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A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas

BACKGROUND: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolim...

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Autores principales: Eroglu, Z, Tawbi, H A, Hu, J, Guan, M, Frankel, P H, Ruel, N H, Wilczynski, S, Christensen, S, Gandara, D R, Chow, W A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430716/
https://www.ncbi.nlm.nih.gov/pubmed/25897676
http://dx.doi.org/10.1038/bjc.2015.126
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author Eroglu, Z
Tawbi, H A
Hu, J
Guan, M
Frankel, P H
Ruel, N H
Wilczynski, S
Christensen, S
Gandara, D R
Chow, W A
author_facet Eroglu, Z
Tawbi, H A
Hu, J
Guan, M
Frankel, P H
Ruel, N H
Wilczynski, S
Christensen, S
Gandara, D R
Chow, W A
author_sort Eroglu, Z
collection PubMed
description BACKGROUND: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted. METHODS: Seventy-one adults with advanced STS who received ⩽2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS). RESULTS: There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19–0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each). CONCLUSIONS: While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
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spelling pubmed-44307162015-05-21 A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas Eroglu, Z Tawbi, H A Hu, J Guan, M Frankel, P H Ruel, N H Wilczynski, S Christensen, S Gandara, D R Chow, W A Br J Cancer Clinical Study BACKGROUND: The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted. METHODS: Seventy-one adults with advanced STS who received ⩽2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS). RESULTS: There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19–0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each). CONCLUSIONS: While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas. Nature Publishing Group 2015-05-12 2015-04-21 /pmc/articles/PMC4430716/ /pubmed/25897676 http://dx.doi.org/10.1038/bjc.2015.126 Text en Copyright © 2015 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Clinical Study
Eroglu, Z
Tawbi, H A
Hu, J
Guan, M
Frankel, P H
Ruel, N H
Wilczynski, S
Christensen, S
Gandara, D R
Chow, W A
A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
title A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
title_full A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
title_fullStr A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
title_full_unstemmed A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
title_short A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
title_sort randomised phase ii trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
topic Clinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4430716/
https://www.ncbi.nlm.nih.gov/pubmed/25897676
http://dx.doi.org/10.1038/bjc.2015.126
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