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LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)

BACKGROUND: MEK inhibitor trials in pediatric low-grade glioma (pLGG) have yielded promising results, but there remains room for improvement since objective responses are rarely complete and disease recurrence after completion of therapy is common. Mirdametinib (PD-0325901) is a highly selective MEK...

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Autores principales: Vinitsky, Anna, Chiang, Jason, Bag, Asim K, Campagne, Olivia, Stewart, Clinton F, Dunphy, Paige, Shulkin, Barry, Li, Qian, Lin, Tong, Hoehn, Mary Ellen, Johnson, Jason N, Towbin, Jeffrey A, Khan, Raja, Tatevossian, Ruth G, Armstrong, Gregory T, Potter, Brian, Conklin, Heather, Shearer, Todd, Scott, Susan, Robinson, Giles W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164943/
http://dx.doi.org/10.1093/neuonc/noac079.336
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author Vinitsky, Anna
Chiang, Jason
Bag, Asim K
Campagne, Olivia
Stewart, Clinton F
Dunphy, Paige
Shulkin, Barry
Li, Qian
Lin, Tong
Hoehn, Mary Ellen
Johnson, Jason N
Towbin, Jeffrey A
Khan, Raja
Tatevossian, Ruth G
Armstrong, Gregory T
Potter, Brian
Conklin, Heather
Shearer, Todd
Scott, Susan
Robinson, Giles W
author_facet Vinitsky, Anna
Chiang, Jason
Bag, Asim K
Campagne, Olivia
Stewart, Clinton F
Dunphy, Paige
Shulkin, Barry
Li, Qian
Lin, Tong
Hoehn, Mary Ellen
Johnson, Jason N
Towbin, Jeffrey A
Khan, Raja
Tatevossian, Ruth G
Armstrong, Gregory T
Potter, Brian
Conklin, Heather
Shearer, Todd
Scott, Susan
Robinson, Giles W
author_sort Vinitsky, Anna
collection PubMed
description BACKGROUND: MEK inhibitor trials in pediatric low-grade glioma (pLGG) have yielded promising results, but there remains room for improvement since objective responses are rarely complete and disease recurrence after completion of therapy is common. Mirdametinib (PD-0325901) is a highly selective MEK1/MEK2 inhibitor that, in preclinical studies, has been reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. As such, we recently launched the SJ901 clinical trial (NCT04923126) to determine the safety, recommended phase 2 dose, pharmacokinetics, and preliminary efficacy of mirdametinib in patients with pLGG when administered continuously. Here, we present preliminary phase 1 data. METHODS: SJ901 is a multi-arm phase I/II trial of mirdametinib in patients >2 and <25 years with LGG. Phase I requires participants to have no prior exposure to MEK inhibitors and recurrent/progressive disease with biopsy-proven evidence of MAPK pathway activation. Three escalating dose levels (2 mg/m2/dose BID, 2.5mg/m2/dose BID and 3mg/m2/dose BID) are planned using a rolling 6 design. RESULTS: Accrual began in June 2021. As of Jan 13, 2022, eleven patients enrolled: 5 on dose level 1 (DL1) and 6 on dose level 2 (DL2). Median age is 10 (3-21) years. Ten patients have somatic gene rearrangements (7 BRAF, 1 MYB, 1 RAF1, 1 FGFR1) and one has an NF1 germline mutation. Four have metastatic disease. No dose-limiting toxicities occurred for DL1 (whereas data are pending for DL2) and only grade 1/2 treatment-related adverse events have been observed. No MEK-related retinopathy or cardiopathy has been observed. Four of the six patients with at least one follow-up disease evaluation have a minor response (>25%-<50% decrease). Median time on therapy is 6.6 (2.2-7) months. No disease progressions have occurred. CONCLUSION: Thus far, mirdametinib is well-tolerated and clinically promising when dosed continuously in patients with recurrent/progressive pLGG. More information will be forthcoming.
