Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

J Transl Med. 2012 Dec 10:10:246. doi: 10.1186/1479-5876-10-246.

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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biopsy
  • Cell Line, Tumor
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Farnesyltranstransferase / antagonists & inhibitors*
  • Farnesyltranstransferase / metabolism
  • Female
  • HSP40 Heat-Shock Proteins / metabolism
  • Humans
  • Interferon-gamma / biosynthesis
  • Male
  • Melanoma / blood
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / pathology*
  • Middle Aged
  • Neoplasm Staging
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinolones / administration & dosage
  • Quinolones / adverse effects
  • Quinolones / pharmacology
  • Quinolones / therapeutic use
  • Signal Transduction / drug effects
  • Skin Neoplasms / blood
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / pathology*
  • T-Lymphocytes / drug effects
  • Treatment Outcome

Substances

  • DNAJA1 protein, human
  • Enzyme Inhibitors
  • HSP40 Heat-Shock Proteins
  • Quinolones
  • Interferon-gamma
  • Farnesyltranstransferase
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • tipifarnib

Associated data

  • ClinicalTrials.gov/NCT00060125