Loncastuximab and Roflumilast Added to R-CHOP (Lo-(Rituximab and Roflumilast) RR-CHOP) for Naïve High-Risk Diffuse Large B-cell Lymphoma (DLBCL)

Exploratory analyses include cell free DNA (cfDNA). Each subject's disease will be biologically characterized at baseline. Enrolled subjects will receive 2 cycles of chemotherapy free therapy composed of loncastuximab 0.15 mg/kg, rituximab 375 mg/m2, and roflumilast 500 ug po daily; followed by 6 cycles of chemoimmunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard of care (SOC) doses, in combination with loncastuximab and roflumilast 500 ug po daily. Loncastuximab at a dose of 0.075 mg/kg will be added to other chemoimmunotherapy agents only for the first three (3) out of six (6) cycles. All subjects will have PET-CT at four time points during the trial: 1) screening, 2) cycle 3 (after the 2 initial chemotherapy free cycles of therapy), 3) cycle 6 (after 3 cycles of loncastuximab, roflumilast and R-CHOP), and 4) at end of therapy (EOT) after completing a total of eight cycles of treatment planned for the trial (two chemotherapy free and six of chemoimmunotherapy). All subjects will have cfDNA monitoring at three time points during the trial: 1) cycle 1 day 1 (baseline), 2) cycle 3 day 1 (after the 2 initial chemotherapy free cycles of therapy), and 3) at end of therapy (EOT) after completing a total of eight cycles of treatment planned for the trial (two chemotherapy free and six of chemoimmunotherapy). Responses will be evaluated by PET-CT as per Lugano response criteria1 and correlated with cfDNA analysis. Cycles are 21 days long.