Background: Primary mediastinal large B-cell lymphoma (PMBL) is a rare and distinct subtype of diffuse large B-cell lymphoma and affects primarily young adults. PMBL has a unique genomic profile that has similarities to classic Hodgkin lymphoma with CD30 expression and genomic alterations in the programmed T-cell death-ligand 1 (PD-L1) locus 9p24.1. The trial CheckMate-436, including relapsed/refractory PMBL patients treated with nivolumab (antibody that binds to immune checkpoint PD-1) and brentuximab vedotin ((BV) anti-CD30 antibody-drug conjugate) 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 with or without radiotherapy, the outcome of patients having rr-PMBL treated with intensive regimens is generally unfavorable. The discovery of new frontline regimens to decrease chemoresistance and toxicities represents an urgent unmet clinical need for PMBL patients. Methods: We are conducting a phase II, open-label, single-center clinical trial 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 with an urgent need for cytoreductive treatment will be excluded. 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. 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). 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, the safety of the combination, and patient-reported outcome. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and Multiplexed ion beam imaging to analyze the tumor microenvironment. The trial is actively accruing at MD Anderson Cancer Center, and 2 out of 40 patients have been enrolled. Clinical trial information: NCT04745949.