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内容記述 |
Introduction: Recurrent malignant brain tumors have a poor prognosis due to limited responses to current treatments, including repeated surgery, re-radiation, and chemotherapy. Hypoxic tissue microenvironments are frequently observed in these aggressive diseases and significantly contribute to their progression and recurrence. Radioactive Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) was initially developed for positron emission tomography (PET) imaging of tumor hypoxia. Among radioactive Cu-ATSM compounds, 64Cu-ATSM has shown promise as a therapeutic agent due to its emission of positrons, β-particles, and Auger electrons. This phase I clinical trial (the STAR-64 study; jRCT registration number: 2091220362) is the world’s first one to evaluate the safety and efficacy of 64Cu-ATSM as a therapeutic agent.Methods: This study was approved by the institutional review boards of National Cancer Center and Kanagawa Cancer Center, and written informed consent was obtained from all participants. Patients were eligible if they had histologically confirmed glioma (Grade III or higher), primary central nervous system malignant lymphoma, or malignant meningioma (Grade II/III). Patients with metastatic brain tumors diagnosed via clinical or imaging criteria were also eligible. 64Cu-ATSM was synthesized using previously established methods. Therapeutic doses ranging from 30 to 150 MBq/kg were administrated intravenously to eligible patients once a week for 4 weeks. The primary endpoint was to determine the maximum tolerated dose (MTD) of 64Cu-ATSM by assessing dose-limiting toxicities (DLTs). Secondary endpoints included overall response, overall survival (OS), progression-free survival (PFS), pharmacokinetics, effective radiation dose, and safety. Pharmacokinetic and biodistribution data were collected in nine patients for up to 48 hours following one of the four weekly administrations. Radiometabolites in plasma and urine were analyzed via thin-layer chromatography. Organ-absorbed doses and effective dose (mSv/MBq) were estimated using OLINDA/EXM software.Results: Twenty patients were enrolled, and 18 were included in the full analysis set. Among them, 9 had glioblastoma, 4 had anaplastic astrocytoma, 1 had anaplastic oligodendroglioma, 2 had malignant meningioma, and 2 had metastatic brain tumors. Intravenously administered 64Cu-ATSM was well tolerated, with an MTD of 99 MBq/kg and no serious adverse events reported. Grade >3 adverse events were observed in 12 patients with lymphocyte count decreased (n=10), seizure (n=2), neutrophil count decreased (n=1), and hyponatremia (n=1).In the full analysis set, two complete responses, nine stable diseases, and seven progressive diseases were observed. The median OS was 29.4 months, and the 1-year OS rate was 76.6 %. Fourteen of 18 patients survived more than 6 months, and 12 survived beyond 1 year. For the subgroup of 9 patients with glioblastoma, the median OS was 17.7 months, and the 1-year OS rate was 64.8 %. The median PFS was 3.8 months, and 1-year PFS was 38.1%.64Cu-ATSM rapidly distributed throughout the body, exhibiting an elimination half-life of approximately 15 hours and a total body clearance of 58.7 mL/h/kg. Pharmacokinetic parameters were not dose-dependent. 64Cu-ATSM remained stable in plasma for 24 hours, although 64Cu dissociated from ATSM in urine. High accumulation was observed in the liver and intestines, while urinary and fecal excretion of radioactivity was minimal (<5%) within 48 hours. The estimated effective dose was 0.037 mSv/MBq.Conclusions: This study demonstrated that intravenous 64Cu-ATSM administration is feasible, well tolerated, and associated with encouraging clinical outcomes in patients with malignant brain tumors. The recommended therapeutic dose was determined to be 99 MBq/kg, with absorbed doses to all organs and tissues estimated to be below threshold levels. Randomized trials are warranted to further evaluate the safety and efficacy of 64Cu-ATSM in this patient population. |
