Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors (LDTam)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by City of Hope Medical Center
Sponsor:
Collaborators:
St. Jude Children's Research Hospital
University Health Network, Toronto
Emory University
University of Michigan
Dana-Farber Cancer Institute
Mayo Clinic
University of California, Los Angeles
University of Washington
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT01196936
First received: September 3, 2010
Last updated: June 4, 2014
Last verified: June 2014
  Purpose

Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells

This phase IIb trial studies how well low-dose tamoxifen citrate works in reducing breast cancer risk in radiation-induced cancer survivors.


Condition Intervention Phase
Breast Cancer
Drug: Tamoxifen Citrate
Drug: Placebo
Procedure: Digital mammography
Other: immunohistochemistry staining method
Other: pharmacological study
Other: laboratory biomarker analysis
Genetic: protein expression analysis
Procedure: fine-needle aspiration
Other: pharmacogenomic studies
Other: questionnaire administration
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Low-Dose Tamoxifen for Radiation-Induced Breast Cancer Risk Reduction: A Phase IIB Randomized Placebo-Controlled Trial

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Efficacy of low dose tamoxifen citrate in reducing mammographic breast density [ Time Frame: At year two post treatment ] [ Designated as safety issue: No ]
    Madena Software System. Will be compared between groups by applying the linear mixed effects model for bivariate normally distributed data.


Secondary Outcome Measures:
  • Proliferative index, defined as the number of cells with unequivocal nuclear staining (Ki-67 expression) out of a total number of ductal epithelial cells contained in RPFNA samples [ Time Frame: Baseline to up to 2 years ] [ Designated as safety issue: No ]
    Analyzed using longitudinal logistic regression with two time points. If cell counts are better approximated by a Poisson distribution, the longitudinal Poisson regression method.

  • Insulin growth factor levels [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    IGF1 and IGFBP3 will be treated as continuous measures. The linear mixed effects model for between group comparisons of measures from 3 time points will be applied. The unstructured mean model and linear in time model will be employed.

  • Number of grade 2-4 toxicities [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    Will be tabulated by treatment arm. Differences by treatment arm will be evaluated using Fisher exact tests.

  • Biomarker levels [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Total cholesterol, low and high density lipoprotein, triglycerides, anti-thrombin III enzymatic assay, and serum bone-specific alkaline phosphatase and urine n-telopeptide measurements will be treated as continuous variables. Transformed to normality as appropriate, the linear mixed effects model will be applied, using the unstructured mean model and linear in time model to assess the effects of low-dose tamoxifen on these measurements over time.

  • Treatment adherence, measured by number of pills taken out of the total prescribed [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The number of pills taken out of the total prescribed in a 3-month period will be modeled as a random effects binomial regression model. The binomial rates from 8 time points (month 3-24) will be modeled as unstructured mean model with 7 indicator variables as well as polynomial models over time. The random-intercept and the random intercept and slope models will be considered. The significance of the time indicators or parameters by treatment interaction will be evaluated for treatment difference in compliance.

  • Patient reported symptoms, measured by questionnaire [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The outcomes will be scored as a 5-point Likert-type scale (0-4) in response to questions on how much the patients are bothered by certain symptoms. The questionnaire will be administered every 6 months. The responses will be treated as normally distributed, as ordinal or dichotomized variable, and the linear mixed effects of general linear mixed model (GLMM) methods will be applied to compare changes between treatment groups. Piecewise models will also be fitted with join point at 6 months, considering linear and curvilinear trajectories between 6 and 24 month time points.


Other Outcome Measures:
  • Patient demographics [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The modifying effects of demographic, clinical, and molecular characteristics on efficacy and safety markers will be examined. A 3-way interaction of time by treatment by modifying variable will be included in the longitudinal model containing a two-way time by treatment group interaction. Modifying effects will be considered statistically significant if the three-way interaction is significant.

  • Clinical primary cancer treatment characteristics [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The modifying effects of demographic, clinical, and molecular characteristics on efficacy and safety markers will be examined. A 3-way interaction of time by treatment by modifying variable will be included in the longitudinal model containing a two-way time by treatment group interaction. Modifying effects will be considered statistically significant if the three-way interaction is significant.

  • Molecular characteristics [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    The modifying effects of demographic, clinical, and molecular characteristics on efficacy and safety markers will be examined. A 3-way interaction of time by treatment by modifying variable will be included in the longitudinal model containing a two-way time by treatment group interaction. Modifying effects will be considered statistically significant if the three-way interaction is significant.

  • Incidence of new breast cancer [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The frequency of events will be compared by treatment group in a 2x2 table using the Fisher exact test, stratified on CYP2D6 status. Poisson regression will also be used in cohort analysis to examine treatment differences in outcomes adjusted for covariates, including CYP2D6.

  • Incidence of DCIS diagnoses [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The frequency of events will be compared by treatment group in a 2x2 table using the Fisher exact test, stratified on CYP2D6 status. Poisson regression will also be used in cohort analysis to examine treatment differences in outcomes adjusted for covariates, including CYP2D6.

