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4-Hydroxytamoxifen or Tamoxifen Citrate in Treating Women With Newly Diagnosed Ductal Breast Carcinoma in Situ

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00952731
First received: August 4, 2009
Last updated: January 31, 2014
Last verified: October 2013

August 4, 2009
January 31, 2014
March 2010
September 2011   (final data collection date for primary outcome measure)
Reduction in the Ki-67 labeling index [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
A 95% confidence interval will be computed.
Demonstration that once daily topical 4-hydroxytamoxifen (4-OHT) gel application results in a reduction in the Ki-67 labeling index of ductal carcinoma in situ lesions that is not inferior to that seen with oral tamoxifen [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00952731 on ClinicalTrials.gov Archive Site
  • Concentrations of 4-OHT, endoxifen, TAM, its bisphenol metabolite, and estradiol [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Descriptive statistics and confidence intervals will be provided.
  • Drug metabolite levels in the two study groups by CYP2D6 polymorphism status [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Descriptive statistics and confidence intervals will be provided.
  • 4-OHT affects known tamoxifen-modulated pathways [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Descriptive statistics and confidence intervals will be provided.
  • TAM metabolite concentrations and estrogen response markers in nipple aspiration fluid (NAF) [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Descriptive statistics and confidence intervals will be provided.
  • Incidence of hot flashes [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Descriptive statistics and confidence intervals will be provided.
  • Changes in coagulation related proteins [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Descriptive statistics and confidence intervals will be provided.
  • E and Z 4-OHT isomers [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Descriptive statistics and confidence intervals will be provided.
  • Comparison of concentrations of 4-OHT, endoxifen, tamoxifen citrate, its bisphenol metabolite, and estradiol in breast tissue and plasma at the time of surgery [ Designated as safety issue: No ]
  • CYP2D6 polymorphism status and comparison of drug metabolite levels by polymorphism status [ Designated as safety issue: No ]
  • Affect of 4-OHT on known tamoxifen-modulated pathways in the breast and serum by IHC and plasma markers [ Designated as safety issue: No ]
  • Tamoxifen metabolite concentrations and estrogen response markers in nipple aspiration fluid samples from affected and unaffected breast [ Designated as safety issue: No ]
  • Comparison of incidence of hot flashes at baseline and before surgery [ Designated as safety issue: No ]
  • Comparison of changes in coagulation related proteins [ Designated as safety issue: No ]
  • Comparison of Z and E 4-OHT isomers in the plasma [ Designated as safety issue: No ]
Not Provided
Not Provided
 
4-Hydroxytamoxifen or Tamoxifen Citrate in Treating Women With Newly Diagnosed Ductal Breast Carcinoma in Situ
Pre-surgical Phase IIB Trial of Transdermal 4-Hydroxytamoxifen vs. Oral Tamoxifen in Women With Duct Carcinoma in Situ of the Breast

This randomized phase II trial is studying 4-hydroxytamoxifen to see how well it works compared with tamoxifen citrate in treating women with newly diagnosed ductal breast carcinoma in situ. Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the use of estrogen by the tumor cells. It is not yet known whether topical tamoxifen causes less damage to normal tissue than systemic tamoxifen in treating patients with ductal carcinoma in situ.

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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 intervention.

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 TSE.

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 analysis.

After completion of study treatment, patients are followed up at 1 month.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Ductal Breast Carcinoma in Situ
  • Estrogen Receptor-positive Breast Cancer
  • Other: placebo
    Given orally and topically
    Other Name: PLCB
  • Drug: afimoxifene
    Given topically
    Other Name: 4-Hydroxy-Tamoxifen
  • Drug: tamoxifen citrate
    Given orally
    Other Names:
    • Nolvadex
    • TAM
    • tamoxifen
    • TMX
  • Procedure: therapeutic conventional surgery
    Undergo TSE
  • Other: questionnaire administration
    Ancillary studies
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (placebo and afimoxifene)

    Patients receive oral placebo once daily and apply topical 4-hydroxytamoxifen gel to both breasts daily.

    In both arms, treatment continues for 6-10 weeks before undergoing TSE.

    Interventions:
    • Other: placebo
    • Drug: afimoxifene
    • Procedure: therapeutic conventional surgery
    • Other: questionnaire administration
    • Other: laboratory biomarker analysis
  • Active Comparator: Arm II (tamoxifen citrate and placebo)

    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.

    Interventions:
    • Other: placebo
    • Drug: tamoxifen citrate
    • Procedure: therapeutic conventional surgery
    • Other: questionnaire administration
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
112
Not Provided
September 2011   (final data collection date for primary outcome measure)

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 cancer
  • 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
Female
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00952731
NCI-2013-00452, NCI-2013-00452, P30CA060553, CDR0000674368, NWU07-9-02, NCI 07-9-02, NWU07-9-02, P30CA060553, N01CN35157
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Seema Khan Northwestern University
National Cancer Institute (NCI)
October 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP