Background: Patients (pts) with DLBCL for whom frontline therapy is unsuccessful and who are ineligible for autologous stem cell transplantation have poor outcomes with salvage therapy. Single-agent loncastuximab tesirine (Lonca), an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer (PBD) toxin, showed antitumor activity and manageable toxicity in pts with R/R B-cell non-Hodgkin lymphoma in a Phase 1 trial (Hamadani et al. Blood 2020; blood.2020007512) and in pts with R/R DLBCL in a Phase 2 trial (Caimi et al. Blood 2020; 136(Suppl 1):35–37). Rituximab (R) is part of standard immunochemotherapy for DLBCL, both as frontline therapy and in subsequent treatments. LOTIS-5 aims to evaluate Lonca + R (Lonca-R) versus (vs) standard immunochemotherapy of R + gemcitabine + oxaliplatin (R-GemOx) in pts with R/R DLBCL. Methods: This is a Phase 3 randomized, open-label, 2-part, 2-arm, multicenter study (NCT04384484). A non-randomized safety run-in (Part 1) will compare the safety of Lonca-R with previous safety data for Lonca after the first 20 pts have completed Cycle 1. Part 2 will be started if no significant increase in toxicity occurs; ̃330 pts will be randomized 1:1 to receive Lonca-R or R-GemOx. The primary objective of the study is to evaluate the efficacy of Lonca-R vs R-GemOx. The primary endpoint is progression-free survival by independent review. Secondary endpoints include overall survival; objective response rate; complete response rate; duration of response; frequency and severity of adverse events; changes from baseline in safety laboratory and clinical variables; concentration and pharmacokinetic parameters of Lonca (conjugated and total antibody, and unconjugated warhead); immunogenicity; and changes in patient-reported outcomes. Time-to-event endpoints will be assessed for the intent-to-treat population using a stratified log-rank test. The dosing regimen of Lonca-R in both parts of the study will be 150 µg/kg Lonca + 375 mg/m² R every 3 weeks (Q3W) for 2 cycles and then 75 µg/kg Lonca + 375 mg/m² R for 6 cycles. The dose regimen of R-GemOx in Part 2 will be 375 mg/m² R, 1000 mg/m² Gem, and 100 mg/m² Ox Q2W for 8 cycles. Key inclusion criteria include age ≥18 years; pathologic diagnosis of DLBCL (including pts with DLBCL transformed from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; ≥1 line of prior systemic therapy; not a candidate for stem cell transplantation; and measurable disease per 2014 Lugano Classification. The study opened in September 2020 and enrollment is ongoing. The trial design was presented at 62^nd American Society of Hematology Annual Meeting and Exposition, December 5–8, 2020. Research Funding: ADC Therapeutics SA. Clinical trial information: NCT04384484