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

Journal of Translational Medicine

Frank Haluska¹  Said M Sebti⁴  Michelle A Blaskovich⁴  Cynthia Bucher⁴  Gerald Linette⁵  Jeffrey Johnson³  Donna Niedzwiecki³  April KS Salama⁶  Thomas F Gajewski² 

[1] ARIAD Pharmaceuticals, Inc., Cambridge, MA, 02139, USA;The University of Chicago, Section of Hematology/Oncology, 5841 S. Maryland Ave., MC2115, Chicago, IL, 60637, USA;CALGB Statistical Center, Durham, NC, 27710, USA;Drug Discovery Department, Moffitt Cancer Center, Tampa, FL, 33612, USA;Washington University, St Louis, MO, USA;Duke University Medical Center, Section of Medical Oncology, Durham, NC, 27710, USA

关键词: T cell activation;    RAS;    R11577;    Tipifarnib;    Farnesyltransferase inhibitor;    Melanoma;   

Others  :  828517
DOI  :  10.1186/1479-5876-10-246

 received in 2012-10-11, accepted in 2012-11-30,  发布年份 2012

【 摘 要 】

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

【 授权许可】

   
2012 Gajewski et al.; licensee BioMed Central Ltd.

【 图 表 】

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