Background: Combining agents with different mechanisms of action may enhance treatment (Tx) efficacy in patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Loncastuximab tesirine (loncastuximab tesirine-lpyl; Lonca), an FDA-approved, CD19-directed, antibody-drug conjugate indicated for R/R diffuse large B-cell lymphoma (DLBCL), showed significant efficacy and manageable toxicity in a phase 2 trial in pts with R/R DLBCL. In preclinical models, Lonca + polatuzumab vedotin (Pola) showed improved efficacy. CD20×CD3 T-cell engaging antibodies and Lonca target different antigens; combining these is expected to increase efficacy. The safety and activity of Lonca combined with other agents in pts with R/R B-NHL will be evaluated in LOTIS-7. Methods: LOTIS-7, a phase 1b, open-label, multicenter, multiarm study (NCT04970901), will enroll ~200 pts with B-NHL in part 1 (dose escalation, 60 pts) and part 2 (dose expansion, 140 pts). Part 2 may include specific subpopulation(s) of B-NHL informed by part 1. Primary endpoints are frequency and severity of adverse events (AE), serious AE, dose-limiting toxicities, and frequency of AE-related dose modifications. Secondary endpoints are overall response rate; duration of response; complete response rate; progression-free, relapse-free, and overall survival; Lonca concentrations; and antidrug antibody titers. Planned arms include Lonca + Pola (arm C), glofitamab (arm E), or mosunetuzumab (arm F). Arm C enrollment is open: pts are treated with Lonca + Pola as an outpatient infusion. In part 1, arm C pts receive Lonca at escalating doses (90-150 µg/kg) and Pola (1.8 mg/kg) on day 1 of each 3-week cycle; pts in arms E and F will receive Lonca 150 µg/kg for 2 cycles, then 75 µg/kg for subsequent cycles + glofitamab (2.5 mg on cycle [C]1 day [D]8, 10 mg on C1D15, 10 or 30 mg for C2-12 D1, arm E) or mosunetuzumab SC (5 mg on C1D1, 15 or 45 mg for C1D8, and 45 mg for C1D15 and C2-8 D1, arm F) after initial step-up dosing. Lonca Tx may continue for up to 1 year or until disease progression, unacceptable toxicity, or other discontinuation criteria. Key eligibility criteria include age ≥18 years, pathologic diagnosis of R/R B-NHL (2016 WHO classification), measurable disease (2014 Lugano classification), Tx failure/intolerance, ≥2 lines of prior therapy (LOT) for part 1 (≥1 LOT for part 2), and ECOG performance status of 0-2. Pts previously receiving a study drug could not enroll in that respective study arm. Pts who received a stem-cell transplant within 60 days (100 days for arms E/F) before study Tx; received allogenic stem cell or solid organ transplant (arms E/F); have lymphoma with active CNS involvement, ascites, edema, or effusion; or have significant comorbidities are excluded. The study opened in December 2021; 12 pts have been enrolled and 9 treated in the Lonca + Pola arm. Clinical trial information: NCT04970901.