Abstract
Background: The CD3xCD20 bispecific antibody epcoritamab has shown significant clinical activity in relapsed/refractory large B-cell lymphoma (LBCL), achieving high complete response (CR) rates and durable remissions. Cytokine release syndrome (CRS) is a common toxicity. Ibrutinib may reverse the tumor-induced T-cell dysfunctional state that commonly accompanies B-cell lymphoid malignancies, thereby improving the efficacy of T-cell-based therapies, including bispecific antibodies (Dubovsky, Blood 2013; Long, JCI 2017). In preclinical models, ibrutinib enhanced the antitumor activity of chimeric antigen receptor (CAR) T-cell therapy and reduced the rate of CRS in xenograft models of B-cell lymphoid malignancies (Fraietta, Blood 2016; Ruella, Clin Cancer Res 2016; Ruellla, Leukemia 2017). T cells from patients with chronic lymphocytic leukemia (CLL) being treated with ibrutinib had more rapid expansion and superior cytotoxic activity in response to a CD3xCD19 bispecific antibody compared with samples from treatment-naïve patients (Mhibik, Blood 2021). Retrospective analyses and clinical trials show that treatment with CAR T cells with concurrent ibrutinib resulted in lower CRS severity and reduced serum concentrations of CRS-associated cytokines despite equivalent in vivo CAR T-cell expansion. In a study using peripheral blood mononuclear cells collected from CLL patients, epcoritamab induced higher cytotoxicity in samples collected from patients receiving treatment with a BTK inhibitor, including patients progressing on the BTK inhibitor at the time of sample collection, compared with treatment-naïve CLL patients (Mhibik, Blood Adv 2023). These data provide a rationale to study the combination of epcoritamab and ibrutinib.
Design and Methods: This is a multicenter phase Ib/II US study (NCT06536049) designed to evaluate the safety and efficacy of the combination of epcoritamab and ibrutinib in relapsed/refractory LBCL. Treatment with ibrutinib will start with a one-week lead-in (Day -7) and continue for the first six 28-day cycles (a total of 25 weeks). Treatment with epcoritamab will start on cycle 1, day 1, and continue for up to 12 cycles (every 1 week (Q1W) in cycles 1-3, Q2W in cycles 4-9, Q4W in cycles 10-12). The study begins with the phase Ib portion of 6 patients treated at dose level (DL) +1 (ibrutinib 420 mg daily and standard dose epcoritamab) with an option to de-escalate to DL -1 (ibrutinib 280 mg daily and standard dose epcoritamab) depending on toxicity. Once the recommended phase II dose (RP2D) is determined, a cohort of 26 patients treated at the RP2D will be enrolled on the phase II portion of the trial. The overall sample size will be 32 patients without dose de-escalation, up to a total of 38 patients if dose de-escalation occurs.
Study Population: Patients with diffuse large B-cell lymphoma, high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double- and triple-hit lymphoma), HGBL NOS, primary mediastinal B-cell lymphoma, or follicular lymphoma grade 3b. Patients must have relapsed or refractory disease and have received prior treatment with an anthracycline in combination with an anti-CD20 monoclonal antibody. Patients must have received ≥2 prior systemic lymphoma treatments or ≥1 prior systemic lymphoma treatment in patients with high-risk disease, defined as primary refractory or relapsed within 12 months of completing anthracycline-based frontline treatment, who are ineligible for CAR T cells. Prior treatment with CAR T cells is allowed if ≥ 30 days.
Study Objectives: The primary objectives are to determine the RP2D of the combination and evaluate the rate and severity of CRS. Secondary objectives are to determine the overall response rate, CR rate, duration of response, and progression-free and overall survivals. Exploratory objectives are to characterize the serum cytokine profile and peripheral blood immune cell subsets using spectral flow cytometry before and after ibrutinib and epcoritamab initiation, compare them to historical controls of epcoritamab monotherapy, and determine whether changes in serum cytokines and/or immune cell subsets correlate with both CRS and response. Further, we will examine tumor samples obtained before starting treatment and at relapse/progression to explore aspects of the microenvironment that may contribute to treatment failure.
Study status: The study is currently enrolling patients.
