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Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial

This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer rece...

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Autores principales: Bruna, Jordi, Videla, Sebastián, Argyriou, Andreas A., Velasco, Roser, Villoria, Jesús, Santos, Cristina, Nadal, Cristina, Cavaletti, Guido, Alberti, Paola, Briani, Chiara, Kalofonos, Haralabos P., Cortinovis, Diego, Sust, Mariano, Vaqué, Anna, Klein, Thomas, Plata-Salamán, Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794691/
https://www.ncbi.nlm.nih.gov/pubmed/28924870
http://dx.doi.org/10.1007/s13311-017-0572-5
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author Bruna, Jordi
Videla, Sebastián
Argyriou, Andreas A.
Velasco, Roser
Villoria, Jesús
Santos, Cristina
Nadal, Cristina
Cavaletti, Guido
Alberti, Paola
Briani, Chiara
Kalofonos, Haralabos P.
Cortinovis, Diego
Sust, Mariano
Vaqué, Anna
Klein, Thomas
Plata-Salamán, Carlos
author_facet Bruna, Jordi
Videla, Sebastián
Argyriou, Andreas A.
Velasco, Roser
Villoria, Jesús
Santos, Cristina
Nadal, Cristina
Cavaletti, Guido
Alberti, Paola
Briani, Chiara
Kalofonos, Haralabos P.
Cortinovis, Diego
Sust, Mariano
Vaqué, Anna
Klein, Thomas
Plata-Salamán, Carlos
author_sort Bruna, Jordi
collection PubMed
description This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)°C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events ≥ 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-017-0572-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-57946912018-02-05 Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial Bruna, Jordi Videla, Sebastián Argyriou, Andreas A. Velasco, Roser Villoria, Jesús Santos, Cristina Nadal, Cristina Cavaletti, Guido Alberti, Paola Briani, Chiara Kalofonos, Haralabos P. Cortinovis, Diego Sust, Mariano Vaqué, Anna Klein, Thomas Plata-Salamán, Carlos Neurotherapeutics Original Article This trial assessed the efficacy of MR309 (a novel selective sigma-1 receptor ligand previously developed as E-52862) in ameliorating oxaliplatin-induced peripheral neuropathy (oxaipn). A discontinuous regimen of MR309 (400 mg/day, 5 days per cycle) was tested in patients with colorectal cancer receiving FOLFOX in a phase II, randomized, double-blind, placebo-controlled, multicenter clinical trial. Outcome measures included changes in 24-week quantitative measures of thermal sensitivity and total neuropathy score. In total, 124 patients were randomized (1:1) to MR309 or placebo. Sixty-three (50.8%) patients withdrew prematurely before completing 12 planned oxaliplatin cycles. Premature withdrawal because of cancer progression was less frequent in the MR309 group (7.4% vs 25.0% with placebo; p = 0.054). MR309 significantly reduced cold pain threshold temperature [mean treatment effect difference (SE) vs placebo: 5.29 (1.60)°C; p = 0.001] and suprathreshold cold stimulus-evoked pain intensity [mean treatment effect difference: 1.24 (0.57) points; p = 0.032]. Total neuropathy score, health-related quality-of-life measures, and nerve-conduction parameters changed similarly in both arms, whereas the proportion of patients with severe chronic neuropathy (National Cancer Institute Common Terminology Criteria for Adverse Events ≥ 3) was significantly lower in the MR309 group (3.0% vs 18.2% with placebo; p = 0.046). The total amount of oxaliplatin delivered was greater in the active arm (1618.9 mg vs 1453.8 mg with placebo; p = 0.049). Overall, 19.0% of patients experienced at least 1 treatment-related adverse event (25.8% and 11.9% with MR309 and placebo, respectively). Intermittent treatment with MR309 was associated with reduced acute oxaipn and higher oxaliplatin exposure, and showed a potential neuroprotective role for chronic cumulative oxaipn. Furthermore, MR309 showed an acceptable safety profile. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-017-0572-5) contains supplementary material, which is available to authorized users. Springer US 2017-09-18 2018-01 /pmc/articles/PMC5794691/ /pubmed/28924870 http://dx.doi.org/10.1007/s13311-017-0572-5 Text en © The Author(s) 2017 Open Access This 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.
spellingShingle Original Article
Bruna, Jordi
Videla, Sebastián
Argyriou, Andreas A.
Velasco, Roser
Villoria, Jesús
Santos, Cristina
Nadal, Cristina
Cavaletti, Guido
Alberti, Paola
Briani, Chiara
Kalofonos, Haralabos P.
Cortinovis, Diego
Sust, Mariano
Vaqué, Anna
Klein, Thomas
Plata-Salamán, Carlos
Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial
title Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial
title_full Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial
title_fullStr Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial
title_full_unstemmed Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial
title_short Efficacy of a Novel Sigma-1 Receptor Antagonist for Oxaliplatin-Induced Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Trial
title_sort efficacy of a novel sigma-1 receptor antagonist for oxaliplatin-induced neuropathy: a randomized, double-blind, placebo-controlled phase iia clinical trial
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794691/
https://www.ncbi.nlm.nih.gov/pubmed/28924870
http://dx.doi.org/10.1007/s13311-017-0572-5
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