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Pre-surgical Phase IIB Trial of Transdermal 4-Hydroxytamoxifen vs. Oral Tamoxifen in Women With Duct Carcinoma in Situ of the Breast

Phase 2
18 Years
Open (Enrolling)
Ductal Breast Carcinoma in Situ, Estrogen Receptor-positive Breast Cancer

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Trial Information

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
before TSE.

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.

Inclusion Criteria:

- Participants must have a diagnosis of estrogen receptor positive (more than 5% cells
staining for ER), grade 2 or 3 (using definition of Page and Lagios) ductal carcinoma
in situ (DCIS) with no evidence of invasion on diagnostic core needle biopsy within
the previous 60 days

- ECOG performance status =< 1(Karnofsky >= 70%)

- Leukocytes >= 3,000/uL

- Absolute neutrophil count (ANC) >= 1,500/uL

- Platelets >= 100,000/uL

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT) =< 1.5 X institutional ULN

- Creatinine within normal institutional limits

- Women of child-bearing potential must agree to practice barrier birth control,
abstinence, or use non-hormonal IUDs from the time that the first pregnancy test is
performed throughout the duration of the study and for three months after cessation
of study drug; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her study physician immediately

- Ability to understand and the willingness to sign a written informed consent document

- Ability and willingness to schedule surgical resection of DCIS lesion for 6-10 weeks
(42-70 days) following the start of study agent

- Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e.
tanning beds) for the 6-10 weeks of study agent dosing

Exclusion Criteria:

- Participants must not have palpable DCIS

- Participants should not have a mass lesion >= 5mm on mammogram or ultrasound, or an
area of calcifications greater than 5cm on mammogram

- Participants with DCIS of comedo subtype (i.e. solid DCIS, nuclear grade 3, and
confluent necrosis) will be excluded

- Participants with a prior history of, or at high risk to develop, thromboembolic
disease will be excluded

- Participants must not have taken exogenous sex hormones since biopsy diagnosing DCIS
and must agree not to use exogenous sex hormones while on study

- Participants must not have taken tamoxifen or other selective estrogen receptor
modulators (SERMs) within 2 years prior to entering the study; women who have
discontinued SERM therapy because of thromboembolic or uterine toxicity, will be
excluded regardless of duration of use

- Participants may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 4-hydroxytamoxifen or tamoxifen

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; women are excluded from enrolling within
3 months of the most recent pregnancy; women must avoid becoming pregnant in the 3
months following the use of study agent

- Women must not have breastfed within three months prior to DCNB; women must agree to
forego breastfeeding for three months following the use of study agent

- Participants must not have any dermatologic conditions resulting in skin breakdown in
the area of gel application

- Participants must not have a history of previous invasive or non-invasive breast

- Participants must not have had a breast reduction or augmentation within the 6 months
prior to first dose of study agents; patients who have had breast implants more than
6 months prior to first dose of study agents will be eligible

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Reduction in the Ki-67 labeling index

Outcome Description:

A 95% confidence interval will be computed.

Outcome Time Frame:

Up to 1 month

Safety Issue:


Principal Investigator

Seema Khan

Investigator Role:

Principal Investigator

Investigator Affiliation:

Northwestern University


United States: Food and Drug Administration

Study ID:




Start Date:

March 2010

Completion Date:

Related Keywords:

  • Ductal Breast Carcinoma in Situ
  • Estrogen Receptor-positive Breast Cancer
  • Breast Neoplasms
  • Carcinoma
  • Carcinoma in Situ
  • Carcinoma, Intraductal, Noninfiltrating
  • Carcinoma, Ductal, Breast



Northwestern UniversityChicago, Illinois  60611