A phase 1/2, safety lead-in and dose expansion, open-label, multicenter trial investigating the safety, tolerability, and preliminary activity of ivosidenib in combination with nivolumab and ipilimumab in previously treated subjects with IDH1-mutated nonresectable or metastatic cholangiocarcinoma.

TPS4197 Background: Cholangiocarcinoma (CCA) is a rare cancer with limited therapeutic options, though molecularly targeted therapies have demonstrated anti-tumor activity in certain subsets. Approximately 15% of patients with intrahepatic CCA harbor activating mutations in isocitrate dehydrogenase-1 (mIDH1), and treatment with the mIDH1 inhibitor, ivosidenib (IVO) improved progression-free survival in the phase 3 ClarIDHy trial. mIDH1 is associated with an immune-excluded tumor microenvironment, and anti-CTLA4 immune checkpoint inhibition (ICI) augments anti-tumor activity when combined with IVO in preclinical models. Preliminary anti-tumor activity of dual immune checkpoint inhibitors (IPI, NIVO) has been reported in biliary tract cancers. Methods: This is a phase 1/2, non-comparative, multicenter, open-label study of IVO, IPI, NIVO, in subjects with unresectable or metastatic CCA with mIDH1. Key eligibility criteria include: a histopathological diagnosis; tumor mIDH1 based on local testing; progression on and/or intolerance to 1-2 prior lines of systemic therapy, at least one of which contained either gemcitabine and/or 5-fluorouracil; prior anti-PD-(L)1 therapy is allowed in the safety lead in; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; at least 1 measurable lesion as defined by RECIST version 1.1. The study has a safety lead-in phase and an expansion phase with 2 different expansion cohorts: cohort 1, ICI-naive; cohort 2, prior ICI allowed. The primary objective is to evaluate the safety and tolerability of IVO in combination with IPI plus NIVO and determine the recommended combination dose (RCD). This phase will enroll ~6 to 12 dose-limiting toxicity (DLT)–evaluable patients. The first 6 patients enrolled will receive IVO 500 mg orally once daily in combination with IPI 1 mg/kg IV infusion and NIVO 3 mg/kg IV infusion concurrently once every 3 weeks for 4 doses followed by NIVO at 480 mg IV once every 4 weeks until progression or unacceptable toxicity (up to a maximum of 24 months of NIVO). DLTs will be evaluated during the first 2 cycles of treatment. An additional 6 patients may be enrolled to assess an alternative dose of ivosidenib 250 mg once daily. Upon determination of the RCD, the two expansion cohorts will be initiated to assess the clinical activity of the triplet combination in patients with and without prior ICI. First patient in occurred in November 2023. Clinical trial information: NCT05921760 .