A Phase II Investigator-Initiated Trial of Epcoritamab with Gemcitabine, Dexamethasone, and Cisplatin (GDP) Salvage Chemotherapy in Relapsed Refractory Large B-Cell Lymphoma

Background and Significance: Approximately 30% of patients with large B cell lymphoma (LBCL) relapse after receiving rituximab-containing chemoimmunotherapy. Patients with rapidly progressing and symptomatic disease often require effective bridging therapy while awaiting CAR T-cell therapy. In addition, a salvage chemotherapy, which offers high response rates, is warranted to improve long-term outcomes. Epcoritamab is a CD3xCD20 bispecific antibody approved for relapsed refractory (RR) DLBCL after ≥2 prior lines of therapy. We hypothesized that the combination of epcoritamab, and gemcitabine, dexamethasone, and cisplatin (GDP) salvage chemotherapy could be effective for RR LBCL patients eligible for CAR T-cell therapy or stem cell transplant.

Study Design and Methods: This is a phase II investigator-initiated multicenter trial evaluating safety and efficacy of epcoritamab with GDP salvage chemotherapy in RR LBCL. Key eligibility criteria will include patients ≥18 years of age with CD20 positive RR LBCL with an eligible subtype, ³1 prior line of therapy, and eligible for CAR T-cell therapy or stem cell transplant (SCT), ECOG PS 0-2, and FDG avid and measurable disease by PET. All patients will receive 3 cycles of epcoritamab and GDP in the outpatient setting. No hospitalization for CRS monitoring is mandated. Epcoritamab will be administered subcutaneously during cycle 1 as weekly step-up doses (0.16/0.8/48 mg) and then weekly from cycle 2 day 1(cycle 2-3). GDP consists of gemcitabine 1000 mg/m² IV on days 1 and 8, cisplatin 75 mg/m² IV on day 1, and dexamethasone 40 mg orally days 1 through 4. Patients can proceed to CAR T-cell therapy or SCT upon completion of cycle 3 per investigator discretion. Patients who do not undergo CAR T-cell therapy or SCT may remain in the study and receive epcoritamab monotherapy for 6 cycles (cycle 4 through cycle 9, each cycle= 28 days), or until unacceptable toxicity, or disease progression per the Lugano Criteria.

The primary end point is complete remission (CR) rate per the Lugano criteria. Secondary end points include overall response rate, duration of response, progression-free survival, overall survival, safety and tolerability of epcoritamab and GDP, and feasibility of peripheral blood T-lymphocytes collection or stem cell mobilization. The sample size is justified using Simon's two-stage minimax design for the alternative CR rate of 65% against the null CR rate of 40%. In the first stage, 14 patients will be accrued. If there are 5 or less CR in these patients, the study will be stopped. Otherwise, 18 additional patients will be accrued for a total of 32. This design will yield a 1-sided type I error rate of 2.5% and power of 80% when the true CR rate is 65%. The study is currently enrolling. The clinicalTrials.gov ID is NCT05852717.

Modi:ADC therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; AstraZeneca: Research Funding; Beigene: Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees.