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Investigational New Drugs

, Volume 30, Issue 6, pp 2391–2399 | Cite as

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

  • Daniel LaheruEmail author
  • Preeti Shah
  • N. V. Rajeshkumar
  • Florencia McAllister
  • Gretchen Taylor
  • Howard Goldsweig
  • Dung T. Le
  • Ross Donehower
  • Antonio Jimeno
  • Sheila Linden
  • Ming Zhao
  • Dongweon Song
  • Michelle A. Rudek
  • Manuel Hidalgo
PHASE II STUDIES

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.

Keywords

Salirasib Gemcitabine Pancreatic cancer Phase I RAS 

Notes

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

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Daniel Laheru
    • 1
    Email author
  • Preeti Shah
    • 1
  • N. V. Rajeshkumar
    • 1
  • Florencia McAllister
    • 1
  • Gretchen Taylor
    • 1
  • Howard Goldsweig
    • 2
  • Dung T. Le
    • 1
  • Ross Donehower
    • 1
  • Antonio Jimeno
    • 3
  • Sheila Linden
    • 1
  • Ming Zhao
    • 1
  • Dongweon Song
    • 4
  • Michelle A. Rudek
    • 1
  • Manuel Hidalgo
    • 5
  1. 1.Department of Medical Oncology, Skip Viragh Center for Pancreatic Cancer Research and Patient CareSidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA
  2. 2.BiovexWoburnUSA
  3. 3.University of Colorado Cancer CenterAuroraUSA
  4. 4.Novartis Pharmaceuticals CorporationFlorham ParkUSA
  5. 5.Centro Nacional de Investigaciones OncologicasUniversidad CEU San Pablo, Centro Integral Oncologia “Clara Campal”MadridSpain

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