Phase I study of the mutant IDH1 inhibitor ivosidenib: Safety and clinical activity in patients with advanced chondrosarcoma Journal Article


Authors: Tap, W. D.; Villalobos, V. M.; Cote, G. M.; Burris, H.; Janku, F.; Mir, O.; Beeram, M.; Wagner, A. J.; Jiang, L.; Wu, B.; Choe, S.; Yen, K.; Gliser, C.; Fan, B.; Agresta, S.; Pandya, S. S.; Trent, J. C.
Article Title: Phase I study of the mutant IDH1 inhibitor ivosidenib: Safety and clinical activity in patients with advanced chondrosarcoma
Abstract: PURPOSE: Surgery is the primary therapy for localized chondrosarcoma; for locally advanced and/or metastatic disease, no known effective systemic therapy exists. Mutations in the isocitrate dehydrogenase 1/2 (IDH1/2) enzymes occur in up to 65% of chondrosarcomas, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a selective inhibitor of mutant IDH1 approved in the United States for specific cases of acute myeloid leukemia. We report outcomes of patients with advanced chondrosarcoma in an ongoing study exploring ivosidenib treatment. PATIENTS AND METHODS: This phase I multicenter open-label dose-escalation and expansion study of ivosidenib monotherapy enrolled patients with mutant IDH1 advanced solid tumors, including chondrosarcoma. Ivosidenib was administered orally (100 mg twice daily to 1,200 mg once daily) in continuous 28-day cycles. Responses were assessed every other cycle using RECIST (version 1.1). RESULTS: Twenty-one patients (escalation, n = 12; expansion, n = 9) with advanced chondrosarcoma received ivosidenib (women, n = 8; median age, 55 years; range, 30-88 years; 11 had received prior systemic therapy). Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. Twelve patients experienced grade ≥ 3 AEs; only one event was judged treatment related (hypophosphatemia, n = 1). Plasma 2-HG levels decreased substantially in all patients (range, 14%-94.2%), to levels seen in healthy individuals. Median progression-free survival (PFS) was 5.6 months (95% CI, 1.9 to 7.4 months); the PFS rate at 6 months was 39.5%. Eleven (52%) of 21 patients experienced stable disease. CONCLUSION: In patients with chondrosarcoma, ivosidenib showed minimal toxicity, substantial 2-HG reduction, and durable disease control. Future studies of ivosidenib monotherapy or rational combination approaches should be considered in patients with advanced mutant IDH1 chondrosarcoma.
Journal Title: Journal of Clinical Oncology
Volume: 38
Issue: 15
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2020-05-20
Start Page: 1693
End Page: 1701
Language: English
DOI: 10.1200/jco.19.02492
PUBMED: 32208957
PROVIDER: scopus
PMCID: PMC7238491
DOI/URL:
Notes: Article -- Export Date: 1 June 2020 -- Source: Scopus
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  1. William Douglas Tap
    374 Tap