Results Of A Completed Phase I Clinical Trial Of Cyt-6091: A Pegylated Colloidal Gold-Tnf Nanomedicine

3586 Background: CYT-6091 is the first tumor-targeted nanomedicine formulation designed to safely deliver an API that itself is not approved for systemic administration due to unacceptable toxicity. CYT-6091, consisting of tumor necrosis factor-α (TNF) covalently linked to pegylated colloidal gold nanoparticles, has been safely administered in preclinical models, demonstrating an increased T1/2 compared to native TNF, a documented trafficking of nanoparticles to tumor, and no hypotension, the known DLT for TNF. Methods: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients. Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 μg/m2 of TNF, up to 600 μg/m2. Vital signs were monitored and blood samples were drawn over 48 h. The primary endpoint of the study was to determine the MTD for CYT-6091. Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Twenty-nine patients were treated. Even at the lowest dose (50 μg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50–600 μg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen. T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 μg/m2, respectively (published T1/2 for native TNF is ∼27 minutes). In the 28 patients eligible for response assessment, there was 1 PR (100 μg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies. Conclusions: CYT-6091 is well tolerated at doses up to 600 μg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned. [Table: see text]