Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma
Open accessAbstract
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.
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Patients with unresectable and/or metastatic chondrosarcoma have poor prognoses, with a median PFS of less than 4 months after first-line chemotherapy.
“patients with unresectable and/or metastatic chondrosarcoma have poor prognoses, with a median PFS of <4 months after first‐line chemotherapy. 43 , 44”
From Nivolumab and sunitinib in patients with advanced bone sarcomas: A multicenter, single‐arm, phase 2 trial (2025) · cites this paper as [44]
Cites
<i>IDH1</i> and <i>IDH2</i> Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847 · see citing works
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154 · see citing works
Self-citationXu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766 · see citing works
Self-citationWard, P. S., Patel, J., Wise, D. R., Abdel-Wahab, O., Bennett, B. D., Coller, H. A., Cross, J. R., Fantin, V. R., Hedvat, C. V., Perl, A. E., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.020 · Cited by 2,020 · see citing works
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Turcan, S., Rohle, D., Goenka, A., Walsh, L. A., Fang, F., Yilmaz, E., Campos, C., Fabius, A. W. M., Lu, C., Ward, P. S., et al. (2012) · Nature · doi:10.1038/nature10866 · Cited by 1,974 · see citing works
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035 · see citing works
Amary, M. F., Bacsi, K., Maggiani, F., Damato, S., Halai, D., Berisha, F., Pollock, R., O'Donnell, P., Grigoriadis, A., Diss, T., et al. (2011) · The Journal of Pathology · doi:10.1002/path.2913 · Cited by 1,023 · see citing works
Gross, S., Cairns, R. A., Minden, M. D., Driggers, E. M., Bittinger, M. A., Jang, H. G., Sasaki, M., Jin, S., Schenkein, D. P., Su, S. M., et al. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20092506 · Cited by 736 · see citing works
Mutant <i>IDH</i> is sufficient to initiate enchondromatosis in mice
Hirata, M., Sasaki, M., Cairns, R. A., Inoue, S., Puviindran, V., Li, W. Y., Snow, B. E., Jones, L. D., Wei, Q., Sato, S., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1424400112 · Cited by 115 · see citing works
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Aran, V., Devalle, S., Meohas, W., Heringer, M., Cunha Caruso, A., Pinheiro Aguiar, D., Leite Duarte, M. E., & Moura Neto, V. (2021) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2021.103340 · Cited by 87 · see citing works
Subbiah, V., Chawla, S. P., Conley, A. P., Wilky, B. A., Tolcher, A., Lakhani, N. J., Berz, D., Andrianov, V., Crago, W., Holcomb, M., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0974 · Cited by 51 · see citing works
Sarcoma care in the era of precision medicine
Wallander, K., Öfverholm, I., Boye, K., Tsagkozis, P., Papakonstantinou, A., Lin, Y., & Haglund de Flon, F. (2023) · Journal of Internal Medicine · doi:10.1111/joim.13717 · Cited by 30 · see citing works
Palmerini, E., Lopez Pousa, A., Grignani, G., Redondo, A., Hindi, N., Provenzano, S., Sebio, A., Lopez Martin, J. A., Valverde, C., Martinez Trufero, J., et al. (2025) · Cancer · doi:10.1002/cncr.35628 · Cited by 29 · see citing works
- 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.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Colorado Anschutz (US)
- Massachusetts General Hospital (US)
- Sarah Cannon (US)
- Phase I Clinical Trials Program, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
- Institut Gustave Roussy (FR)
- South Texas Accelerated Research Therapeutics (US)
- Dana-Farber Cancer Institute (US)
- Agios Pharmaceuticals (United States) (US)
- University of Miami (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2020-05-20
- Volume
- 38
- Issue
- 15
- Pages
- 1693-1701
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC7238491
- OpenAlex
- W3013135065
- Cited by
- 165
- References
- 10
- Citations by year
- 2026: 23 · 2025: 27 · 2024: 32 · 2023: 32 · 2022: 17 · 2021: 26 · 2020: 7 · 2018: 1
- FWCI
- 15.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA008748, P30CA240139)
- Topics
- Health Sciences › Medicine › Rheumatology › Bone Tumor Diagnosis and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- ivosidenib, IDH1 mutation, chondrosarcoma, isocitrate dehydrogenase inhibitors, 2-hydroxyglutarate, D-2-hydroxyglutarate, advanced solid tumors, dose escalation, treatment safety, progression-free survival, hypophosphatemia
- MeSH terms
- Adult, Aged, Aged, 80 and over, Chondrosarcoma, Enzyme Inhibitors, Female, Glycine, Humans, Male, Middle Aged, Pyridines
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