First-in-human, open-label, single-arm phase 1 study of [211At] meta-astatobenzylguanidine in patients with pheochromocytoma or paraganglioma.

Abstract

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, alpha-emitting meta-astatobenzylguanidine labeled with astatine-211 (²¹¹At-MABG) has demonstrated encouraging non-clinical results in mice, yet its clinical potential remains unclear. This first-in-human, open-label, single-arm, phase 1 clinical study aimed to evaluate the safety, pharmacokinetics, and recommended dose of 211At-MABG. 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. No dose-limiting toxicities were observed during the 6-week evaluation period. The cumulative urinary excretion of 211At-MABG reached 65.0% within 72 h, indicating rapid systemic clearance. One, seven, and two patients exhibited a partial response, stable disease, and progressive disease, respectively, during a maximum follow-up period of 12 weeks. A single dose of 211At-MABG at 2.1 MBq/kg was well tolerated and demonstrated predictable pharmacokinetics. Preliminary antitumor activity was observed, including one partial response during the 12-week period. These findings establish the clinical feasibility of ²¹¹At-MABG and provide a translational foundation for multi-dose, dose-escalation, and biomarker-stratified trials.