First-in-Human Study of [At]NaAt as Targeted α-Therapy in Patients with Radioiodine-Refractory Thyroid Cancer (Alpha-T1 Trial).

At, a cyclotron-produced α-emitter, has attracted interest as a potential alternative to radioactive iodine (RAI) because of its superior cytotoxic properties. This first-in-human prospective clinical trial aimed to evaluate the safety and preliminary efficacy of [At]NaAt in patients with differentiated thyroid cancer (DTC). Eleven patients with metastatic RAI-refractory DTC were enrolled in this study. A single intravenous dose of [At]NaAt was administered in the setting of recombinant human thyroid-stimulating hormone stimulation and an iodine-restricted diet. Dose escalation followed a modified 3 + 3 design, with doses of 1.25 ( = 2), 2.5 ( = 3), and 3.5 MBq/kg ( = 6). The primary endpoint was the assessment of adverse events using Common Terminology Criteria for Adverse Events version 5.0 guidelines and dose-limiting toxicities. Secondary endpoints included evaluation of pharmacokinetics, absorbed dose, and therapeutic efficacy. Dose-limiting toxicities occurred in 3 of 6 patients who received 3.5 MBq/kg, consisting of grade 3 hematologic toxicity (lymphopenia or leukopenia) lasting for more than 1 wk. Other major adverse events included salivary gland swelling (predominantly grade 2), xerostomia (grades 1 and 2), nausea (grade 2), decreased appetite (grade 2), and vomiting (grade 2). A reduction of greater than 50% in recombinant human thyroid-stimulating hormone-stimulated thyroglobulin levels was observed in 1 of 3 patients (33%) who received 2.5 MBq/kg and 2 of 5 patients (40%) who received 3.5 MBq/kg. At 6 mo, CT-based evaluation showed stable disease (SD) in 9 patients (90%) and progressive disease in 1 patient (10%). I SPECT imaging revealed SD in the only patient who received 1.25 MBq/kg. Of the 3 patients treated with 2.5 MBq/kg, a partial response was seen in 1 patient (33%) and SD in 2 patients (67%). Of the 5 patients who received 3.5 MBq/kg, complete response, partial response, and progressive disease were noted in 1 patient (20%) each, and SD was found in 2 patients (40%). Targeted α-therapy with [At]NaAt was well tolerated and showed preliminary efficacy in patients with RAI-refractory DTC, supporting further clinical investigations.