A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01
Abstract Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofi...
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2019-12-01
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Online Access: | https://doi.org/10.1186/s12885-019-6442-2 |
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doaj-e66eabef1a354091978ff8f6087684a2 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sébastien Perreault Valérie Larouche Uri Tabori Cynthia Hawkin Sarah Lippé Benjamin Ellezam Jean-Claude Décarie Yves Théoret Marie-Élaine Métras Serge Sultan Édith Cantin Marie-Ève Routhier Maxime Caru Geneviève Legault Éric Bouffet Lucie Lafay-Cousin Juliette Hukin Craig Erker Nada Jabado |
spellingShingle |
Sébastien Perreault Valérie Larouche Uri Tabori Cynthia Hawkin Sarah Lippé Benjamin Ellezam Jean-Claude Décarie Yves Théoret Marie-Élaine Métras Serge Sultan Édith Cantin Marie-Ève Routhier Maxime Caru Geneviève Legault Éric Bouffet Lucie Lafay-Cousin Juliette Hukin Craig Erker Nada Jabado A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01 BMC Cancer Trametinib Glioma Plexiform neurofibroma Neurofibromatosis type 1 BRAF MEK inhibitor |
author_facet |
Sébastien Perreault Valérie Larouche Uri Tabori Cynthia Hawkin Sarah Lippé Benjamin Ellezam Jean-Claude Décarie Yves Théoret Marie-Élaine Métras Serge Sultan Édith Cantin Marie-Ève Routhier Maxime Caru Geneviève Legault Éric Bouffet Lucie Lafay-Cousin Juliette Hukin Craig Erker Nada Jabado |
author_sort |
Sébastien Perreault |
title |
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01 |
title_short |
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01 |
title_full |
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01 |
title_fullStr |
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01 |
title_full_unstemmed |
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01 |
title_sort |
phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the mapk/erk pathway: tram-01 |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2019-12-01 |
description |
Abstract Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017. |
topic |
Trametinib Glioma Plexiform neurofibroma Neurofibromatosis type 1 BRAF MEK inhibitor |
url |
https://doi.org/10.1186/s12885-019-6442-2 |
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doaj-e66eabef1a354091978ff8f6087684a22020-12-27T12:20:26ZengBMCBMC Cancer1471-24072019-12-011911910.1186/s12885-019-6442-2A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01Sébastien Perreault0Valérie Larouche1Uri Tabori2Cynthia Hawkin3Sarah Lippé4Benjamin Ellezam5Jean-Claude Décarie6Yves Théoret7Marie-Élaine Métras8Serge Sultan9Édith Cantin10Marie-Ève Routhier11Maxime Caru12Geneviève Legault13Éric Bouffet14Lucie Lafay-Cousin15Juliette Hukin16Craig Erker17Nada Jabado18Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de MontréalDivision of Hemato-Oncology, Department of Pediatrics, Centre Hospitalier Universitaire de Québec-Université LavalDivision of Hemato-Oncology, Department of Pediatrics, Hospital for Sick ChildrenDepartment of Pathology, Hospital for Sick ChildrenCHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de MontréalDepartment of Pathology, CHU Sainte-Justine, Université de MontréalDepartment of Radiology, CHU Sainte-Justine, Université de MontréalDepartment of Pharmacology, CHU Sainte-Justine, Université de MontréalDepartment of Pharmacology, CHU Sainte-Justine, Université de MontréalCHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de MontréalDivision of Neuropsychology, Centre Hospitalier Universitaire de Québec-Université LavalDivision of Neuropsychology, Centre Hospitalier Universitaire de Québec-Université LavalCHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de MontréalDivision of Neurology, Department of Pediatrics, McGill University Health Center, Montreal Children’s HospitalDivision of Hemato-Oncology, Department of Pediatrics, Hospital for Sick ChildrenDepartments of Oncology and Pediatrics, Alberta Children’s Hospital, University of Calgary, Cumming School of MedicineDivision of Child Neurology and Oncology, BC Children’s Hospital, University of British ColumbiaDivision of Hemato-Oncology, Department of Pediatrics, IWK Health Centre, Dalhousie UniversityDivision of Hemato-Oncology, Department of Pediatrics, McGill University Health Center, Montreal Children’s HospitalAbstract Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.https://doi.org/10.1186/s12885-019-6442-2TrametinibGliomaPlexiform neurofibromaNeurofibromatosis type 1BRAFMEK inhibitor |