Preliminary results of a phase I clinical trial of CYT-6091: A pegylated colloidal gold-TNF nanomedicine

Abstract

3603 Background: CYT-6091, a nanotherapeutic manufactured by covalently linking tumor necrosis factor-a (TNF) onto the surface of 30 nm particles of pegylated colloidal gold, avoids uptake by the reticuloendothelial system (RES) and distributes primarily to solid tumors. In tumor bearing mice, CYT-6091 shows little to no uptake by the RES and increases intra-tumor TNF levels 10-fold. Electron micrographs show the accumulation of gold nanoparticles in tumors, with few particles in healthy tissue. In dogs with naturally occurring cancers and healthy rabbits, CYT-6091 caused fever but no hypotension, the known DLT for TNF. Methods: CYT-6091 is being tested in a phase I open label trial in solid tumor, advanced stage disease patients. Patients (n=3/dose), admitted to the NIH Clinical Center ICU, receive two IV injections of CYT-6091 on day 0 and 14. Doses start at 50 μg/m2 of TNF and increase by 50 μg/m2 increments to 300 μg/m2. Vital signs are monitored and blood samples are drawn over 48 hours. The primary endpoint of the study is to determine the MTD for CYT-6091. Secondary endpoints include PK, disease response (staged 45 days post treatment), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Seven patients have been treated to date. The three treated with the lowest dose (50 μg/m2) exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the seven patients treated with 50, 100 or 150 μg/m2 showed a DLT hypotensive response, and blood chemistries and urinalysis were not significantly different following treatment. PK estimates for the TNF T1/2, administered as CYT-6091, are 117, 145 and 127 minutes for 50, 100 and 150 μg/m2, respectively. Electron micrographs of tumor biopsies and adjacent healthy tissue show as much as a 10-fold increase in the number of gold nanoparticles in tumors from 5 of 6 patients compared to adjacent healthy tissue. Conclusion: These observations are the first definitive demonstration in man of the tumor targeting of a systemically administered, colloidal gold-based nanomedicine. No significant financial relationships to disclose.

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