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Research Articles

First-in-Man Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement

Josep Tabernero, Geoffrey I. Shapiro, Patricia M. LoRusso, Andres Cervantes, Gary K. Schwartz, Glen J. Weiss, Luis Paz-Ares, Daniel C. Cho, Jeffrey R. Infante, Maria Alsina, Mrinal M. Gounder, Rick Falzone, Jamie Harrop, Amy C. Seila White, Iva Toudjarska, David Bumcrot, Rachel E. Meyers, Gregory Hinkle, Nenad Svrzikapa, Renta M. Hutabarat, Valerie A. Clausen, Jeff Cehelsky, Saraswathy V. Nochur, Christina Gamba-Vitalo, Akshay K. Vaishnaw, Dinah W.Y. Sah, Jared A. Gollob and Howard A. Burris III
Josep Tabernero
Medical Oncology, Vall d'Hebron University Hospital
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  • For correspondence: jtabernero@vhebron.net
Geoffrey I. Shapiro
Medical Oncology, Dana-Farber Cancer Institute
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Patricia M. LoRusso
Oncology, Karmanos Cancer Institute
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Andres Cervantes
Department of Hematology and Medical Oncology, University Hospital Valencia
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Gary K. Schwartz
Laboratory of New Drug Development, Department of Medicine, Memorial Sloan-Kettering Cancer Center
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Glen J. Weiss
Cancer and Cell Biology, TGen
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Luis Paz-Ares
Medical Oncology, Hospital Universitario Virgen del Rocío
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Daniel C. Cho
Hematology and Oncology, Beth Israel Deaconess Medical Center
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Jeffrey R. Infante
Drug Development Unit, SCRI/Tennessee Oncology, PLLC
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Maria Alsina
Medical Oncology, Vall d'Hebron University Hospital
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Mrinal M. Gounder
Medicine, Memorial Sloan-Kettering Cancer Center
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Rick Falzone
Clinical, Alnylam Pharmaceuticals
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Jamie Harrop
Clinical, Alnylam Pharmaceuticals
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Amy C. Seila White
Research, Alnylam Pharmaceuticals
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Iva Toudjarska
Research, Alnylam Pharmaceuticals
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David Bumcrot
Research, Alnylam Pharmaceuticals
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Rachel E. Meyers
Research, Alnylam Pharmaceuticals
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Gregory Hinkle
Research, Alnylam Pharmaceuticals
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Nenad Svrzikapa
Research, Alnylam Pharmaceuticals
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Renta M. Hutabarat
Clinical, Alnylam Pharmaceuticals
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Valerie A. Clausen
Clinical, Alnylam Pharmaceuticals
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Jeff Cehelsky
Clinical, Alnylam Pharmaceuticals
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Saraswathy V. Nochur
Development, Alnylam Pharmaceuticals, Inc.
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Christina Gamba-Vitalo
Development, Alnylam Pharmaceuticals, Inc.
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Akshay K. Vaishnaw
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Dinah W.Y. Sah
Research, Alnylam Pharmaceuticals Inc
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Jared A. Gollob
Clinical Development, Alnylam Pharmaceuticals
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Howard A. Burris
Sarah Cannon Research Institute, Sarah Cannon Research Institute
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DOI: 10.1158/2159-8290.CD-12-0429
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Abstract

RNAi is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNPs) have proven effective in delivery of siRNAs to liver and tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in man, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and KSP, in cancer patients. Here we demonstrate detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in liver, pharmacodynamics suggestive of target downregulation, and antitumor activity including complete regression of liver metastases in endometrial cancer. In addition, we show that bi-weekly intravenous administration of ALN-VSP was safe and well-tolerated. These data provide proof of concept for RNAi therapeutics in man and form the basis for further development in cancer.

  • Received September 24, 2012.
  • Revision received December 26, 2012.
  • Accepted January 24, 2013.
  • Copyright © 2013, American Association for Cancer Research.
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Published OnlineFirst January 28, 2013
doi: 10.1158/2159-8290.CD-12-0429

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First-in-Man Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement
Josep Tabernero, Geoffrey I. Shapiro, Patricia M. LoRusso, Andres Cervantes, Gary K. Schwartz, Glen J. Weiss, Luis Paz-Ares, Daniel C. Cho, Jeffrey R. Infante, Maria Alsina, Mrinal M. Gounder, Rick Falzone, Jamie Harrop, Amy C. Seila White, Iva Toudjarska, David Bumcrot, Rachel E. Meyers, Gregory Hinkle, Nenad Svrzikapa, Renta M. Hutabarat, Valerie A. Clausen, Jeff Cehelsky, Saraswathy V. Nochur, Christina Gamba-Vitalo, Akshay K. Vaishnaw, Dinah W.Y. Sah, Jared A. Gollob and Howard A. Burris III
Cancer Discov January 28 2013 DOI: 10.1158/2159-8290.CD-12-0429

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First-in-Man Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement
Josep Tabernero, Geoffrey I. Shapiro, Patricia M. LoRusso, Andres Cervantes, Gary K. Schwartz, Glen J. Weiss, Luis Paz-Ares, Daniel C. Cho, Jeffrey R. Infante, Maria Alsina, Mrinal M. Gounder, Rick Falzone, Jamie Harrop, Amy C. Seila White, Iva Toudjarska, David Bumcrot, Rachel E. Meyers, Gregory Hinkle, Nenad Svrzikapa, Renta M. Hutabarat, Valerie A. Clausen, Jeff Cehelsky, Saraswathy V. Nochur, Christina Gamba-Vitalo, Akshay K. Vaishnaw, Dinah W.Y. Sah, Jared A. Gollob and Howard A. Burris III
Cancer Discov January 28 2013 DOI: 10.1158/2159-8290.CD-12-0429
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