Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)
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
Journal of Translational Medicine 2012, 10:246 doi:10.1186/1479-5876-10-246Published: 10 December 2012
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.
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.
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.
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