title: Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104).
abstract: BACKGROUND
  Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued.
  
  
  METHODS
  A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0-1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7.
  
  
  RESULTS
  Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production.
  
  
  CONCLUSIONS
  Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT00060125.
authors.affiliation: The University of Chicago, Section of Hematology/Oncology, 5841 S, Maryland Ave, MC2115, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
authors.forename: April K S
authors.initials: AK
authors.lastname: Salama
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Johnson
authors.forename: Gerald
authors.initials: G
authors.lastname: Linette
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bucher
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Frank
authors.initials: F
authors.lastname: Haluska
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: C107481:DNAJA1 protein, human; D004791:Enzyme Inhibitors; D050956:HSP40 Heat-Shock Proteins; D015363:Quinolones; D007371:Interferon-gamma; D051231:Farnesyltranstransferase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C402769:tipifarnib