Initial outcome of phase I study of Lu-177 Ludotadipep treatment in metastatic castration-resistant prostate cancer patients

Introduction: Lu-177 Ludotadipep is a novel prostate specific membrane antigen (PSMA) targeting therapeutic agent with albumin binding moiety what results in longer circulation time. In phase I study with dose escalation design, subjects with metastatic castration resistant prostate cancer (mCRPC) were studied for safety and efficacy of Lu-177 Luduotadipep.

Methods: We enrolled subjects with mCRPC from October 2020 to October 2021. Inclusion criteria included positive findings (PSMA-RADS 4, 5) on prostate-specific membrane antigen (PSMA) targeting ¹⁸F-Florastamin PET/CT and low serum testosterone (less than 50 ng/dL). Exclusion criteria were poor bone marrow activity (any of the followings: Hb ≤10.0 g/dL, white blood cell count ≤ 4.0 x 10³/L, platelet count ≤ 100 x 10⁹/L), decreased renal function (serum creatinine ≤ 40 ml/min), or poor performance score. With a starting dose of 50±5 mCi, 6 subjects received the investigational Lu-177 Ludotadipep once. If no dose limiting toxicity (DLT) was observed for 8 weeks, then the dose was sequentially escalated to 75±8 mCi, 100±10 mCi, and then 125±13 mCi, each with 6 subjects per dose. Dose-limiting toxicity (DLT) was defined as common terminology criteria for adverse events grade 4 thrombocytopenia (platelet < 25 x 10⁹/L), grade 4 neutropenia (absolute neutrophil count < 0.5 x 10⁹/L), grade 3 febrile neutropenia (absolute neutrophil count < 1000/mm³ with body temperature > 38.3ºC; or temperature > 38ºC for more than 1 hour), and non-hematologic toxicity of grade 3 or 4.

Results: Of 24 subjects who received Lu-177 Ludotadipep, 2 subjects chose to drop out from the study due to difficulty traveling for follow up exams. Of the 22 subjects eligible for safety evaluation, none showed treatment related DLT (grade 3 or 4 toxicity). There was no treatment related adverse event which required medical intervention. The lower doses (50 mCi and 75 mCi) resulted in PSA response of 50% or greater in 1 of 11 subjects, PSA decrease less than 50% in 3/11, and PSA increase in 7/11 subjects at 8 weeks. The higher doses (100 mCi and 125 mCi) resulted in PSA response of 50% or greater in 5 of 11 subjects, PSA decrease less than 50% in 4/11, and PSA increase in 2/11 subjects at 8 weeks.

Conclusions: Lu-177 Ludotadipep single dose (ranging from 50 mCi to 125 mCi) demonstrated no grade 3 or 4 toxicity. Single administration of the higher dose (100 mCi or 125 mCi) of Lu-177 Ludotadipep resulted in PSA response of 50% or greater in 5 out of 11 mCRPC subjects at 8 weeks.