  • Incidence of clinical toxicity [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The frequency of events will be compared by treatment group in a 2x2 table using the Fisher exact test, stratified on CYP2D6 status. Poisson regression will also be used in cohort analysis to examine treatment differences in outcomes adjusted for covariates, including CYP2D6.


Estimated Enrollment: 230
Study Start Date: September 2010
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (tamoxifen citrate)
Patients receive tamoxifen citrate PO QD for 24 months in the absence of disease progression or unacceptable toxicity.
Drug: Tamoxifen Citrate
5 mg PO Daily
Other Name: Marketed under trade name Nolvadex as 10 mg and 20 mg tablets
Procedure: Digital mammography
Correlative studies
Other: immunohistochemistry staining method
Correlative Studies
Other: pharmacological study
Correlative Studies
Other: laboratory biomarker analysis
Correlative Studies
Genetic: protein expression analysis
correlative studies
Procedure: fine-needle aspiration
Correlative studies
Other: pharmacogenomic studies
correlative studies
Other: questionnaire administration
Ancillary studies
Placebo Comparator: Arm II (placebo)
Patients receive placebo PO QD for 24 months in the absence of disease progression or unacceptable toxicity.
Drug: Placebo
1 tablet daily
Procedure: Digital mammography
Correlative studies
Other: immunohistochemistry staining method
Correlative Studies
Other: pharmacological study
Correlative Studies
Other: laboratory biomarker analysis
Correlative Studies
Genetic: protein expression analysis
correlative studies
Procedure: fine-needle aspiration
Correlative studies
Other: pharmacogenomic studies
correlative studies
Other: questionnaire administration
Ancillary studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the impact of a two-year course of low-dose tamoxifen (tamoxifen citrate) administered at 5 mg per day on surrogate endpoint biomarkers of breast cancer (BC) risk, including: mammographic breast density (MBD), an established radiographic biomarker of BC risk; cytomorphology and proliferative index, tissue biomarkers closely linked to BC risk; and sex steroid hormones and insulin growth factors, circulating biomarkers of BC risk.

II. To establish safety and tolerability of this low-dose tamoxifen regimen, assessing both objective measures (lipid profiles, clotting factors and bone metabolism markers) and patient-reported outcomes.

III. To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year low dose tamoxifen intervention.

IV. To explore the relationship between this low-dose tamoxifen regimen and clinical measures of efficacy (new breast cancer and ductal carcinoma in situ [DCIS] diagnoses) and toxicity (thromboembolic events, reports of hot flashes and gynecological symptoms, liver function abnormalities, and other cancer diagnoses).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive tamoxifen citrate orally (PO) once daily for 24 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO once daily for 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically for up to 10 years.

  Eligibility

Ages Eligible for Study:   25 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Exposure to radiation therapy (RT) delivered to the chest, axilla, and/or supraclavicular areas at a cumulative dose of 12 Gy or more by age 40 years; in addition, patients who received total body irradiation by age 40 may be considered
  • No evidence of active disease from their primary cancer for at least 2 continuous years prior to registration; the indication for RT is not specified but cannot be for primary breast cancer; common examples include, but are not limited to: lymphoma, leukemia, sarcoma, and Wilms tumor occurring in pediatric patients, and lymphoma, leukemia, and sarcoma occurring in young adults; primary cancer therapy must have been completed at least 6 months prior to registration
  • Well-defined menopausal status falling into one of the following categories:

    • Premenopausal, defined as age at registration 45 years old or younger with regular monthly period for at least 6 consecutive months prior to registration
    • Postmenopausal, defined as continuous absence of menstruation for 12 months OR status-post bilateral oophorectomy OR follicle stimulating hormone (FSH) level in the postmenopausal range

Exclusion Criteria:

  • Subsequent malignant neoplasm (SMN) other than those listed below diagnosed within 2 years of study entry; patients with the listed indolent or pre-invasive neoplasms may be eligible if diagnosed within 2 years and all treatment was completed at least 6 months prior to registration:

