35A phase 1/2 trial investigating ivosidenib plus nivolumab and ipilimumab in patients with previously treated mIDH1 CCA
Robin Kate Kelley, James M Cleary, Vaibhav Sahai, Marina Baretti, John Bridgewater, Clement Daniel, Camelia Gliser, Ghassan K Abou-AlfaAbstract
Background
Ivosidenib (IVO), a first-in-class, oral, targeted, small-molecule inhibitor of mIDH1 is approved for the treatment of patients with previously treated locally advanced or metastatic mIDH1 cholangiocarcinoma (CCA). Pre-clinical and clinical data suggest combining mIDH1 inhibitor with immune checkpoint inhibitors (ICI) has synergistic anti-tumor activity in mIDH1 CCA. This study was the first to test IVO plus ipilimumab (IPI) and nivolumab (NIVO) in these patients.
Methods
This phase 1/2, multicenter, open-label study evaluated IVO plus IPI and NIVO in unresectable/metastatic mIDH1 CCA. It consisted of safety lead-in and expansion phases (NCT05921760). Eligible patients had progressed on or were intolerant to 1-2 prior therapies, ECOG PS 0–1, and RECIST v1.1 measurable disease. DLTs were evaluated during the first 2 cycles of study treatment.
Results
The safety lead-in phase enrolled 7 patients: 4 patients to the starting dose of IVO 500 mg QD PO + IPI 1 mg/kg (IV) and NIVO 3 mg/kg (IV). All developed immune-mediated adverse events (IMAEs), including intolerable rashes arising within a median of 12 days (10–41 days) of study treatment initiation. This led to dose de-escalation in IVO to 250 mg QD. All 3 patients enrolled in the IVO 250 mg cohort also developed IMAEs, including rashes. All events of immune-mediated rash required dose modifications, including 3 nonserious and 3 serious grade 3 events, with 1 DLT in the IVO 250 mg cohort. Based on IMAE frequency, onset, and outcome (Table 1), and in the absence of documented radiographic responses, further recruitment was stopped
Conclusions
While no new safety signals were specifically identified for IVO during this prematurely terminated study, IMAEs, including immune-mediated rashes, were observed in 100% of patients. The decision was made to stop the study. Further studies to optimize mIDH1 inhibition in CCA are ongoing including IVO plus durvalumab + gemcitabine/cisplatin in front-line CCA [NCT06501625].