Cargando…

Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study

BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafe...

Descripción completa

Detalles Bibliográficos
Autores principales: van der Hiel, Bernies, Haanen, John B.A.G., Stokkel, Marcel P.M., Peeper, Daniel S., Jimenez, Connie R., Beijnen, Jos H., van de Wiel, Bart A., Boellaard, Ronald, van den Eertwegh, Alfons J.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603097/
https://www.ncbi.nlm.nih.gov/pubmed/28915798
http://dx.doi.org/10.1186/s12885-017-3626-5
_version_ 1783264674725232640
author van der Hiel, Bernies
Haanen, John B.A.G.
Stokkel, Marcel P.M.
Peeper, Daniel S.
Jimenez, Connie R.
Beijnen, Jos H.
van de Wiel, Bart A.
Boellaard, Ronald
van den Eertwegh, Alfons J.M.
author_facet van der Hiel, Bernies
Haanen, John B.A.G.
Stokkel, Marcel P.M.
Peeper, Daniel S.
Jimenez, Connie R.
Beijnen, Jos H.
van de Wiel, Bart A.
Boellaard, Ronald
van den Eertwegh, Alfons J.M.
author_sort van der Hiel, Bernies
collection PubMed
description BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with (18)F-Fluorodeoxyglucose ((18)F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of (18)F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. (18)F-Fluoro-3′-deoxy-3’L-fluorothymidine ((18)F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than (18)F-FDG. METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo (18)F-FDG PET/CT and in 25 patients additional (18)F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both (18)F-FDG and (18)F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
format Online
Article
Text
id pubmed-5603097
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-56030972017-09-21 Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study van der Hiel, Bernies Haanen, John B.A.G. Stokkel, Marcel P.M. Peeper, Daniel S. Jimenez, Connie R. Beijnen, Jos H. van de Wiel, Bart A. Boellaard, Ronald van den Eertwegh, Alfons J.M. BMC Cancer Study Protocol BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with (18)F-Fluorodeoxyglucose ((18)F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of (18)F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. (18)F-Fluoro-3′-deoxy-3’L-fluorothymidine ((18)F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than (18)F-FDG. METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo (18)F-FDG PET/CT and in 25 patients additional (18)F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both (18)F-FDG and (18)F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered. BioMed Central 2017-09-15 /pmc/articles/PMC5603097/ /pubmed/28915798 http://dx.doi.org/10.1186/s12885-017-3626-5 Text en © The Author(s). 2017 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 Study Protocol
van der Hiel, Bernies
Haanen, John B.A.G.
Stokkel, Marcel P.M.
Peeper, Daniel S.
Jimenez, Connie R.
Beijnen, Jos H.
van de Wiel, Bart A.
Boellaard, Ronald
van den Eertwegh, Alfons J.M.
Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study
title Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study
title_full Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study
title_fullStr Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study
title_full_unstemmed Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study
title_short Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study
title_sort vemurafenib plus cobimetinib in unresectable stage iiic or stage iv melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (reposit): study protocol of a phase ii, open-label, multicenter study
topic Study Protocol
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603097/
https://www.ncbi.nlm.nih.gov/pubmed/28915798
http://dx.doi.org/10.1186/s12885-017-3626-5
work_keys_str_mv AT vanderhielbernies vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT haanenjohnbag vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT stokkelmarcelpm vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT peeperdaniels vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT jimenezconnier vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT beijnenjosh vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT vandewielbarta vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT boellaardronald vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT vandeneertweghalfonsjm vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy
AT vemurafenibpluscobimetinibinunresectablestageiiicorstageivmelanomaresponsemonitoringandresistancepredictionwithpositronemissiontomographyandtumorcharacteristicsrepositstudyprotocolofaphaseiiopenlabelmulticenterstudy