Phase 3 randomized study of loncastuximab tesirine plus rituximab versus immunochemotherapy in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): LOTIS-5.

Abstract

TPS7574 Background: Patients (pts) with DLBCL for whom frontline therapy is unsuccessful and who are ineligible for autologous stem cell transplantation have poor outcomes with salvage therapy. Single-agent loncastuximab tesirine (Lonca), an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer (PBD) toxin, showed antitumor activity and manageable toxicity in pts with R/R B-cell non-Hodgkin lymphoma in a Phase 1 trial (Hamadani et al. Blood 2020; blood.2020007512) and in pts with R/R DLBCL in a Phase 2 trial (Caimi et al. Blood 2020; 136(Suppl 1):35–37). Rituximab (R) is part of standard immunochemotherapy for DLBCL, both as frontline therapy and in subsequent treatments. LOTIS-5 aims to evaluate Lonca + R (Lonca-R) versus (vs) standard immunochemotherapy of R + gemcitabine + oxaliplatin (R-GemOx) in pts with R/R DLBCL. Methods: This is a Phase 3 randomized, open-label, 2-part, 2-arm, multicenter study (NCT04384484). A non-randomized safety run-in (Part 1) will compare the safety of Lonca-R with previous safety data for Lonca after the first 20 pts have completed Cycle 1. Part 2 will be started if no significant increase in toxicity occurs; ̃330 pts will be randomized 1:1 to receive Lonca-R or R-GemOx. The primary objective of the study is to evaluate the efficacy of Lonca-R vs R-GemOx. The primary endpoint is progression-free survival by independent review. Secondary endpoints include overall survival; objective response rate; complete response rate; duration of response; frequency and severity of adverse events; changes from baseline in safety laboratory and clinical variables; concentration and pharmacokinetic parameters of Lonca (conjugated and total antibody, and unconjugated warhead); immunogenicity; and changes in patient-reported outcomes. Time-to-event endpoints will be assessed for the intent-to-treat population using a stratified log-rank test. The dosing regimen of Lonca-R in both parts of the study will be 150 µg/kg Lonca + 375 mg/m2 R every 3 weeks (Q3W) for 2 cycles and then 75 µg/kg Lonca + 375 mg/m2 R for 6 cycles. The dose regimen of R-GemOx in Part 2 will be 375 mg/m2 R, 1000 mg/m2 Gem, and 100 mg/m2 Ox Q2W for 8 cycles. Key inclusion criteria include age ≥18 years; pathologic diagnosis of DLBCL (including pts with DLBCL transformed from indolent lymphoma) or high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements; ≥1 line of prior systemic therapy; not a candidate for stem cell transplantation; and measurable disease per 2014 Lugano Classification. The study opened in September 2020 and enrollment is ongoing. The trial design was presented at 62nd American Society of Hematology Annual Meeting and Exposition, December 5–8, 2020. Research Funding: ADC Therapeutics SA. Clinical trial information: NCT04384484.