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A Multicenter Randomized Double-blind Trial of Targretin for Modifying Immunophenotypic Markers Related to Breast Cancer Progression in Breast Tissue From Genetically Identified High Risk Patients

Phase 1
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

A Multicenter Randomized Double-blind Trial of Targretin for Modifying Immunophenotypic Markers Related to Breast Cancer Progression in Breast Tissue From Genetically Identified High Risk Patients

Breast cancer is the most common malignant disease in women of the Western world. In the
U.S. more than 200,000 women will be diagnosed with breast cancer in the next year, and more
than a third of these will eventually die of the disease. Particularly worrisome is the
dramatically increasing incidence of this disease in the past ten years, which all cannot be
attributed to the early detection bias due to increasing use of screening mammography. Now,
one in nine women born in this country will be diagnosed with breast cancer during her
lifetime. Although new systemic treatments for established breast cancer may be reducing
mortality somewhat major breakthroughs have come slowly, and greater attention is now being
directed toward means of breast cancer prevention.

Epidemiologic studies have identified risk factors that are associated with an increased
risk of developing breast cancer. These include Western culture and obesity (providing a
link to dietary fat), family history, hormonal factors such as age at menarche or menopause
(ovariectomy before age 45 is protective), age at first full-term pregnancy, prolonged oral
contraceptive or postmenopausal estrogen use, exposure to radiation, benign breast disease,
and a history of previous breast biopsy. Of these, family history is perhaps the strongest
risk factor. It has long been known that breast cancer is in part a hereditary disease, and
that approximately 3-5% of breast cancer is due to strongly penetrant, single gene
inheritance. Over the past several years, a number of these genes have been cloned including
BRCA-1, BRCA-2, p53, and PTEN, the gene responsible for Cowden's disease. Of these genes,
BRCA-1 and BRCA- 2 are estimated together to be involved in 60 to 70% of all hereditary
breast cancer. Persons with these mutations have an approximate 50 to 80% lifetime risk of
developing breast cancer, and currently there are no preventive options except for surgical
mastectomy. It is therefore a high priority to identify new agents which might be able to
lower this very high risk.

In this study a dose of bexarotene (Targretin capsules) 200 mg/m2/day for 28 days was
selected for a number of reasons. Limiting exposure to 28 days would minimize risk to study
participants, while allowing enough time for relevant changes in biomarkers to occur. 300
mg/m2/day has been shown to be biologically active and therapeutic against cutaneous T-cell
lymphoma in humans. To increase safety while maintaining potential activity in normal breast
tissue, a dose of 200 mg/m2/day was chosen.

The anti-tumor action of retinoids, as well as their potential in chemoprevention, supports
the need to further identify the spectrum of responsive tumors, to identify the molecular
mechanisms associated with retinoid action, and to identify and develop new retinoids that
have unique properties and an improved therapeutic index.

Inclusion Criteria:

- Age > 18 years 2. All subjects must be female 3. Signed informed consent 4. >/- 10%
risk of carrying a BRCA-1 or BRCA-2 mutation. Risk will be estimated using the
probability models developed by Parmigiana, Couch, Myriad I, or Myriad II. The latter
three models require an affected proband; therefore, either the subject or a close
relative (the closest, youngest affected relative) can be used as the proband for the
purposes of calculating risk. If a relative is used as a substitute proband, the
subject's risk is estimated as the model risk for the relative, divided by 2 raised
to the power of the degree of relatedness. For example, suppose the subject's mother,
a first-degree relative, is her closest, youngest affected relative, and the Couch
estimate of risk for the mother is 16.2%. The subject's risk will be half of her
mother's [16.1/(2(1)) = 8.1%] and she would not be eligible. The risk for the subject
must be >/- 10%. Known mutation carriers are eligible regardless of their calculated
probability. A copy of a laboratory report stating results for known carriers must be
available for review as a source document. 5. If subjects are of reproductive
potential, they must be using a reliable contraceptive method or be sexually
abstinent. Reliable methods include tubal ligation, IUD, oral contraceptives, the
combination of spermicide and condom, or cervical cap and spermicide. Subjects must
fulfill these conditions beginning one month before beginning study medications and
ending one month after study termination. 6. Negative serum pregnancy test (bHCG)
done within one month of Day 1 and on Day 1 before study medication is taken. 7.
Adequate renal function, defined by serum creatinine within 1.5 times the
institution's upper limit of normal. 8. Adequate liver function, defined by total
bilirubin, SGOT, alkaline phosphatase and albumin, within 1.5 times the institutions
upper limits of normal. 9. Adequate bone marrow function, defined as a WBC > 4.0, a
platelet count > 100,000 and a hematocrit of >30. 10. Normal triglycerides for the
institution. 11. Normal TSH, T4. Patients on thyroid hormone supplementation are
eligible. 12. Have at least one breast that has never been involved with cancer and
has not been irradiated. 13. Willing to undergo 2 duplicate needle biopsies of the
breast. 14. Willing to have genetic testing for BRCA-1 and BRCA-2 mutations for
research purposes. Results will only be disclosed upon request of the participant.

Exclusion Criteria:

- Exclusion criteria: 1. Pregnancy, lactation or unwillingness to use a reliable
contraceptive method in women of childbearing potential. 2. Abnormal triglycerides,
greater than the institutional upper limit of normal. 3. Severe underlying chronic
illness or disease, such as uncontrolled diabetes. 4. Invasive cancer within the last
1 year, defined from the date of first diagnosis. 5. Current alcohol use >3
drinks/day. 6. History of pancreatitis. 7. Oral Vitamin A supplements greater than
the recommended daily requirement (5,000IU), therapeutic oral or topical Vitamin A
derivatives such as Accutane in the past 3 months prior to Day 1. 8. Tamoxifen or
other SERM use in the past 3 months prior to Day 1. 9. Postmenopausal hormone therapy
use, including estrogens or progestins in the past 3 months prior to Day 1. 10.
Chemotherapy for a neoplasm in the past 1 year. 11. Currently participating in a
study of an investigational agent. 12. Unwillingness to have BRCA-1 and BRCA-2
genetic testing for research purposes. 13. Medications known to be associated with
pancreatic toxicity or to increase triglyceride levels. 14. Biliary tract disease.
15. Uncontrolled hyperlipidemia. 16. Non-toxic goiter or thyroid enlargement.

Type of Study:


Study Design:

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

Outcome Measure:

The objective of this study is to determine whether Targretin, a novel selective synthetic retinoid, can modify immunophenotypic markers related to breast cancer progression in breast tissue from genetically identified high risk patients.

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Susan Hilsenbeck, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine


United States: Food and Drug Administration

Study ID:

H 9315



Start Date:

January 1999

Completion Date:

January 2012

Related Keywords:

  • Breast Cancer
  • immunophenotypic
  • targretin
  • breast
  • cancer
  • retinoid
  • Breast Neoplasms



Cancer Therapy and Research Center San Antonio, Texas  78229
Georgetown University Washington, District of Columbia  20007-2197
Baylor Breast Center Houston, Texas  77030
MDACC Houston, Texas  77030