Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Chemoprevention is the use of certain drugs to keep cancer from forming, growing, or coming back. Estrogen can cause the growth of breast cancer cells. Hormone therapy using arzoxifene or tamoxifen may prevent breast cancer by lowering the amount of estrogen the body makes. The use of arzoxifene or tamoxifen may keep breast cancer from forming in women at high risk for breast cancer. PURPOSE: This randomized phase II trial is studying arzoxifene to see how well it works compared to tamoxifen or a placebo in preventing breast cancer in premenopausal women at high risk for breast cancer.

Detailed Description
-----------------
OBJECTIVES: Compare the effect of arzoxifene vs tamoxifen vs placebo on surrogate endpoints biomarkers, especially systemic insulin-like growth factor levels, in women at high risk for breast cancer. Compare the toxic effects, biologic effects, clinical pharmacology, and pharmacodynamics of these drugs in these participants. Determine the effect of these drugs on surrogate endpoint biomarkers in participants with BRCA1 and BRCA2 mutations. Determine the feasibility of a chemoprevention study in participants with a strong family history of breast cancer. OUTLINE: This is a randomized, placebo-controlled, double-blind study. Participants are randomized to 1 of 3 treatment arms. Arm I: Participants receive oral tamoxifen once daily. Arm II: Participants receive oral arzoxifene once daily. Arm III: Participants receive an oral placebo once daily. In all arms, treatment continues for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment with their assigned study drug for an additional 6 months. Participants randomized to receive placebo are offered treatment with arzoxifene for an additional 6 months. After completion of study treatment, participants are followed annually. PROJECTED ACCRUAL: A total of 120 participants will be accrued for this study.

Official Title
-----------------
A Phase II Study of a Selective Estrogen Receptor Modulator (LY353381) vs. Tamoxifen vs. Placebo in Premenopausal Women With and Increased Risk for Breast Cancer

Conditions
-----------------
Breast Cancer, Hereditary Breast/Ovarian Cancer (brca1, brca2)

