Kilt: a randomized non‐comparative phase ii lysa study of lacutamab with gemox versus gemox in relapsed/refractory peripheral t‐cell lymphoma

Background: Peripheral T-cell Lymphoma (PTCL) is a heterogeneous group of mature T-cell lymphomas (TCL) with adverse outcomes. Current treatment options for relapsing PTCL are limited. KIR3DL2 is a killer immunoglobulin-like receptor that is expressed across different subtypes of TCL, including approximately 40% of PTCL. Lacutamab is a humanized first-in-class monoclonal antibody designed to deplete KIR3DL2-expressing cells via ADCC and phagocytosis. In a previous phase I trial in relapsed/refractory cutaneous TCL, lacutamab showed adequate safety profile with no dose limiting toxicities and a global response rate of 43%. TELLOMAK multi-cohort phase II trial (NCT03902184) in advanced TCL is ongoing. Lacutamab has not been previously investigated as a combination therapy. Preclinical studies have shown that lacutamab selectively killed KIR3DL2-positive primary cells ex vivo from patients with PTCL. A combination of lacutamab with gemcitabine and oxaliplatin (GemOx) enhances NK cell anti-tumor activity in vitro. Methods: This is an open label, multi-center, international, randomized non-comparative phase II trial to compare the safety and efficacy of lacutamab in combination with GemOx vs. GemOx alone in patients with any subtypes of relapsed/refractory KIR3DL2-positive PTCL. The design is non comparative meaning that the control arm will ensure that the assumptions used for sample size calculation are verified. For that reason, randomization is unbalanced in favor of the experimental arm (2:1). Patients are stratified according to R/R status and should have received ≤2 prior systemic therapies. In the experimental arm, patients are treated for 6 cycles of lacutamab 750 mg (intravenous infusion) + GemOx every 3 weeks as induction, and with lacutamab every 4 weeks as maintenance for up to a maximum of 2 years if they reached at least a partial response after induction. All patients should have a KIR3DL2 expression ≥1% as assessed centrally by immunohistochemistry. The primary endpoint is the median modified progression-free survival using the Lugano 2014 criteria. Secondary endpoints include safety, other efficacy endpoints and exploratory biomarker analyses. 56 patients are planned to be enrolled in France, Belgium, Spain and Germany. The trial is currently enrolling in 37 medical centers in France and Belgium. The sponsor of the trial is the Lymphoma Academic Research Organisation (LYSARC) in collaboration with Innate Pharma. Trial registration: NCT04984837. The research was funded by: The research was funded by Innate Pharma Keywords: aggressive T-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract. M. Cheminant Research funding: Innate Pharma J. Bruneau Research funding: Innate Pharma C. Herbaux Honoraria: AbbVie, Janssen, Roche, Gilead Research funding: AbbVie A. Wolfromm Consultant or advisory role Takeda O. Tournilhac Honoraria: Amgen, Janssen, Gilead, Abbvie, BluePrint, Roche Educational grants: Amgen, Janssen, Gilead, Abbvie, BluePrint, Roche P. Gaulard Research funding: Innate Pharma N. Ortonne Research funding: Innate Pharma O. Hermine Research funding: Innate Pharma