Background: Treatment of advanced liver tumors continues to pose significant challenges. Despite advances in immunotherapies, including immune checkpoint blockade, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. The lack of robust clinical efficacy is likely myriad, including immunosuppression by the tumor microenvironment and poor susceptibility of these tumors to immune infiltration and surveillance. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with extensive anti-tumor properties, but therapeutic development of recombinant human IL-12 (rhIL-12) was halted due to significant systemic toxicities. PDS0301 (formerly M9241) is a novel human monoclonal antibody (NHS76) fused to two IL-12 heterodimers. The NHS76 antibody specifically targets histone/DNA complexes in regions of cellular necrosis resulting in accumulation within tumors. Importantly, recent Phase I trials have shown PDS0301 monotherapy to be well tolerated. We hypothesize that synchronization of PDS0301 administration with tumor cell death induced by locoregional and systemic chemotherapies will demonstrate increased efficacy over standard of care therapy. Methods: This is a single center, non-randomized Phase II study to determine the safety and efficacy of PDS0301 in combination with floxuridine (FUDR) administered by hepatic artery infusion pump (HAIP) and systemic chemotherapies in patients with either unresectable metastatic colorectal cancer (mCRC) or intrahepatic cholangiocarcinoma (ICC). Eligibility criteria include histologically or cytologically confirmed colorectal adenocarcinoma metastatic to the liver (Cohort 1) or unresectable intrahepatic cholangiocarcinoma with no evidence of extrahepatic metastases (Cohort 2). Patients will receive HAIP-administered (FUDR) plus PDS0301 at a starting dose of 12mcg/kg in 28-day cycles. Beginning in cycle 2, systemic chemotherapy with FOLFOX (Leucovorin, 5-Fluorouracil [5-FU], and Oxaliplatin) or FOLFIRI (Leucovorin, 5-FU and Irinotecan) for mCRC or GemOx (Gemcitabine and Oxaliplatin) for ICC will be introduced. Patients will be evaluated for response at eight-week intervals. The primary endpoint is overall response rates to PDS0301 and HAIP/systemic combination therapy. Secondary objectives include hepatic progression-free survival (PFS), extra-hepatic PFS, overall survival, and safety. Scientific objectives include determination of microenvironment alterations through pre-and post-treatment biopsies as well as evaluation of peripheral immune subsets and cytokines. To date, we have enrolled 8 of 23 patients in Cohort 1. Clinical trial information: NCT05286814.