Phase ib study to assess the efficacy and safety of epcoritamab in relapsed or refractory post-transplant lymphoproliferative disorder

Abstract Background Post-transplant lymphoproliferative disorders (PTLD) represent a heterogeneous group of immune-deficiency related lymphoid malignancies occurring after solid organ transplant (SOT) or bone marrow transplant. With the expanded access to SOT, PTLD has become an increasingly important complication in the post-transplant setting. In SOT recipients with PTLD who progress following risk-adapted rituximab and front-line chemoimmunotherapy, clinical outcomes are very poor. Few patients are able to tolerate additional cytotoxic chemotherapy and treatment related mortality increases substantially (Dierickx et al, Blood, 2015). Epcoritamab is a bi-specific antibody recognizing the T-cell antigen CD3 and the B-cell antigen CD20, resulting in potent T-cell-mediated killing of CD20-expressing cells. Epcoritamab has been shown to have strong clinical activity and safety in patients with aggressive B-cell lymphomas (Thieblemont et al, JCO, 2023). Here, we present a phase Ib study to assess the safety and efficacy of epcoritamab in relapsed/refractory (r/r) PTLD. These data may provide rationale to support further development of epcoritamab in PTLD including combination therapies in the future. Design and Methods: This is a prospective, multicenter, open-label phase Ib trial (NCT06672705) designed to evaluate the safety and efficacy of administering epcoritamab in r/r PTLD. Patients will undergo weekly dose ramp-up in cycle 1 (0.16mg/0.8mg/48mg) followed by continued dosing at 48mg in dose level 1. If excessive toxicity is observed, patients will undergo weekly dose ramp-up in cycle 1 (0.16mg/0.8mg/24mg) followed by continued dosing at 24mg in dose level (-1). Treatment with epcoritamab will be weekly (Q1W) in cycles 1-3, Q2W in cycles 4-9, and Q4W in cycles 10-12. Patients in complete remission (CR) after 12 cycles will discontinue epcoritamab and enter observation. Patients in a partial remission or stable disease after 12 cycles will be eligible to continue epcoritamab until progression. If patients stop therapy after 12 cycles in a CR, they will be eligible to resume epcoritamab (with C1 dose ramp-up) if disease recurs and there has been no interval therapy. All patients will be followed for up to 3 years from the start of epcoritamab. Study Population: Adult patients with histological evidence of a CD20-positive B-cell PTLD (any histological subtype) following solid organ transplantation (heart, lung, liver, kidney, pancreas, small intestine transplantation or a combination of the organ transplantations mentioned). Treatment failure of rituximab or rituximab plus any concurrent or sequentially administered chemotherapy regimen. Performance status by Karnofsky scale 50%. Adequate organ function (absolute neutrophile count 1.0 x 109/L, platelets 50 x 109/L, eGFR 30mL/min, total bilirubin 3.0 x upper limit of normal (ULN), aspartate/alanine aminotransferase ≤ 3.0 × ULN).Study Objectives: The primary objective is to assess safety of treatment with epcoritamab in subjects with PTLD and determine a recommended phase II dose (RP2D). The secondary endpoints will be to estimate the Objective Response Rate, Clinical Benefit Rate, Best Objective Response Rate, Progression Free Survival, Duration of Complete Response, and Overall Survival. Safety will be assessed with a traditional 3+3 design guiding a dose de-escalation strategy (DL1 and DL(-1)) based on the observation of dose limiting toxicities during the first 28 days after start of Epcoritamab. A maximum of 26 patients will be treated with subcutaneous epcoritamab utilizing a Fleming Two-Stage design with a one-sided error rate of 5% and 80% power to detect an objective response rate of 50% (null hypothesis 20% response rate). Exploratory objectives will evaluate the peripheral blood immunophenotype changes through the course of treatment with epcoritamab, describe the relationship of tumor microenvironment characteristics with clinical response to epcoritamab, characterize Epstein-barr virus (EBV) methylation alterations in EBV positive PTLDs treated with epcoritamab, and describe the relationship between metabolic tumor volume at time of epcoritamab initiation and disease response.