A phase 1/2, multi-center, open-label study to evaluate the safety, tolerability, pharmacokinetics, radiation dosimetry, and preliminary anti-neoplastic activity of LNTH-2403, a LRRC15-targeted ¹⁷⁷ lutetium-labeled monoclonal antibody, in patients with relapsed/refractory osteosarcoma.

Abstract

TPS11587 Background: Treatment for relapsed and refractory (R/R) osteosarcoma (OST) has not changed for decades. R/R OST has a poor prognosis with a 12% 4-month event-free survival (EFS). Leucine-Rich Repeat Containing 15 (LRRC15) is a type I transmembrane protein on OST cells and cancer associated fibroblasts. Approximately 90% of OST express LRRC15; high expression predicts aggressive disease and shorter survival. LNTH-2403 is a high-affinity LRRC15-targeting fully humanized antibody with a 177 lutetium payload. Preclinical data show anti-tumor activity in several OST models, demonstrating LNTH-2403’s potential to treat R/R OST. Methods: This first-in-human, multicenter, open-label phase 1/2 study will evaluate the safety, tolerability, pharmacokinetics (PK), biodistribution (BD), radiation dosimetry (RD), and preliminary anti-neoplastic activity in patients ≥12 years of age with LRRC15-expressing R/R OST. The primary endpoints are to identify the maximum tolerated dose (MTD; phase 1) and 4-month EFS (phase 2). LRRC15 expression by immunohistochemistry will be confirmed by a central lab; pre-screening is allowed. Initiated in Q1 2026, phase 1 will test LNTH-2403 at 30, 50, and 70 mCi/m 2 every 8 weeks in up to ~30 patients. A 3+3 design will be used to define the MTD and estimate the recommended phase 2 dose (RP2D). Phase 2 will evaluate LNTH-2403 at the RP2D in ~25 patients with R/R OST. Retreatment after Cycle 1 is permitted for patients who continue to meet initial eligibility requirements, have cumulative doses to target organs predicted to be below radiation tolerance limits, and whose bone marrow has recovered. Safety testing includes adverse events (AEs), serious AEs (SAEs), laboratory parameters (chemistry, hematology, coagulation, urinalysis), electrocardiograms, vital signs, and physical examinations. BD and RD are based on serial single photon emission computed tomography (SPECT)/computed tomography (CT) and planar imaging. PK data will be generated from serial blood sampling for radioactivity. Overall response rate (ORR) and EFS are defined by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 per investigator reads. As ORR by RECIST is challenging in OST due to tumor calcification, efficacy testing also includes physiologic response by fluorine-18 ( 18 F)-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT whole body scans and magnetic resonance imaging of the primary site, sites of known and presumed metastases, and the chest, abdomen, and pelvis. For this open-label study, all statistical methods will be descriptive in nature with no formal statistical hypotheses. NCT07357519; Research Sponsor: Lantheus. Clinical trial information: NCT07357519 .