Radiopharmaceutical therapy with 225Ac-labeled prostate-specific membrane antigen (225Ac-PSMA) has shown promising results in patients with metastatic castration-resistant prostate cancer (mCRPC). To date, no phase 1 dose-escalation or comprehensive dosimetry study of [225Ac]Ac-PSMA I&T is available. Here, we present the results of the safety, tolerability, and dosimetry data of [225Ac]Ac-PSMA I&T in a phase 1 trial. Methods: Nine patients with mCRPC were treated with an intended 2 cycles of escalating activity of [225Ac]Ac-PSMA I&T, ranging from 8 to 12 MBq. After treatment with [225Ac]Ac-PSMA I&T, patients were closely monitored for adverse events. Tumor response was evaluated using [68Ga]Ga-PSMA I&T PET/MRI at 14 wk after therapy in accordance with RECIST version 1.1. For dosimetry, blood sampling was performed at 13 time points up to 7 d and urine sampling was conducted up to 24 h postinjection. Time-activity curves were calculated using the radionuclide daughters 213Bi and 221Fr. Whole-body planar images with or without SPECT/CT images were acquired up to 10 d postinjection. Results: Adverse events of any grade were observed in 8 of 9 patients. Xerostomia was most frequently (89%) reported, followed by anemia (44%) and malaise (44%). In the third cohort of patients who were treated with 12 MBq, 2 dose-limiting toxicities were observed, resulting in a recommended phase 2 dose of 10 MBq. The median overall survival was 15 mo (95% CI, 0.0-32.5 mo). The median absorbed doses for red marrow, kidneys, salivary glands, and tumors were 0.21, 1.59, 1.43, and 11.22 Gy/MBq, respectively, on the basis of planar images, blood and urine analysis, and [68Ga]Ga-PSMA I&T PET/MRI. Dosimetry based on quantitative SPECT/CT images was not feasible for 225Ac. A prostate-specific antigen response of 50% or greater was observed in 4 (44%) of 9 patients. Response was classified in accordance with RECIST 1.1, with partial response in 1 patient and stable and progressive disease in 3 patients each; 2 patients were not evaluable. Conclusion: The results of this phase 1 trial indicate a recommended phase 2 dose of 10 MBq of [225Ac]Ac-PSMA I&T. Dosimetry of [225Ac]Ac-PSMA I&T was limited to whole-body planar images and blood and urine samples. However, the optimization of 225Ac SPECT/CT imaging may enable future dosimetry of [225Ac]Ac-PSMA I&T.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2026 Apr 22 [Epub ahead of print]
Sui Wai Ling, Mark Konijnenberg, Marcel Segbers, Eline Hooijman, Stijn Koolen, Erik de Blois, Linda C De Jong, Andrea van Puffelen, Quido de Lussanet de la Sabloniere, Frank Bruchertseifer, Elena Livia Chilug, Alfred Morgenstern, Astrid van der Veldt, Tessa Brabander
Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands; ., Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands., Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; and., European Commission, Joint Research Centre, Karlsruhe, Germany.