Randomized Phase II Study of the Addition of Targeted Therapeutic Agents to Tafasitamab-Based Therapy in Non-Transplant-Eligible Patients with Relapsed/Refractory Large B-Cell Lymphoma

The purpose of this study is to compare the usual treatment alone to using tazemetostat or zanubrutinib plus the usual treatment for patients with relapsed or refractory large b-cell lymphoma (LBCL). Relapsed means the LBCL has returned after it responded to treatment. Refractory means the LBCL did not respond to earlier treatment. The addition of tazemetostat or zanubrutinib to the usual treatment could shrink the cancer or extend your time without cancer symptoms coming back. But it may also cause side effects, which the doctors will monitor. This study will help the study doctors find out if this different approach is better, the same or worse than the usual approach. To decide if it is better, the study doctors will be looking to see if the study drugs increase the time before the cancer gets worse by 6 months or more. All of the study drugs (tafasitamab, lenalidomide, tazemetostat, and zanubrutinib) are approved by the FDA for use in people with lymphoma. The usual approach for patients who are not in a study is treatment with chemotherapy, CAR T-cell therapy, stem cell transplant, or a combination of these treatments. All of these therapies are Food and Drug Administration (FDA) approved. Other drug treatments may be used for people who are too frail or if the cancer comes back after other therapies.

Are you Eligible? (Inclusion Criteria)

• Are you 18 years of age or older? Have you been diagnosed with large b-cell lymphoma (LBCL) that has returned after treatment or did not respond to previous treatment? Are you able to make regularly scheduled visits to the clinic for treatment and examinations?