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

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.

• Authors: Thomas F Gajewski, April K S Salama, Donna Niedzwiecki, Jeffrey Johnson, Gerald Linette, Cynthia Bucher, Michelle A Blaskovich, Said M Sebti, Frank Haluska, Cancer and Leukemia Group B
• Journal: Journal of translational medicine (J Transl Med) Vol. 10 Pg. 246 (Dec 10 2012) ISSN: 1479-5876 [Electronic] England
• PMID: 23228035 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)

Chemical References

• DNAJA1 protein, human
• Enzyme Inhibitors
• HSP40 Heat-Shock Proteins
• Quinolones
• Interferon-gamma
• Farnesyltranstransferase
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• tipifarnib

Topics

• Adult
• Aged
• Aged, 80 and over
• Biopsy
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Farnesyltranstransferase (antagonists & inhibitors, metabolism)
• Female
• HSP40 Heat-Shock Proteins (metabolism)
• Humans
• Interferon-gamma (biosynthesis)
• Male
• Melanoma (blood, drug therapy, enzymology, pathology)
• Middle Aged
• Neoplasm Staging
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Quinolones (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Signal Transduction (drug effects)
• Skin Neoplasms (blood, drug therapy, enzymology, pathology)
• T-Lymphocytes (drug effects)
• Treatment Outcome