Phase I dose-escalation study of [¹⁷⁷Lu]Lu-LNC1011, a long-circulating dansyl-modified PSMA theranostics, in metastatic castration-resistant prostate cancer

Rationale: [ 177 Lu]Lu-D-Dan-Phe-PSMA ([ 177 Lu]Lu-LNC1011) is a novel long-circulating prostate-specific membrane antigen (PSMA) therapeutic radioligand.This Phase I study aimed to investigate its safety, dosimetry, and initial treatment efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients.Methods: This open-label, non-randomized, Phase I dose-escalation trial enrolled mCRPC patients with PSMA-positive lesions confirmed by PSMA PET/CT.A total of nine patients received [ 177 Lu]Lu-LNC1011 at administered activity levels of 1.85 GBq, 2.78 GBq, and 3.70 GBq.Results: During the dose-limiting toxicity (DLT) observation period, no DLTs occurred in any activity group.The cumulative absorbed dose to organs increased with the injected activity.The effective dose to the whole body was 1.30E-01 ± 1.91E-02 mSv/MBq.The kidneys received the highest radiation dose (3.33 ± 1.09 Gy/GBq), consistent with the expected biodistribution of PSMA-targeted ligands.For salivary glands and red bone marrow, the absorbed doses were 1.70 ± 1.04 Gy/GBq and 0.11 ± 0.03 Gy/GBq, respectively.The mean absorbed dose to tumors was 12.29 ± 6.50 Gy/GBq.The effective half-life of [ 177 Lu]Lu-LNC1011 was 49.44 ± 12.58 h in the whole body and 128.3 ± 62.79 h in tumor lesions.After two treatment cycles, the 3.70 GBq cohort (n = 3) demonstrated 100% PSA reduction (3/3), with 66.7% (2/3) achieving ≥50% PSA decline; simultaneously, Response Evaluation Criteria in PSMA PET/CT (RECIP) 1.0 assessment showed partial response (PR) in 66.7% (2/3) of patients and stable disease (SD) in 33.3% (1/3).Conclusion: [ 177 Lu]Lu-LNC1011 was well tolerated across all dose levels, delivering high tumor-absorbed doses and prolonged tumor retention.The 3.70 GBq cohort demonstrated notable therapeutic efficacy.These favorable safety, dosimetry, and efficacy findings support the investigation of extended multi-cycle treatment with [¹⁷⁷Lu]Lu-LNC1011 at 3.70 GBq per cycle in future clinical studies.