Phase II Study of Pirtobrutinib with Epcoritamab Combination Therapy in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

The primary objective is twofold: a safety run‑in phase to assess the safety and tolerability of initiating epcoritamab in combination with pirtobrutinib after three cycles of pirtobrutinib monotherapy, and a cohort‑expansion phase to evaluate efficacy as measured by progression‑free survival at 24 months from the first pirtobrutinib dose, reflecting the potential to extend disease control in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. The secondary objectives include evaluation of undetectable minimal residual disease (uMRD4) in bone marrow 12 weeks after the final epcoritamab cycle, assessment of uMRD4 in peripheral blood 12 weeks after day 28 of cycle 24, serial MRD‑depth analyses in peripheral blood after cycles 4, 9, 15, 18, 24 and at 12 weeks, 12 months and 24 months post‑treatment, determination of overall survival, measurement of overall response rate, assessment of event‑free survival, calculation of time on treatment for each agent, time to next treatment, treatment‑free survival, and duration of response. Additional endpoints comprise safety and tolerability monitoring, evaluation of quality of life, and exploratory analyses of the relationship between early MRD status and long‑term outcomes, the comparative performance of MRD testing methodologies, disease dynamics on imaging, immunologic effects of the combination, and correlations with baseline molecular and biological factors.

The trial enrolled adult patients of both sexes with documented relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) following at least one prior systemic therapy, who met International Workshop on Chronic Lymphocytic Leukemia criteria for treatment. Eligible individuals were required to be 18 years of age or older, have an ECOG/WHO performance status of 0–2, and demonstrate adequate bone‑marrow, renal (eGFR ≥ 45 ml/min) and hepatic function as defined by protocol‑specified laboratory thresholds. Negative serology for hepatitis B and C was also required. Both male and female patients were considered, and the population comprised individuals with relapsed/refractory disease but otherwise in sufficient health to tolerate study interventions. The sponsor did not provide information on the total number of participants enrolled, and no specific lifestyle requirements such as diet or physical activity were reported in the source data.

The study is a prospective, phase II, open‑label trial evaluating the combination of oral pirtobrutinib (200 mg daily) and intravenous epcoritamab (48 mg per cycle) in adults with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. After a screening visit to confirm eligibility, participants receive three cycles of pirtobrutinib monotherapy (28 days per cycle). Beginning with cycle 4, epcoritamab is administered concurrently for a total of 12 cycles while pirtobrutinib continues for up to 24 cycles. Study visits occur at baseline (day 1 of cycle 1), at the start of each subsequent cycle for safety assessments, drug dispensing, and efficacy evaluations, and include a final end‑of‑study visit after completion of cycle 24 or earlier discontinuation. The overall participant involvement spans approximately 24 months, plus a follow‑up period for survival and quality‑of‑life assessments. Early termination may occur due to unacceptable toxicity, disease progression, initiation of alternative CLL therapy, withdrawal of consent, or investigator decision based on safety concerns.

The investigational oral agent, marketed as Jaypirca 100 mg film‑coated tablets, contains the BTK inhibitor pirtobrutinib. Each tablet is 100 mg; the dosing schedule calls for a total of 200 mg administered orally once daily throughout 24 treatment cycles. The medication is supplied as film‑coated tablets and is taken by mouth according to the study protocol.

The second investigational product, Epcoritamab (GEN3013), is provided as a 48 mg solution for injection. This bispecific antibody is administered intravenously at a dose of 48 mg per infusion. Treatment with epcoritamab begins after three cycles of pirtobrutinib monotherapy and continues for up to 12 cycles, following the dosing schedule defined in the protocol.

No additional non‑experimental therapies, such as standard‑of‑care agents or placebo, are incorporated into the treatment regimen; the study evaluates the combination of the two investigational agents alone.

Efficacy will be assessed primarily by PFS, defined as the interval from the first dose of pirtobrutinib to the first documented disease progression or death from any cause, evaluated at 24 months. Secondary efficacy parameters include undetectable minimal residual disease (MRD) at a threshold of < 10⁻⁴ in bone marrow (BM) and peripheral blood (PB) in the absence of progression according to IWCLL criteria, overall survival (OS), overall response rate (ORR) based on IWCLL 2018 response categories (CR, CRi, PR), event‑free survival, time‑to‑next‑treatment, and depth of MRD measured at multiple time points (after cycles 4, 9, 15, 18, 24, 12 weeks post‑day 28 of cycle 24, and at 12 and 24 months after cycle 24). Health‑related quality of life will be evaluated using the EORTC QLQ‑C30, QLQ‑CLL17 and PRO‑CTCAE questionnaires.

MRD assessments will be performed by flow cytometry on BM and PB specimens at the specified cycles and by next‑generation sequencing at the end of cycle 18 for BM samples. Imaging studies (CT) will be obtained at baseline, after cycle 9, cycle 18, and 12 weeks post‑cycle 24 to document disease status. Patient‑reported outcomes will be collected via the designated questionnaires at scheduled visits. All efficacy data will be analyzed according to predefined statistical plans, with time‑to‑event endpoints estimated using Kaplan‑Meier methods and response rates summarized with exact confidence intervals.