Epcoritamab in Combination With Dose Adjusted EPOCH-R for High-risk Burkitt Lymphoma (BL), The BEDROCK Study

PRIMARY OBJECTIVES: I. To demonstrate the feasibility of adding epcoritamab to dose adjusted etoposide, prednisone, Oncovin (vincristine), cyclophosphamide, hydroxydaunorubicin-rituximab (DA-EPOCH-R) in the first line treatment of high-risk Burkitt lymphoma (BL) patients with at least one adverse risk factor. (Cohort 1) II. To compare one-year overall survival (OS) of DA-EPOCH-R with or without epcoritamab in newly diagnosed high-risk BL with at least one additional high-risk feature. (Cohort 2) SECONDARY OBJECTIVES: I. To assess response rates and two-year OS. (Cohort 1 and 2) II. To assess one-year progression-free survival (PFS) and event-free survival (EFS) of risk adapted DA-EPOCH-R with or without epcoritamab in newly diagnosed high-risk BL with at least one additional high-risk feature. (Cohort 1 and 2) III. To assess the safety profile and tolerability of proposed treatments including tumor lysis syndrome, infection, cytokine release syndrome (CRS), and immune effector cell associated neurotoxicity syndrome (ICANS). (Cohort 1 and 2) IV. To assess overall response rate (ORR) and duration of response (DoR) of DA-EPOCH-R with or without epcoritamab in newly diagnosed high-risk BL with at least one additional high-risk feature. (Cohort 1 and 2) V. To assess any influence of human immunodeficiency virus (HIV) including HIV viral load and CD4 counts on the outcomes including toxicities. (Cohort 1 and 2) EXPLORATORY OBJECTIVES: I. To assess the predictability of circulating tumor deoxyribonucleic acid (ctDNA) to predict outcomes in this setting. II. To assess the predictability of cell free deoxyribonucleic acid (cfDNA) in the cerebrospinal fluid (CSF) to predict outcomes in this setting. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT 1: Patients receive epcoritamab subcutaneously (SC) on days 1, 8, and 15 OR days 2, 9, and 16 OR days 3, 10, and 17 OR days 8 and 15 of cycle 1 at the determination of the investigators. Patients then receive epcoritamab SC on days 1, 8, and 15 of each cycle thereafter. Patients also receive DA-EPOCH-R consisting of etoposide, doxorubicin, and vincristine IV over 96 hours on days 1-4, prednisone or equivalent orally (PO) twice daily (BID) on days 1-5, cyclophosphamide IV over 1 hour on day 5, and rituximab IV on day 1 or days 1-2 of each cycle. Cycles repeat every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. NOTE: Patients who have received one cycle of DA-EPOCH or CHOP-like therapy off study receive only cycles 1-5). COHORT 2: Patients are randomized to 1 of 2 arms. ARM I: Patients receive DA-EPOCH-R as in Cohort 1 above. ARM II: Patients receive epcoritamab and DA-EPOCH-R as in Cohort 1 above. All patients also undergo multi-gated acquisition scan (MUGA) or echocardiogram (ECHO) during screening, as well as positron emission tomography (PET)/computed tomography (CT), and collection of blood and CSF throughout the study. Patients may also undergo bone marrow biopsy/aspiration during screening and magnetic resonance imaging (MRI) as clinically indicated. After completion of study treatment, patients are followed every 4 months for 2 years.