A phase 1 trial to determine the maximum tolerated dose and patient-specific dosimetry of [Lu]Lu-LNC1003 in patients with metastatic castration-resistant prostate cancer.

Purpose: This translational study aimed to determine the maximum tolerated dose (MTD), safety, dosimetry, and therapeutic efficacy of Lu-PSMA-EB-01 (denoted as [Lu]Lu-LNC1003) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods: A total of 13 patients with mCRPC were recruited in this study. A standard 3 + 3 dose escalation protocol was performed. The following dose levels were ultimately evaluated: 1.11, 1.85, and 2.59 GBq/cycle. Patients received [Lu]Lu-LNC1003 therapy for up to two cycles at a 6-week interval.

Results: Patients received fractionated doses of [Lu]Lu-LNC1003 ranging from 1.11 to 2.59 GBq per cycle. Myelosuppression was dose-limiting at 2.59 GBq, and 1.85 GBq was determined to be the MTD. The total-body effective dose for Lu-LNC1003 was 0.35 ± 0.05 mSv/MBq. The salivary glands were found to receive the highest estimated radiation dose, which was calculated to be 3.61 ± 2.83 mSv/MBq. The effective doses of kidneys and red bone marrow were 1.88 ± 0.35 and 0.22 ± 0.04 mSv/MBq, respectively. The tumor mean absorbed doses for bone and lymph node metastases were 8.52 and 9.51 mSv/MBq. Following the first treatment cycle, PSA decline was observed in 1 (33.3%), 4 (66.7%), and 2 (50.0%) patients at dose levels 1 (1.11 GBq), 2 (1.85 GBq), and 3 (2.59 GBq), respectively. Compared with the baseline serum PSA value, 1 (33.3%) at dose level 1 and 4 (66.6%) patients at dose level 2, presented a PSA decline after the second treatment cycle.

Conclusion: This phase 1 trial revealed that the MTD of [Lu]Lu-LNC1003 is 1.85 GBq. The treatment with multiple cycles at the dose of 1.11 GBq /cycle and 1.85 GBq /cycle was well tolerated. [Lu]Lu-LNC1003 has higher tumor effective doses in bone and lymph nodes metastases while the absorbed dose in the red bone marrow should be closely monitored in future treatment studies with higher doses and multiple cycles. The frequency of administration also needs to be further explored to assess the efficacy and side effects of [Lu]Lu-LNC1003 treatment.

Trial Registration: Lu-PSMA-EB-01 in patients with metastatic castration-resistant prostate cancer (NCT05613738, Registered 14 November 2022). URL of registry https://classic.

Clinicaltrials: gov/ct2/show/NCT05613738.