This phase 2 trial studies the side effects and best dose of tazemetostat and zanubrutinib in combination with tafasitamab and lenalidomide, and to see how well these combinations work in treating patients with large B-cell lymphoma that returned or did not respond to earlier treatment. Tazemetostat is in a class of medications called EZH2 inhibitors. It helps to stop the spread of cancer cells. Zanubrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells. tafasitamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells in the bone marrow. The addition of tazemetostat or zanubrutinib to tafasitamab and lenalidomide may be able to shrink the cancer or extend the time without cancer symptoms coming back.
Histologically confirmed relapsed/refractory LBCL as outlined by the World Health Organization (WHO) guidelines
Follicular lymphoma, grade 3B
Transformed lymphoma
High grade B-cell lymphoma with or without MYC, BCL2 and/or BCL6 rearrangements
Participants must not have active lymphomatous involvement of the central nervous system (CNS) because the treatments used in this study are not effective to sufficiently penetrate the blood brain barrier
Participants must not have known abnormalities associated with myelodysplastic syndrome (MDS) (e.g., del 5q, chr 7 abn) and myeloproliferative neoplasms (MPN) (e.g., JAK2 V617F) observed in cytogenetic testing and deoxyribonucleic acid (DNA) sequencing. Testing is not required for eligibility determination
Participants must not have a known prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute leukemia (T-ALL). Testing is not required for eligibility determination
Participants must not be a candidate based on investigator assessment to receive autologous stem cell transplant (ASCT) or must have declined ASCT. Participants who had disease progression after stem cell transplant or cellular therapy (such as chimeric antigen receptor (CAR) T-cell) are eligible
Sequential
Biospecimen Collection
Procedure/SurgeryUndergo optional collection of blood
Computed Tomography
Procedure/SurgeryUndergo PET/CT and CT
Lenalidomide
DrugGiven PO
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Positron Emission Tomography
Procedure/SurgeryUndergo PET/CT
Quality-of-Life Assessment
Other interventionAncillary studies
Questionnaire Administration
Other interventionAncillary studies
Tafasitamab
Biological/VaccineGiven IV
Tazemetostat
DrugGiven PO
Zanubrutinib
DrugGiven PO
Progression-free survival (PFS)
Will be compared between participants randomized to control Arm 2 (tafasitamab + lenalidomide) versus (vs) experimental Arm 1 (tafasitamab + lenalidomide + tazemetostat), AND control Arm 2 vs experimental Arm 3 (tafasitamab + lenalidomide + zanubrutinib), respectively.
Trial Outcome Index (TOI) score from the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) (Patient Reported Outcome [PRO] Study)
Will compare the trial outcome index (TOI) score between each experimental arm (Arm 1 and Arm 3) to the control arm (Arm 2). The TOI score is composed of the Physical Well-Being, Functional Well-Being, and lymphoma-specific subscale scores. The scores range from 0-116, with higher scores indicating a higher quality of life.
Hazard ratio for PFS in the germinal center B-cell (GCB) subgroup
Will calculate the 80% confidence interval (CI) for the Cox regression time-to-event estimate of the hazard ratio associated with addition of tazemetostat to tafasitamab+lenalidomide combination (Arm 2 vs Arm 1) in the GCB subgroup. If the confidence interval excludes 1, then 80% CI will be calculated for the non-GCB group.
Hazard ratio for PFS in the non-GCB subgroup
Will calculate the 80% CI for the hazard ratio associated with addition of zanubrutinib to tafasitamab+lenalidomide combination (Arm 2 vs Arm 3) in the non-GCB subgroup. If the confidence interval excludes 1, then 80% CI will be calculated for the GCB group.
PFS
Will estimate in GCB and non-GCB large B-cell lymphoma (LBCL) for each treatment. Will be estimated using the method of Kaplan-Meier and 80% confidence interval will be calculated.
Overall response rate (ORR)
Will estimate in GCB and non-GCB LBCL for each treatment. Will be estimated using the method of Kaplan-Meier and 80% confidence interval will be calculated.
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SWOG Cancer Research Network
Lead sponsor
National Cancer Institute (NCI)
Collaborator
BeiGene
Collaborator
Ipsen
Collaborator
Incyte Corporation
Collaborator
