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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Gajewski, TF; Salama, AKS; Niedzwiecki, D; Johnson, J; Linette, G; Bucher, C; Blaskovich, MA; Sebti, SM; Haluska, F; Cancer and Leukemia Group B,

Published Date

  • December 10, 2012

Published In

Volume / Issue

  • 10 /

Start / End Page

  • 246 -

PubMed ID

  • 23228035

Pubmed Central ID

  • 23228035

Electronic International Standard Serial Number (EISSN)

  • 1479-5876

Digital Object Identifier (DOI)

  • 10.1186/1479-5876-10-246

Language

  • eng

Conference Location

  • England