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Cancer Therapy: Clinical

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 Jr., William E. Gannon, Melissa Walker, Geoffrey D. Seidel, Nargiza Yuldasheva and Lawrence Tamarkin
Steven K. Libutti
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Giulio F. Paciotti
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Adriana A. Byrnes
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H. Richard Alexander Jr.
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William E. Gannon
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Melissa Walker
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Geoffrey D. Seidel
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Nargiza Yuldasheva
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Lawrence Tamarkin
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DOI: 10.1158/1078-0432.CCR-10-0978 Published December 2010
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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/m2 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/m2, 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. Clin Cancer Res; 16(24); 6139–49. ©2010 AACR.

Footnotes

  • Note: Current address for S.K. Libutti: Montefiore-Einstein Center for Cancer Care, Montefiore Medical Center/Albert Einstein College of Medicine, Greene Medical Arts Pavillion, 3400 Bainbridge Avenue, Bronx, New York.

  • Current address for H.R. Alexander: Department of Surgery, University of Maryland Medical Center, 22 S. Greene Street, Baltimore, Maryland.

  • Current address for N. Yuldasheva: Department of Internal Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts.

  • G.F. Paciotti and A.A. Byrnes contributed equally to the study.

  • Received April 15, 2010.
  • Revision received September 2, 2010.
  • Accepted September 15, 2010.
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Clinical Cancer Research: 16 (24)
December 2010
Volume 16, Issue 24
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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 Jr., William E. Gannon, Melissa Walker, Geoffrey D. Seidel, Nargiza Yuldasheva and Lawrence Tamarkin
Clin Cancer Res December 15 2010 (16) (24) 6139-6149; DOI: 10.1158/1078-0432.CCR-10-0978

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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 Jr., William E. Gannon, Melissa Walker, Geoffrey D. Seidel, Nargiza Yuldasheva and Lawrence Tamarkin
Clin Cancer Res December 15 2010 (16) (24) 6139-6149; DOI: 10.1158/1078-0432.CCR-10-0978
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