Phase 1 Dose-Escalation Study of [<sup>225</sup>Ac]Ac-PSMA I&T in Patients with Metastatic Castration-Resistant Prostate Cancer: An Analysis of Safety, Tolerability, and Dosimetry.

Abstract

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.