Lebowitz PF, Eng-Wong J, Widemann BC, Balis FM, Jayaprakash N, Chow C, Clark
G, Gantz SB, Venzon D, Zujewski J.
Medical Oncology Clinical Research Unit, National Cancer Institute/NIH, 9000
Rockville Pike, Bethesda, MD 20892, USA. peter.lebowitz@nih.gov
PURPOSE: Farnesyltransferase (FTase) inhibitors, which were designed to inhibit
oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer
models. We studied the safety and toxicity of tipifarnib in combination with
tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics
of tipifarnib were also assessed.
PATIENTS AND METHODS: Patients with metastatic, hormone receptor-positive breast
cancer were enrolled. Two cohorts of patients were treated with tipifarnib at
either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once
daily) was started after 1 week of tipifarnib monotherapy to perform
pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear
cells with tipifarnib alone and with tipifarnib and tamoxifen.
RESULTS: A total of 12 heavily pretreated patients with prior progression on
hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose
level of tipifarnib. At the 300-mg dose, all six patients required dose
reduction of tipifarnib due to toxicities that included grade 2 nausea, rash,
and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and
pharmacodynamic variables were similar in the presence and absence of tamoxifen.
Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood
mononuclear cells. Of the 12 patients treated, there were two partial responses
and one stable disease for >6 months.
CONCLUSIONS: Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20
mg once daily) can be given safely with minimal toxicity. Tamoxifen does not
have a significant effect on tipifarnib pharmacokinetics.
Source :
http://www.docguide.com/news/content.nsf/PaperFrameSet?OpenForm&newsid=8525697700573E1885256FAA002DA232&topabstract=1&u=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15709195