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

Invest New Drugs. 2012 Dec;30(6):2391-9. doi: 10.1007/s10637-012-9818-6. Epub 2012 May 1.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT00867230.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacokinetics
  • Farnesol / administration & dosage
  • Farnesol / analogs & derivatives
  • Farnesol / blood
  • Farnesol / pharmacokinetics
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins p21(ras)
  • Salicylates / administration & dosage
  • Salicylates / blood
  • Salicylates / pharmacokinetics
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Salicylates
  • farnesylthiosalicylic acid
  • Deoxycytidine
  • Farnesol
  • gemcitabine
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins

Associated data

  • ClinicalTrials.gov/NCT00867230