Background: Transplant-ineligible pts with R/R DLBCL have a poor prognosis (Gisselbrecht C, et al. Br J Haematol 2018). Several treatment options are available including platinum-based chemotherapies such as oxaliplatin plus rituximab and gemcitabine (R-GemOx). Adding polatuzumab vedotin to R-GemOx (Pola-R-GemOx) may improve outcomes for pts with a continued unmet medical need. The safety of polatuzumab vedotin and platinum-based therapy combinations must be considered as both are associated with neuropathy. POLARGO (NCT04182204; MO40598) is a Phase III, multicenter, open-label, randomized trial evaluating the safety and efficacy of Pola-R-GemOx vs R-GemOx in pts with R/R DLBCL. Methods: Results from the safety run-in stage of POLARGO are presented. The primary endpoint is the safety and tolerability of polatuzumab vedotin (1.8 mg/kg) + R-GemOx (R, 375 mg/m²; Gem, 1000 mg/m²; Ox, 100 mg/m²) given every 21 days for up to 8 cycles. Safety was assessed by the incidence, nature, and severity of adverse events (AEs; NCI CTCAE v5.0), with a focus on peripheral neuropathy (PN). Dose interruptions and reductions were used to assess tolerability. Granulocyte-colony stimulating factor was given as primary prophylaxis with each cycle (C) of therapy; anti-infective prophylaxis for pneumocystis and herpes virus was mandatory. Results: As of October 26, 2021, 15 pts were enrolled and 11 (73%) pts received ≥4 cycles of Pola-R-GemOx. Median age was 76 (range 47–87) years, 10 (67%) pts had an IPI score of 3–5, 7 (47%) had ≥2 prior therapy lines, and 8 (53%) were refractory to last treatment. Grade (Gr) 3–4 AEs were reported in 5 (33%) pts: thrombocytopenia (20%) and neutropenia (13%) were the most common. Two (13%) pts had serious AEs (Gr 3 febrile neutropenia and Gr 3 infection [n = 1 each]). There were no Gr 5 AEs or AEs leading to drug discontinuation. Eight (53%) pts had Gr 1 or 2 PN; there were no cases of Gr >3 PN. Three (20%) pts had drug interruptions due to PN. Two (13%) pts had a dose reduction of polatuzumab vedotin and oxaliplatin due to PN at C5 and C8, respectively; one pt (7%) had a dose reduction of polatuzumab vedotin due to Gr 4 thrombocytopenia at C2. End-of-treatment (EOT) objective response rate was 40% (95% CI: 16–68) and complete response rate was 27% (95% CI: 8–55); 7 (47%) pts had progressive disease at EOT. Ten (67%) pts received subsequent therapies following Pola-R-GemOx, including CAR-T cell therapy (n = 3) and stem-cell transplant (n = 1). Conclusions: In the safety run-in stage, Pola-R-GemOx was safe and tolerable. PN was manageable with dose interruptions and reductions; no cases of Gr ≥3 PN were observed. The toxicity of this combination did not compromise delivery of subsequent treatments. POLARGO is currently enrolling pts to receive Pola-R-GemOx vs R-GemOx; results will be presented at a future meeting. Clinical trial information: NCT04182204.