A phase I/II study of CDX-1140, a CD40 agonist, in combination with capecitabine and oxaliplatin (CAPOX) and pembrolizumab in subjects with biliary tract carcinoma: Phase 1 results.

4129 Background: Second line therapy shows limited efficacy in biliary tract carcinoma (BTC). We have demonstrated potent anti-tumor effects of anti-CD40/anti-PD1 plus chemotherapy in murine cholangiocarcinoma (Diggs et al. J Hepatol 2021 74:1145). CDX1140 is a human IgG2 activating anti-CD40 antibody. Based on these preclinical studies we conduct a phase I/II study testing the combination of CDX-1140 plus pembrolizumab (pem), capecitabine (cap) and oxaliplatin (ox) in BTC patients previously treated with at least one line of systemic therapy. Safety and tolerability were assessed in the phase I portion. Methods: Between Aug 2024 and Jun 2025 a total of 9 participants were enrolled into the Phase I portion of the trial. 1000 mg cap was given p.o. bid on days 1-14 plus 130 mg/m2 ox i.v. on day 1 of a 21-day treatment cycle. CDX1140 was dosed at 0.72 mg/kg dose level 1 (DL1) and 0.36 mg/kg (DL-1) i.v. on day 8 plus 200 mg pembrolizumab i.v on day 8. The DLT period was 35 days, starting on day 8 of cycle 1 after CDX-1140 administration. Enrolment into the phase II portion was started after the recommended dose of CDX-1140 had been determined. Results: We enrolled a total of 9 patients (pts) into the phase I portion. All patients had received at least one line of prior systemic chemotherapy including antiPD1/PD-L1. 2 out of the first 3 pts treated at DL1 developed a grade 3 thrombocytopenia and we reduced dosing to DL-1. 1 out of 6 pts treated at DL-1 developed a grade 3 thrombocytopenia and DL-1 was considered safe. Other treatment related grade 3/4 AEs were: lymphopenia, leukocytopenia, anemia, skin rash and hypotension. Most patients developed grade 1/2 arthralgia. At data cut-off (Dec/15/25) PFS for the nine patients was 7.3 months (range: 2.3 - 19.1 months). DCR was 56 % with 2 patients demonstrating a PR and 3 pts with SD. Conclusions: We have completed the phase I portion of our trial and demonstrate that CDX1140 plus pem, cap and ox is safe and tolerable in pts with BTC. No new and or unexpected toxicities were observed. We observed encouraging clinical responses. Patients will be enrolled to the phase II portion and updated results will be presented. Clinical trial information: NCT05849480 .