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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
  Purpose

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.


Condition Intervention Phase
Ductal Breast Carcinoma in Situ
Estrogen Receptor-positive Breast Cancer
Other: placebo
Drug: afimoxifene
Drug: tamoxifen citrate
Procedure: therapeutic conventional surgery
Other: questionnaire administration
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Pre-surgical Phase IIB Trial of Transdermal 4-Hydroxytamoxifen vs. Oral Tamoxifen in Women With Duct Carcinoma in Situ of the Breast

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Enrollment: 112
Study Start Date: March 2010
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Other: placebo
Given orally and topically
Other Name: PLCB
Drug: afimoxifene
Given topically
Other Name: 4-Hydroxy-Tamoxifen
Procedure: therapeutic conventional surgery
Undergo TSE
Other: questionnaire administration
Ancillary studies
Other: laboratory biomarker analysis
Correlative studies
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.

Other: placebo
Given orally and topically
Other Name: PLCB
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00952731

Locations
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
Investigators
Principal Investigator: Seema Khan Northwestern University
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00952731     History of Changes
Other Study ID Numbers: NCI-2013-00452, NCI-2013-00452, P30CA060553, CDR0000674368, NWU07-9-02, NCI 07-9-02, NWU07-9-02, P30CA060553, N01CN35157
Study First Received: August 4, 2009
Last Updated: January 31, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma
Carcinoma in Situ
Carcinoma, Ductal, Breast
Carcinoma, Intraductal, Noninfiltrating
Adenocarcinoma
Breast Diseases
Carcinoma, Ductal
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Ductal, Lobular, and Medullary
Neoplasms, Glandular and Epithelial
Skin Diseases
Afimoxifene
Citric Acid
Tamoxifen
Anticoagulants
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Bone Density Conservation Agents
Chelating Agents
Estrogen Antagonists
Estrogen Receptor Modulators
Hematologic Agents
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on November 20, 2014