PMID- 32208957
OWN - NLM
STAT- MEDLINE
DCOM- 20210129
LR  - 20240328
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 38
IP  - 15
DP  - 2020 May 20
TI  - Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical 
      Activity in Patients With Advanced Chondrosarcoma.
PG  - 1693-1701
LID - 10.1200/JCO.19.02492 [doi]
AB  - 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.
FAU - Tap, William D
AU  - Tap WD
AD  - Memorial Sloan Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Villalobos, Victor M
AU  - Villalobos VM
AD  - University of Colorado Anschutz Medical Campus, Aurora, CO.
FAU - Cote, Gregory M
AU  - Cote GM
AD  - Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital 
      Cancer Center, Boston, MA.
FAU - Burris, Howard
AU  - Burris H
AD  - Sarah Cannon Research Institute, Nashville, TN.
FAU - Janku, Filip
AU  - Janku F
AD  - Phase I Clinical Trials Program, Department of Investigational Cancer 
      Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
FAU - Mir, Olivier
AU  - Mir O
AD  - Department of Ambulatory Care, Gustave Roussy Cancer Campus, Villejuif, France.
FAU - Beeram, Murali
AU  - Beeram M
AD  - START Center for Cancer Care, San Antonio, TX.
FAU - Wagner, Andrew J
AU  - Wagner AJ
AD  - Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - Jiang, Liewen
AU  - Jiang L
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Wu, Bin
AU  - Wu B
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Choe, Sung
AU  - Choe S
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Yen, Katharine
AU  - Yen K
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Gliser, Camelia
AU  - Gliser C
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Fan, Bin
AU  - Fan B
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Agresta, Sam
AU  - Agresta S
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Pandya, Shuchi S
AU  - Pandya SS
AD  - Agios Pharmaceuticals, Cambridge, MA.
FAU - Trent, Jonathan C
AU  - Trent JC
AD  - Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL.
LA  - eng
SI  - ClinicalTrials.gov/NCT02073994
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA240139/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200324
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Pyridines)
RN  - Q2PCN8MAM6 (ivosidenib)
RN  - TE7660XO1C (Glycine)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Chondrosarcoma/*drug therapy
MH  - Enzyme Inhibitors/pharmacology/*therapeutic use
MH  - Female
MH  - Glycine/*analogs & derivatives/pharmacology/therapeutic use
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Pyridines/pharmacology/*therapeutic use
PMC - PMC7238491
EDAT- 2020/03/27 06:00
MHDA- 2021/01/30 06:00
PMCR- 2021/05/20
CRDT- 2020/03/27 06:00
PHST- 2020/03/27 06:00 [pubmed]
PHST- 2021/01/30 06:00 [medline]
PHST- 2020/03/27 06:00 [entrez]
PHST- 2021/05/20 00:00 [pmc-release]
AID - 1902492 [pii]
AID - 10.1200/JCO.19.02492 [doi]
PST - ppublish
SO  - J Clin Oncol. 2020 May 20;38(15):1693-1701. doi: 10.1200/JCO.19.02492. Epub 2020 
      Mar 24.