title: Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in patients with refractory hematologic malignancies.
abstract: BACKGROUND
  Rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme.
  
  
  METHODS
  We report on a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1 to 21 of a 28-day cycle in a "3+3" dose escalation design.
  
  
  RESULTS
  Seventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1-29). Three patients each were enrolled at a dose level of 100, 200, 400, 600, and 800 mg twice daily and 2 patients at a dose level of 900 mg twice daily. No dose-limiting toxicities were encountered. Grade 1/2 diarrhea was the only frequent nonhematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral antidiarrheal agents. Eight (47%) patients (4 with myelodysplastic syndrome, 2 with acute myeloid leukemia, 1 with chronic myelomonocytic leukemia, and 1 with chronic myeloid leukemia) had hematological improvement; 1 in 3 lineages, 1 in 2 lineages, and 6 in 1 lineage. None of the patients achieved complete remission. The responses lasted for a median of 10 weeks (range, 5-115). The study was discontinued because of financial constraints.
  
  
  CONCLUSIONS
  Salirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be used in combination therapy.
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.
authors: Talha
authors: T
authors: Badar
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.
authors: Jorge E
authors: JE
authors: Cortes
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.
authors: Farhad
authors: F
authors: Ravandi
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.
authors: Susan
authors: S
authors: O'Brien
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.
authors: Srdan
authors: S
authors: Verstovsek
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.
authors: Guillermo
authors: G
authors: Garcia-Manero
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.
authors: Hagop
authors: H
authors: Kantarjian
authors: Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. Electronic address: gborthak@mdanderson.org.
authors: Gautam
authors: G
authors: Borthakur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D005204:Farnesol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D011905:Genes, ras / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D012459:Salicylates / Q000008:administration & dosage / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D016896:Treatment Outcome; D048490:raf Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D048490:raf Kinases
keywords: Farnesylation; Leukemia; RAS mutation; RAS/RAF/MAPK activation; Targeted therapy