    • Non-melanoma cancers of the skin
    • Thyroid cancer
    • Cervical cancer confined to the cervix or cervical intraepithelial neoplasia (CIN)
    • Ductal carcinoma in situ (DCIS) or breast intraepithelial neoplasia (IEN) (includes atypical hyperplasia and lobular carcinoma in situ [LCIS]), or
    • Superficial or non-invasive transitional cell carcinoma of the bladder
  • For women with a prior history of DCIS or breast IEN, only one breast could have been involved and all therapy must have been completed at least 6 months prior to registration; in addition women with a prior history of invasive breast cancer may also be eligible, as long as only one breast was involved, they were diagnosed at least 2 years prior to study entry, and therapy was completed at least 6 months prior to study entry
  • Bilateral breast implants or status-post bilateral prophylactic mastectomy
  • Evidence of malignant breast disease on any form of breast imaging; the study only requires annual mammography; however, annual breast magnetic resonance imaging (MRI) is considered standard of care in this patient population (per Children's Oncology Group [COG] or National Comprehensive Cancer Network [NCCN] follow-up guidelines), and breast ultrasound may be indicated if a palpable lesion is detected on screening clinical breast exam; abnormal imaging may require additional radiographs and/or breast biopsy; patients who are found to have benign breast disease with or without atypia may continue on study as long as there is no evidence of malignancy; if there is evidence of malignancy, and only one breast is involved, they may be reapproached 6 months after completion of therapy for consideration of the trial
  • Baseline categorical mammographic density scored as BIRAD 1, or extremely fatty, in both breasts; if the patient has a prior history of IEN (DCIS, LCIS, or atypical hyperplasia), the contralateral breast must not have a mammographic density score of BIRAD 1; this determination will be made at the local site
  • Current or recent use (within 6 months of registration or baseline mammogram, whichever is first) of any of the following: systemic hormone replacement therapy (includes oral or transdermal formulations); Vagifem and Estring, two formulations of locally applied vaginal estrogen associated with minimal systemic absorption, may be allowed; other estrogen-containing vaginal creams, while not an exclusion, should be avoided whenever possible; patients with a history of hormone modifying herbal supplements are eligible, but patients will be asked to avoid their use after on study
  • Current or recent use (within 6 months of registration or baseline mammogram, whichever is first) of any of the following: hormonal forms of contraception (includes oral, transdermal, implanted, and injectable formulations): selective estrogen receptor modifiers; aromatase inhibitors; GnRH analogs; androgens or antiandrogens
  • Concurrent use of warfarin and strong inhibitors or CYP2D6 will not be allowed
  • A personal history or a strong family of thromboembolism, including deep venous thrombosis (DVT), pulmonary embolus (PE), or cerebrovascular accident (CVA); a personal history of transient ischemic attack (TIA) or retinal vein thrombosis will also not be allowed; in addition, patients with a condition known to increase hypercoagulability, such as Factor V Leiden disease, will be excluded; patients with atrial fibrillation will be excluded, due to risk of CVA, but patients with coronary artery disease or congestive heart failure without atrial fibrillation will be allowed to participate
  • Current intrauterine pregnancy or plans to become pregnant within two years; in addition, currently nursing mothers will be excluded
  • Serum creatinine > 2X the institutional norm
  • Total bilirubin > 2X the institutional norm
  • Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) > 2X the institutional norm
  • Unable to provide consent
  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: NCT01196936

Contacts
Contact: Michelle Banzet, MA 800 250-8430 survivortrial@coh.org
Contact: Zahira Hernandez, NP 800 250-8430 survivortrial@coh.org

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Smita Bhatia, MD, MPH    800-826-4673    becomingapatient@coh.org   
Principal Investigator: Smita Bhatia, MD, MPH         
Sub-Investigator: F. Lennie Wong, PhD         
University of California at Los Angeles (UCLA ) Recruiting
Los Angeles, California, United States, 90095
Contact: Patricia Ganz    310-206-1404    pganz@ucla.edu   
Principal Investigator: Patricia Ganz         
United States, Georgia
Emory University School of Medicine Withdrawn
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Tara Henderson, MD    773-702-5192      
Principal Investigator: Tara Henderson, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Judy Garber    617-632-2282    judy_garber@dfci.harvard.edu   
Principal Investigator: Judy Garber         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109-5718
Contact: Sofia Merajver, MD, PhD    734-936-6884    smerajve@umich.edu   
Principal Investigator: Sofia Merajver, MD, PhD         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Anne H. Blaes, MD    612-626-8138    blaes004@umn.edu   
Principal Investigator: Anne H. Blaes, MD         
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Sandhya Pruthi, MD    507-293-1605    Pruthi.sandhya@mayo.edu   
Principal Investigator: Sandhya Pruthi, MD         
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Melissa Hudson, MD    901-595-4644    melissa.hudson@stjude.org   
Principal Investigator: Melissa Hudson, MD         
United States, Texas
MD Anderson Recruiting
Houston, Texas, United States, 77030
Contact: Diane M. Weber    713-563-5752    DWeber@mdanderson.org   
Principal Investigator: Therese B. Bevers, MD         
United States, Washington
Seattle Cancer Care Alliance Recruiting
Seattle, Washington, United States, 98109
Contact: Larissa Korde    206-288-7409    lkorde@u.washington.edu   
Principal Investigator: Larissa Korde         
Canada, Ontario
University Health Network, Toronto Active, not recruiting
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
City of Hope Medical Center
St. Jude Children's Research Hospital
University Health Network, Toronto
Emory University
University of Michigan
Dana-Farber Cancer Institute
Mayo Clinic
University of California, Los Angeles
University of Washington
Investigators
Principal Investigator: Smita Bhatia, MD, MPH City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT01196936     History of Changes
Other Study ID Numbers: 08218, R01CA140245-01, NCI-2010-01976
Study First Received: September 3, 2010
Last Updated: June 4, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by City of Hope Medical Center:
Cancer survivors
Low Dose Tamoxifen
Breast Cancer Risk Reduction

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms, Radiation-Induced
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Radiation Injuries
Wounds and Injuries
Citric Acid
Tamoxifen
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Estrogen Receptor Modulators
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on August 28, 2014