Combination Immunotherapy for the Treatment of Chemotherapy-refractory Metastatic MSS CRC

This is a Phase 1b/2, open-label study evaluating the safety, tolerability, and efficacy of nadunolimab (anti-IL-1RAP) in combination with toripalimab (anti-PD-1) in adults with chemotherapy-refractory metastatic microsatellite stable (MSS) colorectal cancer. The Phase 1b portion serves as a safety run-in with up to 6 subjects to assess the safety of a single dose of the combination therapy. Following this, Phase 2 will enroll up to 21 subjects, with the first 6 from Phase 1b included in the Phase 2 analysis to assess the primary efficacy endpoint. Eligible participants must have biopsy-confirmed MSS colorectal cancer (non-MSI-high or pMMR), whose disease has progressed during or following 5-FU, oxaliplatin and/or irinotecan-based chemotherapy with or without a biological agent. Subjects must have have measurable disease and tumor accessible for core needle biopsy. Participants will receive nadunolimab 5 mg/kg and toripalimab 240 mg intravenously every three weeks, continuing for up to one year or until disease progression. Primary objectives: For Phase 1/b, to determine the safety and tolerability of combination immunotherapy in subjects with chemotherapy-refractory metastatic non-MSI-high/pMMR CRC. For Phase 2, to determine the efficacy of combination immunotherapy in subjects with chemotherapy-refractory metastatic non-MSI-high/pMMR CRC as measured by the objective response rate (ORR) achieved. Subjects will undergo core needle biopsies, blood collection, and repeat imaging throughout the study. This study is conducted at Mount Sinai Hospital under IRB and PRMC oversight. The results will provide important information on the safety and potential efficacy of combining nadunolimab and toripalimab in a population with limited treatment options.