Intervention / Treatment
-----------------
* Drug: arzoxifene hydrochloride
* Drug: tamoxifen citrate
* Other: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Estimated probability of carrying a BRCA1 or BRCA2 mutation ≥ 10% AND meets one of the following criteria: Participants must have first-degree relatives (FDRs)* or second-degree relatives (SDRs)* (with an intervening male relative) with breast or ovarian cancer who satisfy one of the following criteria: High-risk breast/ovarian cancer (non-Jewish families) One FDR ≤ 40 years old** diagnosed with breast cancer At least two FDRs or SDRs diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer One FDR or one SDR diagnosed with breast cancer at ≤ 50 years old OR had bilateral breast cancer AND one FDR or SDR diagnosed with ovarian cancer Three FDRs and/or SDRs diagnosed with breast or ovarian cancer (at least one in case of ovarian cancer) Two FDRs and/or SDRs diagnosed with ovarian cancer One male FDR or SDR diagnosed with breast cancer and one FDR or SDR (male or female) diagnosed with breast or ovarian cancer Moderate-risk breast /ovarian cancer (non-Jewish families) Two FDRs diagnosed with breast cancer with one ≤ 50 years old and/or both < 60 years old One FDR and one SDR (mother or sister and maternal aunt or maternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 118 years One FDR and one SDR (mother or sister and paternal aunt or paternal grandmother) diagnosed with breast cancer if the sum of their ages is ≥ 78 years Two SDRs (both maternal or both paternal) diagnosed with breast cancer if the sum of their ages is ≤ 98 years One FDR with ovarian cancer High-risk breast/ovarian cancer (Jewish families ) At least one FDR or SDR diagnosed with breast cancer at ≤ 50 years old At least one FDR or SDR diagnosed with ovarian cancer At least one FDR or SDR diagnosed with breast cancer at any age AND one FDR or SDR diagnosed with breast and/or ovarian cancer At least one male FDR or SDR diagnosed with breast cancer NOTE: *FDRs are parents, siblings, and children of the participant; SDRs are aunts, uncles, grandparents, grandchildren, nieces, nephews, or half siblings of the participant NOTE: **Age is approximated to the earliest age possible (e.g., a relative diagnosed in their 40's should be considered 40) Patterns of cancer cases must all be on the maternal or paternal side of the family Participants not meeting any of the above FDR or SDR criteria may provide medical documentation stating that they, a FDR, or a SDR carry BRCA1 or BRCA2 mutations Participants with a prior history of breast cancer are eligible provided they have a remaining breast that has not been irradiated, all therapy for breast cancer was completed more than 2 years ago, and they are premenopausal No ovarian cyst during screening No more than 12 months since prior Pap smear with normal cytological results OR human papilloma virus negative if atypical squamous cells of uncertain significance (ASCUS) present No higher degrees of atypia beyond ASCUS on Pap smear No known history of osteoporosis (bone mineral density > 1.5 standard deviations below young adult norms) Hormone receptor status Not specified PATIENT CHARACTERISTICS: Menopausal status Premenopausal, as defined by 1 of the following: Last menstrual period < 6 months ago Less than 45 years old AND underwent partial hysterectomy OR follicle-stimulating hormone within institutional pre-menopausal range within the past 3 months Sex Female Performance status ECOG 0-1 Life expectancy More than 2 years Hematopoietic WBC ≥ 3,000/mm^3 Platelet count ≥ 125,000/mm^3 Hemoglobin ≥ 10 g/dL Hepatic Bilirubin ≤ 1.5 mg/dL AST < 2 times upper limit of normal (ULN) Albumin ≥ 3.0 g/dL PT/PTT ≤ 1.25 times ULN Renal Creatinine ≤ 1.5 mg/dL OR Creatinine clearance ≥ 60 mL/min Cardiovascular No history of deep venous thrombosis Pulmonary No history of pulmonary embolism Other Not pregnant or nursing Negative pregnancy test Fertile participants must use effective barrier-method contraception during and for 3 months after completion of study treatment No other malignancy within the past 2 years except curatively treated basal cell or squamous cell skin cancer or cervical cancer ≤ stage I No known addiction Not undergoing treatment for an illicit drug addiction Willing and able to undergo required study procedures (e.g., research-related breast biopsies) PRIOR CONCURRENT THERAPY: Chemotherapy More than 2 years since prior chemotherapy Endocrine Therapy At least 3 months since prior oral contraceptives or intramuscular progestational agent At least 3 months since prior luteinizing-hormone releasing hormone (LHRH) agonists or antagonists if agent was administered daily or monthly At least 6 months since prior LHRH agonists or antagonists if agent was administered every 3 months At least 6 months since prior antiestrogens (e.g., tamoxifen, toremifene, and raloxifene) No concurrent progestational or contraceptive agents Radiotherapy See Disease Characteristics More than 2 years since prior radiotherapy Surgery No prior prophylactic bilateral mastectomy Other No concurrent cholestyramine No concurrent routine warfarin, bromocriptine, or phenobarbital No other concurrent investigational agents

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Participants receive oral tamoxifen once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment for an additional 6 months. | Drug: tamoxifen citrate<br>* Given orally<br>|
| Experimental: Arm II<br>Participants receive oral arzoxifene once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered the opportunity to continue treatment for an additional 6 months. | Drug: arzoxifene hydrochloride<br>* Given orally<br>|
| Placebo Comparator: Arm III<br>Participants receive an oral placebo once daily once daily for 6 months in the absence of disease progression or unacceptable toxicity. After the completion of 6 months of treatment, participants are offered treatment with arzoxifene for an additional 6 months. | Drug: arzoxifene hydrochloride<br>* Given orally<br>Other: placebo<br>* Given orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ki67 in breast tissue of enrolled patients | The primary endpoint was changed in Ki67 in breast tissue of enrolled patients |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity |  |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hereditary breast/ovarian cancer (BRCA1, BRCA2), breast cancer