Pre-surgical Phase IIB Trial of Transdermal 4-Hydroxytamoxifen vs. Oral Tamoxifen in Women With Duct Carcinoma in Situ of the Breast
I. To demonstrate that once daily topical application of a gel formulation of
4-hydroxytamoxifen (4-OHT) to the breasts results in a reduction in the Ki-67 labeling index
of ductal carcinoma in situ (DCIS) lesions that is not inferior to that seen with oral
tamoxifen (TAM) 20 mg daily for 6-10 weeks, when comparing the base-line diagnostic core
needle biopsy (DCNB) to the therapeutic surgical excision (TSE) sample.
I. To compare concentrations of 4-OHT, endoxifen, TAM, its bisphenol metabolite, and
estradiol in breast adipose tissue and plasma obtained at surgery following 6-10 weeks of
II. To compare drug metabolite levels in the two study groups by CYP2D6 polymorphism status.
III. To demonstrate that 4-OHT affects known tamoxifen-modulated pathways in the breast and
plasma in a similar manner to TAM, using IHC and serum markers.
IV. To evaluate TAM metabolite concentrations and estrogen response markers in nipple
aspiration fluid (NAF) from the unaffected breast in relation to the same metabolites in
tissue samples from the affected breast.
V. To compare the incidence of hot flashes between the TAM and 4-OHT groups at baseline and
VI. To compare changes in coagulation related proteins in women on the gel and the oral arms
at baseline and before TSE.
VII. To compare E and Z isomers of 4-OHT in the plasma of oral and topical groups before
OUTLINE: This is a multicenter study. Patients are stratified according to participating
center (Northwestern University vs Duke University vs Washington University) and menopausal
status (pre- vs postmenopausal). Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive oral placebo once daily and apply topical 4-hydroxytamoxifen gel to
both breasts daily.
ARM II: Patients receive oral tamoxifen citrate once daily and apply topical placebo gel to
both breasts daily.
In both arms, treatment continues for 6-10 weeks before undergoing TSE.
At baseline and the day before or the day of TSE, patients complete the BESS questionnaire
for symptom assessment and blood and nipple aspirate samples are collected for further
After completion of study treatment, patients are followed up at 1 month.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Reduction in the Ki-67 labeling index
A 95% confidence interval will be computed.
Up to 1 month
United States: Food and Drug Administration
|Northwestern University||Chicago, Illinois 60611|