Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine

Abstract

Purpose: A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients.

Experimental design: CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart.

Results: Doses from 50 μg/m(2) to 600 μg/m(2) were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 μg/m(2), did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNF's dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue.

Conclusions: These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers.

Figure 1

CYT-6091 induces a predictable redistribution of lymphocytes and neutrophils. All patients from all the dosing groups of CYT-6091 were sorted into three dose cohorts: HIGH (400, 500, 600 μg/m²), MEDIUM (200, 250, 300 μg/m²), and LOW (50, 100, 150 μg/m²). Data are presented as the mean±S.E.M for the counts from two of the three dosing cohorts.

Figure 2

Effect of CYT-6091 on blood pressure (BP). Patients were grouped into three cohorts as described in Figure 1. Data are presented as the mean±S.E.M. Mean systolic BP did not drop below 80 mmHg, a threshold for hypotension requiring medical intervention.

Figure 3

Electron micrographs from a patient with inoperable ductal carcinoma of the breast. Magnification is 20,000 X, and the line at the bottom is 0.4 μm. Black dots in the tumor micrograph are nanoparticles of gold.