Background: Doublet chemotherapy (paclitaxel plus either platinum or topotecan) with bevacizumab (if eligible) is recommended for first-line treatment of recurrent (not amenable to curative therapy) or metastatic cervical cancer (r/mCC; Tewari 2014). In the second-line setting, there are limited data for currently available treatment options. Tisotumab vedotin (TV) is an investigational antibody-drug conjugate (ADC) composed of a tissue factor (TF)-directed human monoclonal antibody covalently linked to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. TV is directed to cells expressing TF and releases MMAE upon internalization, resulting in cell cycle arrest and apoptotic cell death. TV has anti-tumor activity on multiple tumor types and kills tumor cells by direct cytotoxicity, bystander cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and in a manner consistent with immunogenic cell death. In a recent phase 2 pivotal trial (innovaTV 204), TV demonstrated a clinically meaningful objective response rate (ORR) of 24% and median duration of response (DOR) of 8.3 months, as well as a manageable and tolerable safety profile with most adverse events being mild to moderate, in r/mCC patients with disease progression on or after chemotherapy. These findings support further investigation of TV in patients with r/mCC who progress on available first-line treatment options. Methods: The innovaTV 301 trial (NCT04697628) is a global, randomized, open-label, phase 3 clinical trial evaluating the efficacy and safety of TV in patients with previously treated r/mCC. Eligible patients must be ≥18 years, have r/mCC, and have experienced disease progression after receiving 1-2 prior lines of therapy (either standard of care systemic chemotherapy doublet or platinum-based therapy [if eligible; paclitaxel+cisplatin+bevacizumab, paclitaxel+carboplatin+bevacizumab, or paclitaxel+topotecan/nogitecan+bevacizumab]). Approximately 482 patients will be randomized 1:1 to receive 21-day cycles of either TV (2.0 mg/kg IV once every 3 weeks) or investigator’s choice of chemotherapy: topotecan (1 or 1.25 mg/m² IV; Day 1 [D1] to D5 of each cycle), vinorelbine (30 mg/m² IV; D1 and D8 of each cycle), gemcitabine (1000 mg/m² IV; D1 and D8 of each cycle), irinotecan (100 or 125 mg/m² IV; weekly for 28days, then every 42 days), or pemetrexed (500 mg/m² IV, D1 of each cycle). The primary endpoint of this trial is overall survival. Key secondary endpoints are progression-free survival, ORR, time to response, DOR, safety, and quality of life outcomes. The study is currently enrolling and will have sites open in the US, EU, Japan, Latin America, Taiwan, Singapore, and South Korea. Clinical trial information: NCT04697628