Targeted inhibition of farnesyltransferase in locally advanced breast cancer: a phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide.
OBJECTIVE
To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo.


METHODS
Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination.


RESULTS
When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib.


CONCLUSIONS
Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.
Sparano
Joseph A
JA
New York Phase II Consortium, Albert Einstein Cancer Center, Montefiore Medical Center-Weiler Division, Department of Oncology, 2 S, Room 47-48, 1825 Eastchester Rd, Bronx, NY 10461, USA. jsparano@montefiore.org
Moulder
Stacy
S
Kazi
Aslamuzzaman
A
Vahdat
Linda
L
Li
Tianhong
T
Pellegrino
Christine
C
Munster
Pam
P
Malafa
Mokenge
M
Lee
David
D
Hoschander
Shira
S
Hopkins
Una
U
Hershman
Dawn
D
Wright
John J
JJ
Sebti
Said M
SM
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; D015363:Quinolones; D004317:Doxorubicin; D003520:Cyclophosphamide; D051231:Farnesyltranstransferase; C402769:tipifarnib