LONDONIntermittent dosing with R115777 (tipifarnib, also known as Zarnestra) is equally effective as continuous dosing in advanced breast cancer patients, but has significantly less hematologic toxicity, according to a study presented at the American Society of Clinical Oncology 38th annual meeting (ASCO abstract 138).
"This is the first time this novel treatment involving signal transduction inhibition has been tried in a phase II study," said lead author Stephen R.D. Johnston, MD, consultant in medical oncology, Royal Marsden Hospital in London. "Breast is one of the cancers where Zarnestra may prove useful."
R115777 is a potent, orally active nonpeptidomimetic inhibitor of the enzyme farnesyl protein transferase. This class of compounds was initially developed as a therapeutic strategy for tumors with oncogenic Ras mutations because of their action at a key step in the post-translational processing of the Ras protein. By specifically blocking isoprenylation of proteins involved in growth factor dependent cellular signal transduction pathways, these compounds inhibit cell signaling in Ras-transformed cells.
Farnesyl transferase inhibitors have additional effects on other signaling pathways in cancer cells that may also prove useful against breast cancer and other tumors without oncogenic Ras mutations. R115777 in particular has been effective against a variety of breast tumor cell lines regardless of Ras status, and has reduced proliferation in human breast cancer xenografts in vivo.
Two Cohorts of Patients
In this study of 76 patients with locally advanced, recurrent, or progressive metastatic breast cancer, investigators sequentially recruited two cohorts of patients. The first cohort of 41 patients received a continuous dosing regimen of R115777 at 400 mg, later reduced to 300 mg, twice daily. The second cohort of 35 patients received an intermittent cyclical dosing regimen of R115777 at 300 mg twice daily for 21 days every 4 weeks, with 7 days of rest between treatments.
The two cohorts were well matched for demographic and clinical variables, with overall median age 53.5 years (range 32-82) and Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. Prior treatment for advanced disease was similar in both cohorts, including adjuvant endocrine therapy in two-thirds of both groups, and prior chemotherapy in 46% of those on continuous dosing vs 63% of those on intermittent dosing. No patients were deemed eligible for further endocrine therapy, because they had failed tamoxifen(Drug information on tamoxifen) or were estrogen-receptor negative.