Clinical trial NCT01196936: Low-Dose Tamoxifen Citrate in Reducing Breast Cancer Risk in Radiation-Induced Cancer Survivors
Official title: Low-Dose Tamoxifen for Radiation-Induced Breast Cancer Risk Reduction: A Phase IIB Randomized Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Cancer survivors
Low Dose Tamoxifen
Breast Cancer Risk Reduction
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: St. Jude Children's Research Hospital
name: University Health Network, Toronto
name: University of Michigan
name: Dana-Farber Cancer Institute
name: Mayo Clinic
name: University of Washington
name: City of Hope National Medical Center
name: M.D. Anderson Cancer Center
name: University of Chicago
name: University of Minnesota
name: University of Colorado, Denver
name: Wake Forest University
First posted: 2010-09-09
Enrollment: 84
Sex: FEMALE
Minimum age (years): 25
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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 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

Primary outcomes:
measure: Mammographic Breast Density
timeFrame: At year two post treatment
Secondary outcomes:
measure: Insulin Growth Factor Levels (IGF1)
timeFrame: Up to 2 years
measure: Number of Grade 2-4 Toxicities
timeFrame: Up to 2 years
measure: Biomarker Levels
timeFrame: Up to 2 years
measure: Percentage of Pills Taken Out of the Total Prescribed
timeFrame: Up to 2 years
measure: Number of Participants With Different Patient Reported Symptoms, Measured by Questionnaire
timeFrame: Up to 2 years
measure: Insulin Growth Factor Levels (IGF3 )
timeFrame: Up to 2 years
measure: Biomarker Levels - Alkaline Phosphatase
timeFrame: Up to 2 years
measure: Biomarker Levels - Urine N-telopeptide
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado, Anschutz Medical Campus
state: Colorado
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Toronto
country: Canada
facility: University Health Network, Toronto
state: Ontario
Study officials:
affiliation: University of Alabama at Birmingham
name: Smita Bhatia, MD
role: PRINCIPAL_INVESTIGATOR
References: