Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205.
BACKGROUND
Fulvestrant produces a clinical benefit rate (CBR) of approximately 45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib-fulvestrant combination in HR-positive MBC.


METHODS
Postmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1-21 every 28 days. The primary end point was CBR.


RESULTS
The CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%).


CONCLUSIONS
The target CBR of 70% for the tipifarnib-fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation.
Li
T
T
New York Cancer Consortium, Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA. tli@montefiore.org
Christos
P J
PJ
Sparano
J A
JA
Hershman
D L
DL
Hoschander
S
S
O'Brien
K
K
Wright
J J
JJ
Vahdat
L T
LT
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D016896:Treatment Outcome
D015363:Quinolones; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D000077267:Fulvestrant; D004958:Estradiol; D051231:Farnesyltranstransferase; C402769:tipifarnib