• AG-120是mIDH1的口服抑制剂——一种识别新靶点的全新化合物;
  • 截止2016年12月16日,共73例胆管癌患者参与实验,25例剂量递增,49例剂量扩充(一期临床实验);
  • 无剂量限制性毒性,相关AE(≥5%):疲劳(21%),恶心(18%),呕吐(12%),腹泻(10%)、食欲下降(8%),味觉障碍(5%)、QT间期延长(5%);
  • 72例可评价,4例PR,40例SD,PFS为6个月(4%),8例已使用AG-120治疗超1年;
  • AG-120具有良好的安全性,并可长期稳定病情。

Phase I study of AG-120, an IDH1 mutant enzyme inhibitor: Results from the cholangiocarcinoma dose escalation and expansion cohorts



Abstract & Authors:展开

Background: Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (mIDH1) occur in patients (pts) with cholangiocarcinoma (CC) and are detected in up to 25% of intrahepatic CC. mIDH1 produce the oncometabolite, D-2-hydroxyglutarate (2-HG), resulting in epigenetic and genetic dysregulation and oncogenesis. AG-120 is a first-in-class, potent, oral inhibitor of mIDH1 tested in this phase I study in mIDH1 solid tumors, including CC.
Methods: AG-120 was escalated in a 3+3 design from 100 mg twice daily to 1200 mg once daily (QD) in 28-day cycles (N = 60, mIDH1 advanced solid tumors). Key eligibility for CC: recurrence of progressive mIDH1 CC following standard therapy (dose escalation) or at least a prior gemcitabine-based regimen (expansion cohort). Response (RECIST 1.1) was assessed every 8 weeks. Plasma and tumor tissue were collected for exploratory analyses.
Results: Based on the safety, pharmacokinetic, and pharmacodynamic data from dose escalation, the 500 mg QD dose was selected for expansion in mIDH1 CC and other mIDH1 solid tumors. As of Dec 16, 2016, 73 pts with mIDH1 CC had been dosed in the dose escalation (n = 24) and expansion (n = 49) cohorts. Demographics: M/F = 24/49, median number of prior therapies = 2 (range 1–5), ECOG 0–1 = 26/47. There were no dose-limiting toxicities. Treatment-related adverse events (AEs) in ≥5% pts: fatigue (21%), nausea (18%), vomiting (12%), diarrhea (10%), decreased appetite (8%), dysgeusia (5%), QT prolongation (5%). Two (3%) pts experienced related grade 3 AEs: fatigue and low phosphorus. There were no AG-120-related AEs leading to discontinuation. Among the 72 efficacy evaluable (≥1 post baseline response assessment or discontinued prematurely) mIDH1 CC pts (24 in escalation and 48 in expansion cohort), 6% (n = 4) had a confirmed partial response and 56% (n = 40) experienced stable disease. The progression-free survival rate at 6 months was 40%, and 8 pts have been treated with AG-120 for ≥1 year.
Conclusions: In this pretreated mIDH1 CC population, AG-120 was associated with a favorable safety profile and prolonged stable disease. A global, phase III, randomized, placebo-controlled study of AG-120 in mIDH1 CC has been initiated (ClarIDHy).

All Authors:
Maeve Aine Lowery