ABCL-021: FRONT-MIND: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study Comparing Efficacy and Safety of Tafasitamab + Lenalidomide + R-CHOP vs R-CHOP Alone for Newly-Diagnosed High-Intermediate and High-Risk Diffuse Large B-Cell Lymphoma (DLBCL)

Context Tafasitamab is an Fc-modified, humanized anti-CD19 monoclonal antibody, which induces enhanced in vitro antibody-dependent cell-mediated cytotoxicity and phagocytosis. Preclinical studies data suggest that tafasitamab+lenalidomide may synergistically enhance cytotoxicity to malignant B-cells. Tafasitamab+lenalidomide is FDA-approved in adult patients with relapsed/refractory DLBCL who are ineligible for autologous stem cell transplantation. R-CHOP is the current standard of care (SOC) for patients with newly-diagnosed DLBCL. Data from the Phase Ib FIRST-MIND (NCT04134936) study in newly-diagnosed DLBCL patients suggest that tafasitamab+lenalidomide when added to R-CHOP is tolerable in patients with treatment-naive DLBCL. Objective To assess the efficacy and safety of tafasitamab+lenalidomide+R-CHOP vs R-CHOP alone in previously untreated, high-intermediate and high-risk patients with DLBCL. Design FRONT-MIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. Patients will be followed-up for up to 60 months after end of treatment. Setting Patients will be enrolled from approximately 350 centers in America, Europe, and Asia-Pacific. Patients Eligible patients (n=880) will be aged 18–80 years with previously untreated local biopsy-proven, CD20-positive DLBCL (IPI ≥3 if >60 years/age-adjusted IPI 2–3 if ≤60 years), and ECOG PS 0–2. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded. Interventions Patients will be randomized to receive six 21-days (D) cycles of tafasitamab (12 mg/kg intravenous [IV], D 1, 8, and 15)+lenalidomide (25 mg orally, D1–10)+R-CHOP or six 21-D cycles of tafasitamab placebo (D1, 8, and 15)+lenalidomide placebo (orally, D1–10)+R-CHOP. Main Outcome Measures The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include investigator-assessed event-free survival, overall survival, and safety. Results Not yet available. Conclusions As 30–50% of patients overall relapse or are refractory to first-line therapy, there remains a high unmet need to improve treatment options for newly diagnosed patients, particularly those with high-risk DLBCL. The combination of tafasitamab, lenalidomide, and R-CHOP may have synergistic potential. Preliminary data from the FIRST-MIND study suggest that tafasitamab±lenalidomide+R-CHOP is tolerable in patients with treatment-naive DLBCL. The present study will provide further evaluation of clinical benefits and safety when adding tafasitamab+lenalidomide to current SOC in newly diagnosed patients with high-intermediate and high-risk DLBCL treated with R-CHOP.