[¹⁷⁷Lu]Lu-PSMA is an effective class of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response may be partially explained by the presence of micrometastatic deposits, which are energy-sheltered and receive low absorbed radiation with ¹⁷⁷Lu due to the approximately 0.7-mm mean pathlength. ¹⁶¹Tb has abundant emission of Auger and conversion electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. ¹⁶¹Tb has shown in vitro and in vivo efficacy superior to that of ¹⁷⁷Lu. We aim to demonstrate that [¹⁶¹Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 patients with mCRPC. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy (unless medically unsuitable) and androgen receptor pathway inhibitor; prostate-specific membrane antigen–positive disease on [⁶⁸Ga]Ga-PSMA-11 or [¹⁸F]DCFPyL PET/CT (SUV_max ≥ 20); no sites of discordance on [¹⁸F]FDG PET/CT; adequate bone marrow, hepatic, and renal function; an Eastern Cooperative Oncology Group performance status of no more than 2, and no prior treatment with another radioisotope. The dose escalation is a 3 + 3 design to establish the safety of 3 prespecified activities of [¹⁶¹Tb]Tb-PSMA-I&T (4.4, 5.5, and 7.4 GBq). The maximum tolerated dose will be defined as the highest activity level at which a dose-limiting toxicity occurs in fewer than 2 of 6 participants. The dose expansion will include 24 participants at the maximum tolerated dose. Up to 6 cycles of [¹⁶¹Tb]Tb-PSMA-I&T will be administered intravenously every 6 wk, with each subsequent activity reduced by 0.4 GBq. The coprimary objectives are to establish the maximum tolerated dose and safety profile (Common Terminology Criteria for Adverse Events version 5.0) of [¹⁶¹Tb]Tb-PSMA-I&T. Secondary objectives include measuring absorbed radiation dose (Gy), evaluating antitumor activity (prostate-specific antigen 50% response rate, radiographic and prostate-specific antigen progression-free survival, overall survival, objective response rate), and evaluating pain (Brief Pain Inventory–Short Form) and health-related quality of life (Functional Assessment of Cancer Therapy–Prostate and Functional Assessment of Cancer Therapy–Radionuclide Therapy). Conclusion: Enrollment was completed in February 2024. Patients are still receiving [¹⁶¹Tb]Tb-PSMA-I&T.

[ ¹⁷⁷ Lu]Lu-PSMA 是治疗转移性去势抵抗性前列腺癌 (mCRPC) 患者的一类有效疗法；然而，进步是不可避免的。响应持久性有限的部分原因可能是微转移沉积物的存在，这些沉积物受到能量遮挡，并且由于平均路径长度约为 0.7 毫米，因此接收¹⁷⁷ Lu 的低吸收辐射。 ¹⁶¹ Tb 具有丰富的俄歇电子和转换电子发射，可在较短的路径上沉积更高浓度的辐射，特别是针对单个肿瘤细胞和微转移。 ¹⁶¹ Tb 在体外和体内的功效均优于¹⁷⁷ Lu。我们的目标是证明 [ ¹⁶¹ Tb]Tb-PSMA-I&T 能够以可接受的安全性向转移性前列腺癌部位提供有效的辐射。方法：这项单中心、单臂、I/II 期试验将招募 30 名 mCRPC 患者。关键资格标准包括诊断为 mCRPC，并在至少一种紫杉烷化疗（除非医学上不合适）和雄激素受体途径抑制剂后出现进展； [ ⁶⁸ Ga]Ga-PSMA-11 或 [ ¹⁸ F]DCFPyL PET/CT 检测前列腺特异性膜抗原阳性疾病（SUV _max ≥ 20）； [ ¹⁸ F]FDG PET/CT 上没有不一致的位点；足够的骨髓、肝、肾功能；东部肿瘤合作组表现状态不超过 2，并且之前未接受过其他放射性同位素治疗。剂量递增采用 3 + 3 设计，旨在确定 [ ¹⁶¹ Tb]Tb-PSMA-I&T（4.4、5.5 和 7.4 GBq）的 3 种预先指定活性的安全性。 最大耐受剂量将定义为 6 名参与者中少于 2 名发生剂量限制性毒性的最高活动水平。剂量扩展将包括 24 名最大耐受剂量的参与者。每 6 周静脉注射最多 6 个周期的 [ ¹⁶¹ Tb]Tb-PSMA-I&T，每个后续活性减少 0.4 GBq。共同主要目标是确定 [ ¹⁶¹ Tb]Tb-PSMA-I&T 的最大耐受剂量和安全性（不良事件通用术语标准 5.0 版）。次要目标包括测量吸收辐射剂量 (Gy)、评估抗肿瘤活性（前列腺特异性抗原 50% 缓解率、放射照相和前列腺特异性抗原无进展生存期、总生存期、客观缓解率）以及评估疼痛（简要疼痛量表） –简表）和健康相关的生活质量（癌症治疗的功能评估 – 前列腺和癌症治疗的功能评估 – 放射性核素治疗）。结论：入组于 2024 年 2 月完成。患者仍在接受 [ ¹⁶¹ Tb]Tb-PSMA-I&T。