Open Access Research

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

Thomas F Gajewski1*, April KS Salama2, Donna Niedzwiecki3, Jeffrey Johnson3, Gerald Linette4, Cynthia Bucher5, Michelle A Blaskovich5, Said M Sebti5, Frank Haluska6 and the Cancer and Leukemia Group B

Author Affiliations

1 The University of Chicago, Section of Hematology/Oncology, 5841 S. Maryland Ave., MC2115, Chicago, IL, 60637, USA

2 Duke University Medical Center, Section of Medical Oncology, Durham, NC, 27710, USA

3 CALGB Statistical Center, Durham, NC, 27710, USA

4 Washington University, St Louis, MO, USA

5 Drug Discovery Department, Moffitt Cancer Center, Tampa, FL, 33612, USA

6 ARIAD Pharmaceuticals, Inc., Cambridge, MA, 02139, USA

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Journal of Translational Medicine 2012, 10:246  doi:10.1186/1479-5876-10-246

Published: 10 December 2012

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

Keywords:
Melanoma; Farnesyltransferase inhibitor; Tipifarnib; R11577; RAS; T cell activation