Abstract
BackgroundLiposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use.This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions.ResultsThe T½z for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188Re-liposome. 188Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response.ConclusionThis phase 0 exploratory IND study shows that nanocarrier 188Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial.Trial registrationTaiwan FDA MA1101G0 (Jan 31, 2012).
Highlights
Cancer is a leading cause of death worldwide, and there is a crucial need for effective treatments [1]
Patient selection An open-label, single-arm phase 0 trial was conducted at Taipei Veterans General Hospital (TVGH), Taipei, Taiwan, following the guidelines for exploratory IND study that were published by the US Food and Drug Administration (FDA) in 2006 [35] and approved by the Taiwanese FDA and the Institutional Review Board of the TVGH
The results show good tumor targeting, pharmacokinetics, biodistribution, and dosimetry for the intravenous administration of 111 MBq 188Re-liposome in a subset of 12 cancer patients who had exhausted all available therapies for their metastatic cancer
Summary
Cancer is a leading cause of death worldwide, and there is a crucial need for effective treatments [1]. Many of the pharmacological properties of conventional chemotherapy drugs are improved by using this drug delivery system, which is composed primarily of lipids and/or polymers These novel therapeutic complexes improve the pharmacokinetics (PK), biodistribution (BD), and safety (lower toxicity) of the coupled chemotherapeutic drugs. In several preclinical studies with various tumor-bearing mice models, 188Reliposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial
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