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

Abstract

4015 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). Clinical trial information: NCT02073994.

Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances

“…AG-120 is a first-in-class, potent, oral inhibitor of mutant IDH1 and was examined in a phase 1 study in mutant IDH1 solid tumors including iCCA. (42) AG-120 was well tolerated, and of the 73 patients with IDH1 mutant advanced CCA enrolled, 72 were evaluable for efficacy. Six percent (n = 4) had a confirmed partial response, and 56% (n = 40) experienced stable disease.…”

Tremelimumab in Combination With Microwave Ablation in Patients With Refractory Biliary Tract Cancer

“…A phase II study in patients with fibroblast growth factor receptor (FGFR)‐altered advanced BTC found impressive antitumour activity of BGJ398 (a selective pan‐FGFR kinase inhibitor), with a disease‐control rate of 82%, and a manageable safety profile . An interim analysis of data from BTC with isocitrate dehydrogenase (IDH) mutation showed a disease‐control rate of 62% with IDH inhibitor …”

Is the IDH Mutation a Good Target for Chondrosarcoma Treatment?

“…Ivosidenib had an acceptable tolerability profile, with only few dose reductions or discontinuations due to toxicities noted in the phase 1 trial; the most frequent side effects encountered in the AML population were diarrhoea, leucocytosis, febrile neutropenia, nausea, fatigue, QT prolongation, pyrexia and anaemia [77]. In the cholangiocarcinoma cohort of the same trial, the most frequent side effects of ivosidenib reported were fatigue, nausea, diarrhoea, abdominal pain, decreased appetite and vomiting [78,79]. The chondrosarcoma patients experienced decreased appetite, long QT, nausea, anaemia and peripheral oedema [80].…”