Sequential Study of 225Ac-LNC1011 in the Treatment of Metastatic Castration-Resistant Prostate Cancer

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has demonstrated considerable potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). By incorporating albumin-binding motifs into PSMA radioligands, the circulation time in the bloodstream can be prolonged, leading to significantly enhanced tumor uptake and therapeutic efficacy. LNC1011 employs dansylated Amino Acid as a novel, relatively weak yet high-performance albumin-binding moiety, achieving an optimal balance among increased tumor accumulation, improved safety, and refined diagnostic performance. This enables a unified theranostic approach within a single molecular framework. Alpha-emitting radionuclides, represented by Ac-225, generate alpha particles during decay. Their linear energy transfer is nearly 100-fold higher than that of β-emitters such as Lu-177, resulting in significantly enhanced tumor cell kill. This has earned them the designation of "scalpel-like radiotherapy." Moreover, alpha particles have an extremely short range (only a few cell diameters), causing minimal damage to surrounding normal tissues and almost no notable side effects, thereby conferring an excellent safety profile. In this clinical study, we will follow a "3+3" trial design to evaluate the safety and efficacy of different doses of 225Ac-LNC1011 in patients with mCRPC. The initial dose of 225Ac-LNC1011 is set at 3.70 MBq (100 μCi). Approximately three subjects will be enrolled at the current dose level. If no dose-limiting toxicity (DLT) is observed, the next cohort will receive an escalated dose of 5.55 MBq (150 μCi). If again no DLT occurs, the subsequent cohort will be escalated to 7.40 MBq (200 μCi), which is the planned maximum dose. It should be noted that if one DLT occurs at any dose level, three additional patients will be enrolled at the same dose. If only one DLT is observed among the total of six subjects, dose escalation may proceed. If two or more DLTs occur, dose de-escalation or trial termination will be initiated. Subjects in all dose cohorts will receive up to four treatment cycles at 8- to 12-week intervals. All participants will undergo safety follow-up during the trial and for 12 months after its completion.