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 or were estrogen-receptor negative.