Results from the safety lead-in for a phase 1b/2 study of ivosidenib plus durvalumab and gemcitabine/cisplatin as first-line therapy in patients with locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation.

558 Background: Cholangiocarcinomas (CCAs) are rare cancers that are often advanced and incurable at diagnosis. Durvalumab (DURVA) + gemcitabine/cisplatin (GEM/CIS) is approved for first-line treatment for CCA. This study (NCT06501625) evaluates the safety/tolerability of ivosidenib (IVO) + DURVA/GEM/CIS to determine the recommended combination dose (RCD) (safety lead-in phase, SLI) and the preliminary activity of this combination (expansion phase). Here we present the SLI results. Methods: Patients (pts) with locally advanced unresectable or metastatic mIDH1 CCA with ECOG 0 or 1 and at least 1 measurable lesion (RECIST v1.1) were dosed in the SLI. Treatment with up to 1 cycle of DURVA/GEM/CIS was permitted prior to study treatment initiation. Pts received IVO 500 mg QD + DURVA 1500 mg IV infusion every 3 weeks for up to 8 cycles + GEM 1000 mg/m 2 IV and CIS 25 mg/m 2 IV on days 1 and 8 of each cycle, followed by IVO 500 mg QD and DURVA 1500 mg every 4 weeks of each cycle. DLTs were evaluated during the first cycle of study treatment. Results: Seven pts with locally advanced or metastatic mIDH1 CCA (based on local or central testing) were enrolled in the SLI: age range, 37-75 years, 3 (43%) female, and 3 (43%) received 1 cycle of DURVA/GEM/CIS prior to study treatment. Through the data cut off of July 10, 2025, pts received 1–5 cycles with 6 (86%) ongoing. All pts reported a treatment-emergent adverse event (AE); 4 pts (57%) required a dose interruption and 1 (14%) required a dose reduction. One pt (14%) discontinued study treatment due to an adverse event (the only DLT), which was an AE of drug-induced liver injury, with LFT and bilirubin elevation that resolved after discontinuation of the quadruplet. Six pts were DLT evaluable, and 1 was not DLT evaluable, due to receiving <75% of the planned dose of IVO during the first cycle. This pt experienced an adverse event of special interest (AESI) of grade 3 QT prolongation requiring IVO dose reduction, but with re-escalation to full dose IVO 500 mg + DURVA/GEM/CIS during the second cycle after optimization of electrolytes and resolution of QT prolongation within 7 days, not assessed as a DLT. No other pts experienced AESIs. All pts experienced an AE, and 6 (86%) had a grade ≥3 AE. Two pts (29%) had a serious AE — 1 was the DLT of drug-associated liver injury and 1 was a non-treatment related cholangitis that recovered with resumption of IVO at full. One pt had a partial response and 6 had stable disease at the time of the data cut-off. IVO 500 mg + DURVA/GEM/CIS was confirmed as the RCD and the expansion phase was initiated. Conclusions: IVO at 500 mg QD + DURVA /GEM/CIS demonstrated a safety profile similar to DURVA/GEM/CIS. This dose will be evaluated further during the expansion phase, which will enroll ~40 pts. Clinical trial information: NCT06501625 .