First-in-Human, Open-label, Single-Arm Phase I Study of [211At] meta -Astatobenzylguanidine in Patients with Pheochromocytoma or Paraganglioma

Abstract Purpose: The efficacy of current therapeutic options for pheochromocytomas and paragangliomas, such as 131I-meta-iodobenzylguanidine (131I-MIBG), is limited owing to low complete response rates and a requirement for prolonged radiation isolation. In this regard, α-emitting meta-astatobenzylguanidine labeled with astatine-211 (211At-MABG) has demonstrated encouraging nonclinical results in mice, yet its clinical potential remains unclear. This first-in-human, open-label, single-arm phase I clinical study aimed to evaluate the safety, pharmacokinetics (PK), and recommended dose of 211At-MABG. Patients and Methods: Ten participants with unresectable or metastatic treatment-refractory pheochromocytomas or paragangliomas and confirmed 123I-MIBG uptake were enrolled between June 2022 and May 2025. Using a 3 + 3 dose-escalation design (0.65, 1.3, and 2.1 MBq/kg), they received a single intravenous dose of 211At-MABG. Results: No dose-limiting toxicities were observed during the 6-week evaluation period. The cumulative urinary excretion of 211At-MABG reached 65% within 72 hours, indicating rapid systemic clearance. One, 7, and 2 patients exhibited a partial response (PR), stable disease, and progressive disease, respectively, during a maximum follow-up period of 12 weeks. Conclusions: A single dose of 211At-MABG at 2.1 MBq/kg was well tolerated and demonstrated predictable PK. Preliminary antitumor activity was observed, including 1 PR during the 12-week period. These findings establish the clinical feasibility of 211At-MABG and provide a translational foundation for multidose, dose-escalation, and biomarker-stratified trials.