A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

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, Re-188-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 Re-188-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 72h after intravenous injection of 111MBq of Re-188-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 T(1/2)z for Re-188-liposome in blood and plasma are 36.7314.00h and 52.0245.21h, 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 +/- 0.01mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of Re-188-liposome. Re-188-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 Re-188-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).