Background: Isocitrate dehydrogenase-1 (IDH1) is mutated in up to 25% of cholangiocarcinomas, especially intrahepatic cholangiocarcinoma. Ivosidenib is an oral, targeted inhibitor of mutant IDH1 (mIDH1) approved in the USA for the treatment of mIDH1 acute myeloid leukaemia in newly diagnosed patients ineligible for intensive chemotherapy and patients with relapsed or refractory disease. Ivosidenib is under clinical evaluation in a phase 1 study that aims to assess its safety and tolerability in patients with mIDH1 solid tumours. Here we report data for the mIDH1-cholangiocarcinoma cohort. Methods: We did a phase 1 dose-escalation and expansion study of ivosidenib monotherapy in mIDH1 solid tumours at 12 clinical sites in the USA and one in France. The primary outcomes were safety, tolerability, maximum tolerated dose, and recommended phase 2 dose. Eligible patients had a documented mIDH1 tumour based on local testing, an Eastern Cooperative Oncology Group performance status of 0 or 1, one or more previous lines of therapy, and evaluable disease by Response Evaluation Criteria in Solid Tumors version 1.1. During dose escalation, ivosidenib was administered orally at 200–1200 mg daily in 28-day cycles in a standard 3 + 3 design; during expansion, patients received the selected dose on the basis of pharmacodynamic, pharmacokinetic, safety, and activity data from dose escalation. Safety and clinical activity analyses were reported for all patients with mIDH1-cholangiocarcinoma who were enrolled and received at least one dose of study treatment. Enrolment is complete, and the study is ongoing. This trial is registered at ClinicalTrials.gov, number NCT02073994. Findings: Between March 14, 2014 and May 12, 2017, 73 patients with mIDH1-cholangiocarcinoma were enrolled and received ivosidenib. No dose-limiting toxicities were reported and maximum tolerated dose was not reached; 500 mg daily was selected for expansion. Common (≥20%) adverse events, regardless of cause, were fatigue (31 [42%]; two [3%] grade ≥3), nausea (25 [34%]; one [1%] grade ≥3), diarrhoea (23 [32%]), abdominal pain (20 [27%]; two [3%] grade ≥3), decreased appetite (20 [27%]; one [1%] grade ≥3), and vomiting (17 [23%]). Common grade 3 or worse adverse events were ascites (four [5%]) and anaemia (three [4%]); the only treatment-related grade 3 or worse adverse event in more than one patient was fatigue (two [3%]). Two (3%) patients had serious adverse events leading to on-treatment death (Clostridioides difficile infection and procedural haemorrhage); neither was assessed by the investigator as related to treatment. 46 (63%) patients had adverse events deemed related to ivosidenib, of which four (5%) were grade 3 or higher (two [3%] for fatigue; one [1%] each for decreased blood phosphorus and increased blood alkaline phosphatase). One serious adverse event was considered possibly related to treatment (grade 2 supraventricular extrasystoles). Four (5%; 95% CI 1·5–13·4) patients had a partial response. Median progression-free survival was 3·8 months (95% CI 3·6–7·3), 6-month progression-free survival was 40·1% (28·4–51·6), and 12-month progression-free survival was 21·8% (12·3–33·0). Median overall survival was 13·8 months (95% CI 11·1–29·3); however, data were censored for 48 patients (66%). Interpretation: Ivosidenib might offer a well tolerated option for patients with mIDH1-cholangiocarcinoma. An ongoing, global phase 3 study is evaluating ivosidenib versus placebo in patients with previously treated nonresectable or metastatic mIDH1-cholangiocarcinoma. Funding: Agios Pharmaceuticals, Inc.
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