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

Steven K. Libutti, Giulio F. Paciotti, Adriana A. Byrnes, H. Richard Alexander, William E. Gannon, Melissa Walker, Geoffrey D. Seidel, Nargiza Yuldasheva, Lawrence Tamarkin

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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/m2 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.

Original languageEnglish (US)
Pages (from-to)6139-6149
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number24
DOIs
StatePublished - Dec 15 2010

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Nanomedicine
Gold Colloid
Pharmacokinetics
Tumor Necrosis Factor-alpha
Antipyretics
Maximum Tolerated Dose
Poisons
Neoplasms
Gold
Nanoparticles
Biopsy
Therapeutics
Hypotension
human TNF protein
CYT-6091
Electron Microscopy
Research Design
Fever
Clinical Trials
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Libutti, S. K., Paciotti, G. F., Byrnes, A. A., Alexander, H. R., Gannon, W. E., Walker, M., ... Tamarkin, L. (2010). Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clinical Cancer Research, 16(24), 6139-6149. https://doi.org/10.1158/1078-0432.CCR-10-0978

Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. / Libutti, Steven K.; Paciotti, Giulio F.; Byrnes, Adriana A.; Alexander, H. Richard; Gannon, William E.; Walker, Melissa; Seidel, Geoffrey D.; Yuldasheva, Nargiza; Tamarkin, Lawrence.

In: Clinical Cancer Research, Vol. 16, No. 24, 15.12.2010, p. 6139-6149.

Research output: Contribution to journalArticle

Libutti, SK, Paciotti, GF, Byrnes, AA, Alexander, HR, Gannon, WE, Walker, M, Seidel, GD, Yuldasheva, N & Tamarkin, L 2010, 'Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine', Clinical Cancer Research, vol. 16, no. 24, pp. 6139-6149. https://doi.org/10.1158/1078-0432.CCR-10-0978
Libutti, Steven K. ; Paciotti, Giulio F. ; Byrnes, Adriana A. ; Alexander, H. Richard ; Gannon, William E. ; Walker, Melissa ; Seidel, Geoffrey D. ; Yuldasheva, Nargiza ; Tamarkin, Lawrence. / Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 24. pp. 6139-6149.
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AU - Alexander, H. Richard

AU - Gannon, William E.

AU - Walker, Melissa

AU - Seidel, Geoffrey D.

AU - Yuldasheva, Nargiza

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