Background: There is a high unmet need for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) that has progressed on novel hormonal therapies (NHTs) due to acquired resistance to treatment. Tissue factor (TF) is a transmembrane protein that functions as a factor VIIa receptor and initiates the extrinsic coagulation cascade. Its overexpression has been associated with disease progression and poor prognosis in multiple solid tumor types, including mCRPC. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to zovodotin, an auristatin-based payload with a protease-cleavable linker. The zovodotin payload of XB002 is designed to have lower off-target payload deconjugation and improved tolerability compared with other auristatin-based ADCs. In preclinical studies, XB002 demonstrated antitumor activity and encouraging safety without affecting coagulation. JEWEL-101 (NCT04925284) is a phase 1, open-label, multicenter, first-in-human study evaluating XB002 alone and in combination regimens. The study consists of a dose-escalation stage to determine the recommended dose and/or maximum tolerated dose of XB002, and a tumor-specific cohort expansion stage to evaluate the safety and preliminary antitumor activity 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 cohort in pts with mCRPC. Methods: Pts with mCRPC and primary histology of adenocarcinoma are eligible; neuroendocrine differentiation and other histological features are also permitted. Pts must have documented progressive disease after 1–3 prior systemic therapies, including at least 1 prior NHT for metastatic castration-sensitive or castration-resistant disease. Prior taxane-based chemotherapy is optional, and bone-only disease without soft-tissue tumor components is allowed. No prior treatment with TF-targeting or auristatin-based ADCs is allowed, and pts with significant ocular disorders are excluded. PN not impacting activities of daily living is acceptable, and concomitant use of anticoagulants is permitted. Pts in the mCRPC cohort will be treated with XB002 single agent. The primary outcome is objective response rate per investigator assessment. Secondary outcomes 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.