; KW-2450; insulin-like growth factor receptor-1; phase I; pre-clinical

PMID:
26850678
PMCID:
PMC4832855
DOI:
10.1111/cas.12906
[Indexed for MEDLINE]
Free PMC Article

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