Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole
Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10...
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doaj-e78fa8802280460695e1175fa5a253532020-11-25T02:59:56ZengSAGE PublishingTherapeutic Advances in Medical Oncology1758-83592018-07-011010.1177/1758835918786858Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozoleHiroshi UmeharaYoshimi MaekawaFumito KoizumiMakiko ShimizuToshio OtaTamer M. FouadJie WilleyHidekuni KaitoNorihiko ShiraishiDaisuke NakashimaShiro AkinagaNaoto T. UenoBackground: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.https://doi.org/10.1177/1758835918786858 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hiroshi Umehara Yoshimi Maekawa Fumito Koizumi Makiko Shimizu Toshio Ota Tamer M. Fouad Jie Willey Hidekuni Kaito Norihiko Shiraishi Daisuke Nakashima Shiro Akinaga Naoto T. Ueno |
spellingShingle |
Hiroshi Umehara Yoshimi Maekawa Fumito Koizumi Makiko Shimizu Toshio Ota Tamer M. Fouad Jie Willey Hidekuni Kaito Norihiko Shiraishi Daisuke Nakashima Shiro Akinaga Naoto T. Ueno Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole Therapeutic Advances in Medical Oncology |
author_facet |
Hiroshi Umehara Yoshimi Maekawa Fumito Koizumi Makiko Shimizu Toshio Ota Tamer M. Fouad Jie Willey Hidekuni Kaito Norihiko Shiraishi Daisuke Nakashima Shiro Akinaga Naoto T. Ueno |
author_sort |
Hiroshi Umehara |
title |
Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole |
title_short |
Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole |
title_full |
Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole |
title_fullStr |
Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole |
title_full_unstemmed |
Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole |
title_sort |
preclinical and phase i clinical studies of kw-2450, a dual igf-1r/ir tyrosine kinase inhibitor, in combination with lapatinib and letrozole |
publisher |
SAGE Publishing |
series |
Therapeutic Advances in Medical Oncology |
issn |
1758-8359 |
publishDate |
2018-07-01 |
description |
Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated. |
url |
https://doi.org/10.1177/1758835918786858 |
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