Background: Patients (pts) with metastatic pancreatic and esophageal cancers have poor prognosis, with 5-year survival rates of 3% and 6%, respectively (SEER 22). Tissue factor (TF), a factor VIIa receptor involved in initiation of the extrinsic coagulation cascade, is overexpressed in these tumors and has been associated with poor outcomes. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to the linker-payload zovodotin. Zovodotin consists of an auristatin-based payload with a stable protease-cleavable linker; it is designed to have lower off-target payload deconjugation and improved tolerability versus other auristatin-based ADCs. In preclinical studies, XB002 showed encouraging safety and antitumor activity without affecting coagulation. JEWEL-101 (NCT04925284) is a phase 1, dose-escalation and multi-cohort expansion study evaluating XB002 alone and in combination with nivolumab or bevacizumab in pts with advanced solid tumors. Preliminary results from the dose-escalation stage showed XB002 was well tolerated at multiple dose levels, with low-grade ocular toxicity and no bleeding events or treatment-related peripheral neuropathy (PN).¹ Presented here is the design of the expansion cohorts for pancreatic and esophageal cancers. Methods: Eligible pts must have an inoperable, locally advanced, metastatic, or recurrent solid tumor. Pts with pancreatic adenocarcinoma will receive XB002 single agent. Pts enrolled with esophageal squamous cell carcinoma (ESCC) will be randomized between 2 cohorts to receive either XB002 single agent or XB002 plus nivolumab. All pts in the pancreatic cancer and ESCC cohorts must have ECOG performance status of 0–1, measurable disease per RECIST v1.1, and have received 1–2 prior lines of systemic anticancer therapy, and radiographically progressed during or after their last therapy. Prior immunotherapy is allowed for pancreatic cancer and required for ESCC if locally considered standard of care and pts are eligible. Key exclusion criteria include prior treatment with TF-targeting or auristatin-based ADCs, and significant ocular disorders. Concomitant anticoagulants are permitted, and pts with PN are eligible, provided it is not impacting activities of daily living. The primary objective is objective response rate per RECIST v1.1 by investigator. Secondary objectives include safety, pharmacokinetics, immunogenicity, progression-free survival, duration of response, and overall survival. Enrollment is ongoing in the United States, Europe, and the Asia-Pacific region. 1. Ulahannan et al. ENA 2022. Clinical trial information: NCT04925284.