Introduction: Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma and affects primarily young adults. PMBCL shares several features with classic Hodgkin lymphoma, such as 9p24.1 amplification, increased programmed cell death protein 1 (PD-1) ligand, and CD30 expression. The trial CheckMate-436 treated relapsed/refractory (rr) PMBCL patients with nivolumab (antibody that binds to PD-1) and brentuximab vedotin ((BV) anti-CD30 antibody-drug conjugate), who showed an overall response rate (ORR) of 73% and complete response rate (CRR) of 43% (Zinzani et al. JCO 2019). Although most PMBL patients can be cured with frontline chemoimmunotherapy (CIT) with or without radiotherapy (XRT), the outcome of patients having rr-PMBCL is generally unfavorable. The discovery of new frontline regimens represents an unmet need for PMBL patients. We hypothesize that BV+Nivolumab will show ORR in frontline therapy at least as high as in the rr setting, may avoid chemoresistance, could deescalate the intensity of CIT, and alleviate the need for consolidative XRT. Methods: We are conducting a phase II, open-label, single-center clinical trial NCT04745949 combining BV-Nivolumab alone and then combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for patients with previously untreated PMBL. Patients 18 years or older with previously untreated PMBL, stage I to stage IV disease are eligible. However, patients previously treated with up to one cycle of standard-of-care therapy are eligible. Patients will receive BV 1.8 mg/Kg IV and Nivolumab 240 mg flat dose IV day 1 for cycles 1 and 2, in a 21-day cycle. During cycles 3 and 4, R-CHP will be added to BV-Nivolumab. Patients who have achieved complete response (CR) at PET/CT before cycle 5 will receive 2 more cycles of BV-Nivolumab+R-CHP (cycle 5 and 6) and BV-Nivolumab only for cycles 7 and 8 (A). In case of CR on PET/CT after cycle 8, therapy will be considered completed. Patients in PR on PET/CT before cycle 5 will receive 4 more cycles of BV-Nivolumab+R-CHP (cycles 5–8 (B)). The primary endpoint is CRR at the end of therapy (EOT). The maximum sample size for the PMBL cohort is 40 patients, with a target CRR at EOT of 70%. The null hypothesis is that the true CRR at EOT is 50%, and the alternative hypothesis is that the true CRR at EOT is 70%. The Simon's optimal two-stage design controls the one-sided type I error rate at 0.06 and yields the power of 0.8. The secondary endpoints will include the response rate of BV-Nivolumab+R-CHP at the end of the immune lead-in, landmark survival outcomes, safety, and patient-reported outcome. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and multiplex immunofluorescence to analyze the tumor microenvironment. The research was funded by: Seagen, BMS (drug support only) Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract R. E. Steiner Research funding: Seagen, BMS, GSK, Rafael Pharmaceuticals P. Strati Consultant or advisory role Roche-Genentech, Kite-Gilead, Hutchinson MediPharma, Astrazeneca-Acerta, ADC Therapeutics, Sobi and TG Therapeutics Research funding: Astrazeneca-Acerta, ALX Oncology and ADC Therapeutics S. Ahmed Consultant or advisory role Tessa Therapeutic's advisory committee Research funding: Seattle Genetics, Merck, Xencor, and Tessa Therapeutics J. R. Westin Consultant or advisory role Research funding: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Abbvie, SeaGen, MonteRosa, Regeneron Research funding: Kite/Gilead, BMS, Novartis, Genentech, AstraZeneca, Morphosys/Incyte, ADC Therapeutics, Kymera, Calithera