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Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study
BACKGROUND: Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Previous studies have demonstrated anti-tumour activities of famitinib against a w...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235389/ https://www.ncbi.nlm.nih.gov/pubmed/30382933 http://dx.doi.org/10.1186/s40880-018-0330-z |
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author | Chen, Qiuyan Tang, Linquan Liu, Na Han, Feng Guo, Ling Guo, Shanshan Wang, Jianwei Liu, Huai Ye, Yanfang Zhang, Lu Liu, Liting Wang, Pan Li, Yingqin He, Qingmei Yang, Xiaoqun Tang, Qingnan Li, Yang Liang, YuJing Sun, XueSong Xie, Chuanmiao Mo, Yunxian Guo, Ying Sun, Rui Mo, Haoyuan Cao, Kajia Guo, Xiang Zeng, Musheng Mai, Haiqiang Ma, Jun |
author_facet | Chen, Qiuyan Tang, Linquan Liu, Na Han, Feng Guo, Ling Guo, Shanshan Wang, Jianwei Liu, Huai Ye, Yanfang Zhang, Lu Liu, Liting Wang, Pan Li, Yingqin He, Qingmei Yang, Xiaoqun Tang, Qingnan Li, Yang Liang, YuJing Sun, XueSong Xie, Chuanmiao Mo, Yunxian Guo, Ying Sun, Rui Mo, Haoyuan Cao, Kajia Guo, Xiang Zeng, Musheng Mai, Haiqiang Ma, Jun |
author_sort | Chen, Qiuyan |
collection | PubMed |
description | BACKGROUND: Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Previous studies have demonstrated anti-tumour activities of famitinib against a wide variety of advanced-stage solid cancers. We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We also evaluated the feasibility of contrast-enhanced ultrasound (D-CEUS) as a predictor of early tumour response to famitinib and to correlate functional parameters with clinical efficacy. METHODS: The trial was conducted in subjects with stage III or IVa-b NPC using a 3 + 3 design of escalating famitinib doses. Briefly, subjects received 2 weeks of famitinib monotherapy followed by 7 weeks of famitinib plus CCRT. D-CEUS of the neck lymph nodes was performed at day 0, 8 and 15 after famitinib was administered before starting concurrent chemoradiotherapy. End points included safety, tolerability and anti-tumour activity. RESULTS: Twenty patients were enrolled (six each for 12.5, 16.5 and 20 mg and two for 25 mg). Two patients in the 25 mg cohort developed dose-limiting toxicities, including grade 4 thrombocytopenia and grade 3 hypertension. The most common grade 3/4 adverse events were leukopenia, neutropenia and radiation mucositis. D-CEUS tests showed that more than 60% of patients achieved a perfusion parameter response after 2 weeks taking famitinib alone, and the parameter response was associated with disease improvement. In the famitinib monotherapy stage, three patients (15%) showed partial responses. The complete response rate was 65% at the completion of treatment and 95% 3 months after the treatment ended. After a median follow-up of 44 months, the 3-year progression-free survival (PFS) and distant metastasis-free survival were 70% and 75%, respectively. Subjects with a decrease of perfusion parameter response, such as peak intensity decreased at least 30% after 1 week of famitinib treatment, had higher 3-year PFS (90.9% vs. 44.4%, 95% CI 73.7%–100% vs. 11.9%–76.9%, P < 0.001) than those with an increase or a reduction of less than 30%. CONCLUSIONS: The recommended famitinib dose for phase II trial is 20 mg with CCRT for patients with local advanced NPC. D-CEUS is a reliable and early measure of efficacy for famitinib therapies. Further investigation is required to confirm the effects of famitinib plus chemoradiotherapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40880-018-0330-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6235389 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-62353892018-11-20 Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study Chen, Qiuyan Tang, Linquan Liu, Na Han, Feng Guo, Ling Guo, Shanshan Wang, Jianwei Liu, Huai Ye, Yanfang Zhang, Lu Liu, Liting Wang, Pan Li, Yingqin He, Qingmei Yang, Xiaoqun Tang, Qingnan Li, Yang Liang, YuJing Sun, XueSong Xie, Chuanmiao Mo, Yunxian Guo, Ying Sun, Rui Mo, Haoyuan Cao, Kajia Guo, Xiang Zeng, Musheng Mai, Haiqiang Ma, Jun Cancer Commun (Lond) Original Article BACKGROUND: Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Previous studies have demonstrated anti-tumour activities of famitinib against a wide variety of advanced-stage solid cancers. We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We also evaluated the feasibility of contrast-enhanced ultrasound (D-CEUS) as a predictor of early tumour response to famitinib and to correlate functional parameters with clinical efficacy. METHODS: The trial was conducted in subjects with stage III or IVa-b NPC using a 3 + 3 design of escalating famitinib doses. Briefly, subjects received 2 weeks of famitinib monotherapy followed by 7 weeks of famitinib plus CCRT. D-CEUS of the neck lymph nodes was performed at day 0, 8 and 15 after famitinib was administered before starting concurrent chemoradiotherapy. End points included safety, tolerability and anti-tumour activity. RESULTS: Twenty patients were enrolled (six each for 12.5, 16.5 and 20 mg and two for 25 mg). Two patients in the 25 mg cohort developed dose-limiting toxicities, including grade 4 thrombocytopenia and grade 3 hypertension. The most common grade 3/4 adverse events were leukopenia, neutropenia and radiation mucositis. D-CEUS tests showed that more than 60% of patients achieved a perfusion parameter response after 2 weeks taking famitinib alone, and the parameter response was associated with disease improvement. In the famitinib monotherapy stage, three patients (15%) showed partial responses. The complete response rate was 65% at the completion of treatment and 95% 3 months after the treatment ended. After a median follow-up of 44 months, the 3-year progression-free survival (PFS) and distant metastasis-free survival were 70% and 75%, respectively. Subjects with a decrease of perfusion parameter response, such as peak intensity decreased at least 30% after 1 week of famitinib treatment, had higher 3-year PFS (90.9% vs. 44.4%, 95% CI 73.7%–100% vs. 11.9%–76.9%, P < 0.001) than those with an increase or a reduction of less than 30%. CONCLUSIONS: The recommended famitinib dose for phase II trial is 20 mg with CCRT for patients with local advanced NPC. D-CEUS is a reliable and early measure of efficacy for famitinib therapies. Further investigation is required to confirm the effects of famitinib plus chemoradiotherapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40880-018-0330-z) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-01 /pmc/articles/PMC6235389/ /pubmed/30382933 http://dx.doi.org/10.1186/s40880-018-0330-z Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Original Article Chen, Qiuyan Tang, Linquan Liu, Na Han, Feng Guo, Ling Guo, Shanshan Wang, Jianwei Liu, Huai Ye, Yanfang Zhang, Lu Liu, Liting Wang, Pan Li, Yingqin He, Qingmei Yang, Xiaoqun Tang, Qingnan Li, Yang Liang, YuJing Sun, XueSong Xie, Chuanmiao Mo, Yunxian Guo, Ying Sun, Rui Mo, Haoyuan Cao, Kajia Guo, Xiang Zeng, Musheng Mai, Haiqiang Ma, Jun Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study |
title | Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study |
title_full | Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study |
title_fullStr | Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study |
title_full_unstemmed | Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study |
title_short | Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study |
title_sort | famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation study |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235389/ https://www.ncbi.nlm.nih.gov/pubmed/30382933 http://dx.doi.org/10.1186/s40880-018-0330-z |
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