Epcoritamab Plus Ibrutinib for the Treatment of Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES: I. Determine the recommended phase II dose (RP2D) and safety of epcoritamab plus ibrutinib. II. Determine the rate and severity of cytokine release syndrome (CRS). SECONDARY OBJECTIVES: I. Determine the complete response (CR) rate (Lugano 2014) after cycle 12 or the last dose of treatment if stopped earlier. II. Determine the overall response rate (ORR) (CR + partial response \[PR\]) (Lugano 2014), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) of patients treated at the RP2D. III. Determine the best ORR and CR rate (Lugano 2014). EXPLORATORY OBJECTIVES: I. Characterize cytokine profile following ibrutinib and epcoritamab and explore whether levels of cytokine production correlate with both the appearance of CRS and ORR. II. Analyze peripheral blood mononuclear cells collected pre-ibrutinib, pre-epcoritamab, and throughout treatment using spectral flow cytometry to assess the effect of ibrutinib on T-cell numbers and function. III. Examine tumor samples attained before starting treatment and at relapse and explore aspects of the microenvironment that may contribute to epcoritamab failure. IV. Measure circulating tumor deoxyribonucleic acid (DNA) (ctDNA) to correlate its presence with response by positron emission tomography (PET) imaging and track the emergence of treatment-resistant clones. OUTLINE: Patients receive ibrutinib orally (PO) once daily (QD) on days -7 to 28 of cycle 1 and on days 1 to 28 of remaining cycles, as well as epcoritamab subcutaneously (SC) on days 1, 8, 15 and 22 of cycles 1-3, days 1 and 15 of cycles 4-9, and on day 1 of remaining cycles. Treatment repeats every 28 days for up to 6 cycles of ibrutinib and up to 12 cycles of epcoritamab in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, computed tomography (CT) and PET/CT throughout the study. Patients may also undergo bone marrow aspiration and biopsy on study. After completion of study treatment, patients are followed up every 3 months for 2 years then every 6 months for up to 5 years.