Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial
| العنوان: | Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial |
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| المؤلفون: | Ingo K. Mellinghoff, Min Lu, Patrick Y. Wen, Jennie W. Taylor, Elizabeth A. Maher, Isabel Arrillaga-Romany, Katherine B. Peters, Benjamin M. Ellingson, Marc K. Rosenblum, Saewon Chun, Kha Le, Ania Tassinari, Sung Choe, Youssef Toubouti, Steven Schoenfeld, Shuchi S. Pandya, Islam Hassan, Lori Steelman, Jennifer L. Clarke, Timothy F. Cloughesy |
| المصدر: | Nature medicine, vol 29, iss 3 |
| بيانات النشر: | Springer Science and Business Media LLC, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | Brain Neoplasms, Pyridines, Clinical Trials and Supportive Activities, Immunology, Neurosciences, Evaluation of treatments and therapeutic interventions, Glioma, General Medicine, Medical and Health Sciences, Isocitrate Dehydrogenase, General Biochemistry, Genetics and Molecular Biology, Brain Disorders, Brain Cancer, Orphan Drug, Rare Diseases, Pharmaceutical Preparations, Clinical Research, 5.1 Pharmaceuticals, 6.1 Pharmaceuticals, Mutation, Genetics, Humans, Development of treatments and therapeutic interventions, Cancer |
| الوصف: | Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197. |
| وصف الملف: | application/pdf |
| تدمد: | 1546-170X 1078-8956 0334-3197 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ae9f679f7f754d03e40b27a62bb7565c https://doi.org/10.1038/s41591-022-02141-2 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....ae9f679f7f754d03e40b27a62bb7565c |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 1546170X 10788956 03343197 |
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