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spelling pubmed-91649432022-06-05 LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG) Vinitsky, Anna Chiang, Jason Bag, Asim K Campagne, Olivia Stewart, Clinton F Dunphy, Paige Shulkin, Barry Li, Qian Lin, Tong Hoehn, Mary Ellen Johnson, Jason N Towbin, Jeffrey A Khan, Raja Tatevossian, Ruth G Armstrong, Gregory T Potter, Brian Conklin, Heather Shearer, Todd Scott, Susan Robinson, Giles W Neuro Oncol Low Grade Glioma BACKGROUND: MEK inhibitor trials in pediatric low-grade glioma (pLGG) have yielded promising results, but there remains room for improvement since objective responses are rarely complete and disease recurrence after completion of therapy is common. Mirdametinib (PD-0325901) is a highly selective MEK1/MEK2 inhibitor that, in preclinical studies, has been reported to have superior blood-brain-barrier penetration compared to other MEK inhibitors. As such, we recently launched the SJ901 clinical trial (NCT04923126) to determine the safety, recommended phase 2 dose, pharmacokinetics, and preliminary efficacy of mirdametinib in patients with pLGG when administered continuously. Here, we present preliminary phase 1 data. METHODS: SJ901 is a multi-arm phase I/II trial of mirdametinib in patients >2 and <25 years with LGG. Phase I requires participants to have no prior exposure to MEK inhibitors and recurrent/progressive disease with biopsy-proven evidence of MAPK pathway activation. Three escalating dose levels (2 mg/m2/dose BID, 2.5mg/m2/dose BID and 3mg/m2/dose BID) are planned using a rolling 6 design. RESULTS: Accrual began in June 2021. As of Jan 13, 2022, eleven patients enrolled: 5 on dose level 1 (DL1) and 6 on dose level 2 (DL2). Median age is 10 (3-21) years. Ten patients have somatic gene rearrangements (7 BRAF, 1 MYB, 1 RAF1, 1 FGFR1) and one has an NF1 germline mutation. Four have metastatic disease. No dose-limiting toxicities occurred for DL1 (whereas data are pending for DL2) and only grade 1/2 treatment-related adverse events have been observed. No MEK-related retinopathy or cardiopathy has been observed. Four of the six patients with at least one follow-up disease evaluation have a minor response (>25%-<50% decrease). Median time on therapy is 6.6 (2.2-7) months. No disease progressions have occurred. CONCLUSION: Thus far, mirdametinib is well-tolerated and clinically promising when dosed continuously in patients with recurrent/progressive pLGG. More information will be forthcoming. Oxford University Press 2022-06-03 /pmc/articles/PMC9164943/ http://dx.doi.org/10.1093/neuonc/noac079.336 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Low Grade Glioma
Vinitsky, Anna
Chiang, Jason
Bag, Asim K
Campagne, Olivia
Stewart, Clinton F
Dunphy, Paige
Shulkin, Barry
Li, Qian
Lin, Tong
Hoehn, Mary Ellen
Johnson, Jason N
Towbin, Jeffrey A
Khan, Raja
Tatevossian, Ruth G
Armstrong, Gregory T
Potter, Brian
Conklin, Heather
Shearer, Todd
Scott, Susan
Robinson, Giles W
LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)
title LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)
title_full LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)
title_fullStr LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)
title_full_unstemmed LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)
title_short LGG-22. SJ901: Phase I/II evaluation of single agent mirdametinib (PD-0325901), a brain-penetrant MEK1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (LGG)
title_sort lgg-22. sj901: phase i/ii evaluation of single agent mirdametinib (pd-0325901), a brain-penetrant mek1/2 inhibitor, for the treatment of children, adolescents, and young adults with low-grade glioma (lgg)
topic Low Grade Glioma
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164943/
http://dx.doi.org/10.1093/neuonc/noac079.336
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