First-in-human phase I study of hypoxia-targeting 64Cu-ATSM radioligand therapy in patients with malignant brain tumors (STAR-64)

Background Hypoxic microenvironments throughout tumors contribute to proliferation and resistance to chemoradiotherapy. Copper-64 diacetyl-bis( N 4 -methylthiosemicarbazone) ( 64 Cu-ATSM) is a first-in-class drug enabling hypoxia-targeting radioligand therapy with β − particles and high-linear energy transfer Auger electrons, originally employed for positron emission tomography imaging. We report the first-in-human study of 64 Cu-ATSM therapy in patients with recurrent brain tumors. Patients and methods This phase I dose-escalation trial (STAR-64, jRCT2091220362) evaluated intravenous 64 Cu-ATSM administered four times at 30, 60, 99, or 150 MBq/kg weekly in patients with recurrent malignant brain tumors, using the 3 + 3 design. Primary objectives were to assess dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD). Secondary objectives included efficacy, pharmacokinetics, and organ dosimetry. Results Eighteen patients received 64 Cu-ATSM: grade 3 glioma (anaplastic astrocytoma and anaplastic oligodendroglioma) 27.8%, grade 4 glioma (glioblastoma) 50%, malignant meningioma 11.1%, and metastatic brain tumors 11.1%. DLTs, consisting only of grade 3 lymphopenia, were observed in four patients: one at 60 MBq/kg, one at 99 MBq/kg, and two at 150 MBq/kg. The MTD was established as 99 MBq/kg. Two patients had a radiographic complete response by RECIST v1.1 with long-term survival: ≥45 months for a patient with anaplastic oligodendroglioma (60 MBq/kg) and ≥23 months for a patient with glioblastoma (99 MBq/kg). The 1-year and median overall survival (OS) were 76.6% and 29.4 months, respectively, in all 18 patients; 12 patients (66.7%) were long-term survivors of ≥12 months. Among nine patients with glioblastoma, the 1-year and median OS were 64.8% and 17.7 months, respectively, suggesting favorable preliminary outcomes compared with historical references. Pharmacokinetic and dosimetry analyses revealed a clinically favorable distribution and organ radiation doses of 64 Cu-ATSM, supporting the selected dosing regimen and schedule. Conclusions 64 Cu-ATSM therapy was well tolerated and demonstrated preliminary efficacy in patients with recurrent malignant brain tumors, particularly glioblastoma, supporting further evaluation in an ongoing phase III study (STEP-64, jRCT2031240090).