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Integrated preclinical and clinical development of S-trans, trans-farnesylthiosalicylic acid (FTS, Salirasib) in pancreatic cancer

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Summary

Purpose S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). Patients and methods In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200–800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients’ biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. Results Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. Conclusion The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

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Author’s Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this manuscript. Those relationships marked with a “C” were compensated.

Employment or Leadership position: None

Consultant or Advisory Role: Rudek (C)

Stock Ownership: None

Research Funding: Laheru, Rudek

Expert Testimony: None

Other remuneration: None

Author information

Author notes

  1. Antonio Jimeno

    Present address: University of Colorado Cancer Center, Aurora, CO, USA

  2. Dongweon Song

    Present address: Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA

  3. Manuel Hidalgo

    Present address: Centro Nacional de Investigaciones Oncologicas, Universidad CEU San Pablo, Centro Integral Oncologia “Clara Campal”, Madrid, Spain

Authors and Affiliations

  1. Department of Medical Oncology, Skip Viragh Center for Pancreatic Cancer Research and Patient Care, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting- Blaustein Cancer Research Building, Room 4M09, 1650 Orleans Street, Baltimore, MD, 21231, USA

    Daniel Laheru, Preeti Shah, N. V. Rajeshkumar, Florencia McAllister, Gretchen Taylor, Dung T. Le, Ross Donehower, Sheila Linden, Ming Zhao & Michelle A. Rudek

  2. Biovex, Woburn, MA, USA

    Howard Goldsweig

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  1. Daniel Laheru
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Corresponding author

Correspondence to Daniel Laheru.

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Disclaimers:

Funding for the study described in this manuscript was provided by Concordia Pharmaceuticals. Concordia Pharmaceuticals is a client of ClinOps, LLC, and Averion International Corp. At the time of the study, Dr. Rudek was a paid consultant to Averion International. The terms of this arrangement were being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Supported by:

Concordia Pharmaceuticals, Inc. This research was supported by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005). The project described was supported in part by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

Trial registration

Clinicaltrials.gov identifier: NCT00867230

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Laheru, D., Shah, P., Rajeshkumar, N.V. et al. Integrated preclinical and clinical development of S-trans, trans-farnesylthiosalicylic acid (FTS, Salirasib) in pancreatic cancer. Invest New Drugs 30, 2391–2399 (2012). https://doi.org/10.1007/s10637-012-9818-6

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  • DOI: https://doi.org/10.1007/s10637-012-9818-6

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