A Phase 2 Trial Investigating Epcoritamab in Patients with Previously Treated Waldenstrom Macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (WM-NET3)

Background and Significance:

Waldenström Macroglobulinemia (WM) is a rare indolent B-cell lymphoproliferative disorder which is defined by the presence of lymphoplasmacytic lymphoma (LPL) cells involving the bone marrow and production of a monoclonal IgM paraprotein. While upfront chemoimmunotherapy is highly effective, there is no standard-of-care therapy for relapsed patients who have progressed on BTK inhibitor therapy, and their prognosis is generally poor. Epcoritamab is a fully humanized CD20xCD3 T-cell-engaging bispecific antibody that redirects T-cells to eliminate B-cells and has shown promising activity in B-cell non-Hodgkin lymphomas in several pivotal trials leading to the regulatory approval in relapsed diffuse large B-cell and follicular lymphoma, following 2 or more prior lines or therapy.

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Study Design and Methods:

This single-arm, multicenter, phase 2 study will evaluate the efficacy and safety of epcoritamab in patients with relapsed or refractory (R/R) WM/LPL. It consists of a safety lead-in portion followed by a phase 2 portion to evaluate efficacy endpoints. The safety lead-in cohort will receive epcoritamab at a target dose of 24 mg. Patients in the Phase 2 efficacy cohort will be treated at a target dose of 48 mg. Of note, patients enrolled in the safety lead-in will subsequently be eligible for dose escalation to 48 mg and be able to complete an additional 12 months at that dose. Safety data will continue to be recorded; however, these patients will not be included in the efficacy analysis.

Epcoritamab will be administered at a target dose of 24 or 48 mg subcutaneously over 28-day cycles for a maximum of 12 cycles. In cycles 1-3, epcoritamab will be given once per week (days 1, 8, 15, and 22); in cycles 4-9, every two weeks (days 1 and 15); and in cycles 10-12, once every four weeks (day 1). For cycle 1, a step-up dosing schedule will be utilized consisting of a priming dose of 0.16 mg (day 1), an intermediate dose of 0.8 mg (day 8), and a full dose of either 24 mg or 48 mg (day 15 onward). Patients with histologically confirmed R/R WM/LPL who have received ≥1 prior line of systemic therapy (including a BTK inhibitor) and have an Eastern Cooperative Oncology Group performance status of 0-2 meeting criteria for initiation of treatment per 2^nd International Workshop for WM (IWWM2) criteria are eligible for enrollment. Exclusion criteria include known or suspected central nervous system (CNS) involvement (i.e., Bing-Neel Syndrome) or current uncontrolled CNS disease (including stroke, epilepsy, or vasculitis).

The primary endpoint of this trial is the overall response rate (ORR) per modified IWWM6 criteria. A Simon's optimal two-stage design will be used for conducting the trial. The null hypothesis is that the true response rate is 0.5, and the alternative hypothesis is that the true response rate is 0.8. With a 2-sided alpha of 0.05 and a power of 80%, the sample size needed to reject the null hypothesis is 20 patients. Secondary endpoint include the rate of minor response (MR), partial response (PR), very good partial response (VGPR), and complete response (CR) at best response and after completing 6 months of study therapy, duration of response (DOR), the estimated 2-yr progression-free survival rate, time to next treatment (TTNT), and the estimated 2-yr overall survival rate. As exploratory objectives, we will evaluate serial single cell RNA to gauge changes in immune repertoire triggered by the bispecific expansion of immune cells and serial circulating tumor DNA for minimal residual disease detection and clonal evolution.

If this study meets its primary endpoint, epcoritamab could be added to the armamentarium of safe and effective treatment options for WM patients.

von Keudell:Pharmacyclics: Consultancy, Honoraria; Merck: Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy; Genmab: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Sarosiek:ADC Therapeutics: Research Funding; BeiGene: Honoraria, Research Funding; Cellectar Biosciences: Honoraria, Research Funding. Branagan:Adapative: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Genzyme: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding. Anderson:Cellectar Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Treon:BeiGene, Inc.: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Parexel: Honoraria, Research Funding; Eli Lilly: Research Funding; AbbVie/Pharmacyclics: Honoraria, Research Funding. Castillo:Janssen: Consultancy; Mustang Bio: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Cellectar Biosciences: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; AbbVie: Consultancy, Research Funding.