Phase I clinical trial of 64Cu-ATSM for malignant brain tumors.

2052 Background: Malignant brain tumors such as glioblastoma have poor prognosis. Current standard therapies such as surgery, radiotherapy, and chemotherapy were frequently insufficient. Hypoxic tissue microenvironments induced by rapid cellular growth within tumor lesions lead to treatment resistance. Methods: Eligible patients had a histological diagnosis of grade III/IV glioma, primary central nervous system malignant lymphoma (PCNSL), or grade II/III malignant meningioma based on the most recent pathological diagnosis prior to enrollment, or metastatic brain tumor based on clinical course or imaging. Diacetyl-bis( N 4 -methylthiosemicarbazone) radiolabeled with Cu-64 ( 64 Cu-ATSM) was synthesized as described elsewhere. 64 Cu-ATSM was administered intravenously once a week for 4 weeks. Adverse events were assessed using the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). The trial had a traditional single arm open-label 3 + 3 design with four 64 Cu-ATSM dose cohorts: 30, 60, 99, and 150 MBq/kg. The primary objective was to assess dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) of 64 Cu-ATSM. Overall survival (OS), progression-free survival (PFS), pharmacokinetics, and 64 Cu-ATSM effective radiation dose were evaluated as secondary endpoints. Results: In total, 20 patients were registered at National Cancer Center Hospital or Kanagawa Cancer Center. Eighteen patients who received 64 Cu-ATSM were included in the primary analysis. None of the 3 patients at 30 MBq/kg, 1 of 6 patients at 60 MBq/kg, and 1 of 6 patients at 99 MBq/kg developed DLT (grade 3 lymphocytopenia). Two of 3 patients at 150 MBq/kg developed DLT (grade 4 lymphocytopenia). Therefore, additional patient recruitment was terminated. The MTD was considered to be 99 MBq/kg. No serious adverse events caused by 64 Cu-ATSM administration were not reported. Median OS was 29.4 months and 1-year OS was 76.6%. Median PFS was 3.8 months and 1-year PFS was 19.0%. 64 Cu-ATSM was rapidly distributed to body organs after intravenous administration and subsequently disappeared gradually. The liver (0.23 mSv/MBq) received relatively high doses, with an estimated effective dose of 0.037 mSv/MBq. Conclusions: Intravenous administration of 64 Cu-ATSM was feasible and well tolerated in patients with malignant brain tumors. The recommended dose for future trials is 99 MBq/kg. The initial efficacy outcomes obtained in this study warrant more clinical evaluation of this new treatment approach for brain tumors with no currently available treatment options. Clinical trial information: jRCT2091220362 .