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
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
Affiliations
Sébastien Perreault
Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal
Valérie Larouche
Division of Hemato-Oncology, Department of Pediatrics, Centre Hospitalier Universitaire de Québec-Université Laval
Uri Tabori
Division of Hemato-Oncology, Department of Pediatrics, Hospital for Sick Children
Cynthia Hawkin
Department of Pathology, Hospital for Sick Children
Sarah Lippé
CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal
Benjamin Ellezam
Department of Pathology, CHU Sainte-Justine, Université de Montréal
Jean-Claude Décarie
Department of Radiology, CHU Sainte-Justine, Université de Montréal
Yves Théoret
Department of Pharmacology, CHU Sainte-Justine, Université de Montréal
Marie-Élaine Métras
Department of Pharmacology, CHU Sainte-Justine, Université de Montréal
Serge Sultan
CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal
Édith Cantin
Division of Neuropsychology, Centre Hospitalier Universitaire de Québec-Université Laval
Marie-Ève Routhier
Division of Neuropsychology, Centre Hospitalier Universitaire de Québec-Université Laval
Maxime Caru
CHU Sainte-Justine Research Center, CHU Sainte-Justine, Université de Montréal
Geneviève Legault
Division of Neurology, Department of Pediatrics, McGill University Health Center, Montreal Children’s Hospital
Éric Bouffet
Division of Hemato-Oncology, Department of Pediatrics, Hospital for Sick Children
Lucie Lafay-Cousin
Departments of Oncology and Pediatrics, Alberta Children’s Hospital, University of Calgary, Cumming School of Medicine
Juliette Hukin
Division of Child Neurology and Oncology, BC Children’s Hospital, University of British Columbia
Craig Erker
Division of Hemato-Oncology, Department of Pediatrics, IWK Health Centre, Dalhousie University
Nada Jabado
Division of Hemato-Oncology, Department of Pediatrics, McGill University Health Center, Montreal Children’s Hospital
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.
