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Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors

Background: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to deter...

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Autores principales: Kao, Chien-Chang, Ho, Ching-Liang, Yang, Ming-Hsin, Tsai, Yi-Ta, Liu, Shu-Yu, Chang, Ping-Ying, Wu, Yi-Ying, Chen, Jia-Hong, Huang, Tzu-Chuan, Yehn, Ren-Hua, Dai, Ming-Shen, Chen, Yeu-Chin, Sun, Guang-Huan, Cha, Tai-Lung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031611/
https://www.ncbi.nlm.nih.gov/pubmed/35456276
http://dx.doi.org/10.3390/jcm11082183
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author Kao, Chien-Chang
Ho, Ching-Liang
Yang, Ming-Hsin
Tsai, Yi-Ta
Liu, Shu-Yu
Chang, Ping-Ying
Wu, Yi-Ying
Chen, Jia-Hong
Huang, Tzu-Chuan
Yehn, Ren-Hua
Dai, Ming-Shen
Chen, Yeu-Chin
Sun, Guang-Huan
Cha, Tai-Lung
author_facet Kao, Chien-Chang
Ho, Ching-Liang
Yang, Ming-Hsin
Tsai, Yi-Ta
Liu, Shu-Yu
Chang, Ping-Ying
Wu, Yi-Ying
Chen, Jia-Hong
Huang, Tzu-Chuan
Yehn, Ren-Hua
Dai, Ming-Shen
Chen, Yeu-Chin
Sun, Guang-Huan
Cha, Tai-Lung
author_sort Kao, Chien-Chang
collection PubMed
description Background: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers. Methods: Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPK(S308) in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile. Results: Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPK(S308) in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR). Conclusions: Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective.
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spelling pubmed-90316112022-04-23 Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors Kao, Chien-Chang Ho, Ching-Liang Yang, Ming-Hsin Tsai, Yi-Ta Liu, Shu-Yu Chang, Ping-Ying Wu, Yi-Ying Chen, Jia-Hong Huang, Tzu-Chuan Yehn, Ren-Hua Dai, Ming-Shen Chen, Yeu-Chin Sun, Guang-Huan Cha, Tai-Lung J Clin Med Article Background: Combination therapy with the administration of GW5074 and sorafenib significantly induced necrotic death in various cancer cells in vivo, as well as prolonging the survival of an animal disease model due to significant suppression of the primary and metastatic lesions. We sought to determine the safety, tolerability, pharmacokinetics, and anti-tumor activity of this co-administration therapy in patients with refractory advanced solid cancers. Methods: Twelve patients were enrolled. Eligible subjects received different dosages of GW5074 in one of the three dose cohorts (Cohort 1: 750 mg daily, Cohort 2: 1500 mg daily, Cohort 3: 750 mg twice daily) plus 200 mg of sorafenib daily to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) at phase 1. Furthermore, the expression level of phosphorylated DAPK(S308) in primary tumor, metastatic tumor, and circulating tumor cells (CTC) were evaluated to investigate the relationship between biomarker and the efficacy profile. Results: Among the 12 enrolled patients in this phase 1 trial, most adverse effects (AE) were grade 1, with two being grade 3. The most frequent AE of all grades were weight loss and hypertension, occurring in 16.7% of participants. Eight patients (66.7%) had the disease controlled by receiving co-administration therapy of GW5074 and sorafenib. GW5074 was found to have poor absorption, as increasing the dosage did not result in a significant increase in the bioavailability of GW5074 in subjects. Furthermore, the expression level of phosphorylated DAPK(S308) in tumor and CTCs were correlated with the disease control rate (DCR) and duration of response (DOR). Conclusions: Co-administration therapy of GW5074 and sorafenib demonstrated a favorable safety profile and showed anti-tumor activity in a variety of tumor types. However, the solubility of GW5074 is not satisfactory. A future phase 2a trial will be carried out using the new salted form that has been proven to be more effective. MDPI 2022-04-14 /pmc/articles/PMC9031611/ /pubmed/35456276 http://dx.doi.org/10.3390/jcm11082183 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kao, Chien-Chang
Ho, Ching-Liang
Yang, Ming-Hsin
Tsai, Yi-Ta
Liu, Shu-Yu
Chang, Ping-Ying
Wu, Yi-Ying
Chen, Jia-Hong
Huang, Tzu-Chuan
Yehn, Ren-Hua
Dai, Ming-Shen
Chen, Yeu-Chin
Sun, Guang-Huan
Cha, Tai-Lung
Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors
title Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors
title_full Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors
title_fullStr Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors
title_full_unstemmed Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors
title_short Phase I Targeted Combination Trial of Sorafenib and GW5074 in Patients with Advanced Refractory Solid Tumors
title_sort phase i targeted combination trial of sorafenib and gw5074 in patients with advanced refractory solid tumors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031611/
https://www.ncbi.nlm.nih.gov/pubmed/35456276
http://dx.doi.org/10.3390/jcm11082183
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