Phase 1/2 pidnarulex (RNA Pol I inhibitor, G-quadruplex stabilizer) + cemiplimab (PD-1)

This NCI-sponsored Phase 1 dose-finding plus randomized Phase 2 study tests whether adding cemiplimab (Regeneron/Sanofi’s PD-1–blocking monoclonal antibody) can improve outcomes versus pidnarulex alone in refractory microsatellite-stable, pMMR/non–MSI-high metastatic/unresectable colorectal cancer, including patients with unresectable liver metastases. Pidnarulex (CX-5461) is a small-molecule RNA polymerase I (Pol I) inhibitor and G-quadruplex stabilizer intended to disrupt ribosome biogenesis/transcriptional stress in tumor cells, while cemiplimab aims to restore antitumor T-cell activity by blocking PD-1. Phase 1 gives the combination on a 28-day cycle (cemiplimab days 1/15; pidnarulex days 1/8) to establish safety and a recommended dose; Phase 2 randomizes patients to pidnarulex alone versus the combination with mandated imaging and serial blood draws, and tumor biopsies in Phase 2 arms. The scientific angle is an “immune-sensitization” strategy in MSS colorectal cancer, where checkpoint monotherapy has low activity; current care after progression is sequential systemic therapy such as fluoropyrimidine/oxaliplatin/irinotecan-based regimens with targeted options when eligible (anti-VEGF, anti-EGFR for RAS/RAF–wild type left-sided disease), and later-line regorafenib or trifluridine/tipiracil ± bevacizumab, so this explores a novel DNA/RNA-stress mechanism paired with PD-1 blockade.