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Phase I Study of the Mutant IDH1 Inhibitor Ivosidenib: Safety and Clinical Activity in Patients With Advanced Chondrosarcoma
Journal of Clinical Oncology ( IF 42.1 ) Pub Date : 2020-05-20 , DOI: 10.1200/jco.19.02492
William D Tap 1, 2 , Victor M Villalobos 3 , Gregory M Cote 4 , Howard Burris 5 , Filip Janku 6 , Olivier Mir 7 , Murali Beeram 8 , Andrew J Wagner 9 , Liewen Jiang 10 , Bin Wu 10 , Sung Choe 10 , Katharine Yen 10 , Camelia Gliser 10 , Bin Fan 10 , Sam Agresta 10 , Shuchi S Pandya 10 , Jonathan C Trent 11
Affiliation  

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.

中文翻译:


突变 IDH1 抑制剂 Ivosidenib 的 I 期研究:晚期软骨肉瘤患者的安全性和临床活性



目的 手术是局部软骨肉瘤的主要治疗方法。对于局部晚期和/或转移性疾病,尚无已知的有效全身治疗方法。多达 65% 的软骨肉瘤中发生异柠檬酸脱氢酶 1/2 (IDH1/2) 突变,导致致癌代谢物 D-2-羟基戊二酸 (2-HG) 积累。 Ivosidenib (AG-120) 是一种突变 IDH1 的选择性抑制剂,在美国获批用于治疗急性髓系白血病的特定病例。我们在一项正在进行的探索 ivosidenib 治疗的研究中报告了晚期软骨肉瘤患者的结果。患者和方法 这项 ivosidenib 单药治疗的 I 期多中心开放标签剂量递增和扩展研究纳入了突变 IDH1 晚期实体瘤(包括软骨肉瘤)患者。 Ivosidenib 以连续 28 天为一个周期口服给药(100 mg 每天两次至 1,200 mg 每天一次)。每隔一个周期使用 RECIST(1.1 版)评估疗效。结果 21 名晚期软骨肉瘤患者(升级,n = 12;扩张,n = 9)接受了 ivosidenib(女性,n = 8;中位年龄,55 岁;范围,30-88 岁;11 例之前接受过全身治疗) 。治疗中出现的不良事件 (AE) 大多为 1 级或 2 级。12 名患者经历了 ≥ 3 级 AE;仅判断一项事件与治疗相关(低磷血症,n = 1)。所有患者的血浆 2-HG 水平均大幅下降(范围为 14%-94.2%),降至健康个体的水平。中位无进展生存期 (PFS) 为 5.6 个月(95% CI,1.9 至 7.4 个月); 6 个月时的 PFS 率为 39.5%。 21 名患者中有 11 名 (52%) 病情稳定。结论 在软骨肉瘤患者中,ivosidenib 显示出最小的毒性、显着的 2-HG 降低和持久的疾病控制。 对于晚期 IDH1 突变软骨肉瘤患者,未来应考虑对 ivosidenib 单药治疗或合理联合治疗进行研究。
更新日期:2020-05-20
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