Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; Results of a first-in-human phase I trial Journal Article

   

Authors:	Mellinghoff, I. K.; Penas-Prado, M.; Peters, K. B.; Burris, H. A. 3rd; Maher, E. A.; Janku, F.; Cote, G. M.; de la Fuente, M. I.; Clarke, J. L.; Ellingson, B. M.; Chun, S.; Young, R. J.; Liu, H.; Choe, S.; Lu, M.; Le, K.; Hassan, I.; Steelman, L.; Pandya, S. S.; Cloughesy, T. F.; Wen, P. Y.
Article Title:	Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; Results of a first-in-human phase I trial
Abstract:	Purpose: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. Patients and Methods: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG. © 2021 The Authors; Published by the American Association for Cancer Research
Journal Title:	Clinical Cancer Research
Volume:	27
Issue:	16
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2021-08-15
Start Page:	4491
End Page:	4499
Language:	English
DOI:	10.1158/1078-0432.Ccr-21-0611
PUBMED:	34078652
PROVIDER:	scopus
PMCID:	PMC8364866
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85113784794&doi=10.1158%2f1078-0432.CCR-21-0611&partnerID=40&md5=1924bfec56e6e13592f67e6680b7580d
Notes:	Article -- Export Date: 1 October 2021 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/187013