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

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

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  • 1The University of Chicago, Section of Hematology/Oncology, 5841 S, Maryland Ave, MC2115, Chicago, IL 60637, USA. tgajewsk@medicine.bsd.uchicago.edu

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.

PMID:
23228035
PMCID:
PMC3543225
DOI:
10.1186/1479-5876-10-246
[PubMed - indexed for MEDLINE]
Free PMC Article
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