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Denosumab

Patients receive denosumab SC q6m for up to 5 years in the absence of disease progression or unacceptable toxicity.

Patients receive placebo SC q6m for up to 5 years in the absence of disease progression.

Placebo

Quality-of-Life Assessment

Judy E. Garber, MD, MPH

Site Public Contact

Darcy V. Spicer

Marie E. Wood

Nicholas DiBella

Claudine Isaacs

Seema A. Khan

Katharine A. Yao

Kendrith M. Rowland

Lauren Nye

Nadine M. Tung

Judy E. Garber

Melissa L. Pilewskie

Kathleen J. Yost

Sandhya Pruthi

John A. Ellerton

Katherine D. Crew

Lori F. Gentile

Judith O. Hopkins

Sagar D. Sardesai

Susan M. Domchek

Phuong L. Mai

Rachel D. Wooldridge

Isabelle Bedrosian

Sarah V. Colonna

Kara K. Landry

Masey M. Ross

This phase III trial compares denosumab to placebo for the prevention of breast cancer in women with a BRCA1 germline mutation. A germline mutation is an inherited gene change which, in the BRCA1 gene, is associated with an increased risk of breast and other cancers. Denosumab is a monoclonal antibody that is used to treat bone loss in order to reduce the risk of bone fractures in healthy people, and to reduce new bone growths in cancer patients whose cancer has spread to their bones. Research has shown that denosumab may also reduce the risk of developing breast cancer in women carrying a BRCA1 germline mutation.

PRIMARY OBJECTIVE:

I. To evaluate the reduction in the risk of any breast cancer (invasive or ductal carcinoma in situ \[DCIS\]) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

SECONDARY OBJECTIVES:

I. To determine the reduction in the risk of invasive breast cancer in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

II. To determine the reduction in the risk of invasive triple negative breast cancer (TNBC) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

III. To determine the reduction in risk of ovarian, fallopian and peritoneal cancers (in women who have not undergone prophylactic bilateral salpingo-oophorectomy \[PBSO\]) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

IV. To determine the reduction in risk of other (i.e. non-breast and nonovarian) malignancies, including those known to be associated with BRCA1 germline mutations in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

V. To determine the reduction in the risk of clinical fractures in pre- and postmenopausal women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

VI. To compare rates of breast biopsies and rate of benign breast lesions in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive denosumab subcutaneously (SC) every 6 months (q6m) for up to 5 years in the absence of the development of breast cancer or unacceptable toxicity.

ARM B: Patients receive placebo SC q6m for up to 5 years in the absence of the development of breast cancer.

After completion of study treatment, patients are followed up every 12 months for 5 years.

Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation

BRCA-P: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, International Phase 3 Study to Determine the Preventive Effect of Denosumab on Breast Cancer in Women Carrying a BRCA1 Germline Mutation

Time to breast cancer (invasive or DCIS) will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model.

Will be compared between the two treatment arms using a stratified Cox proportional hazards regression model. Time to ovarian cancer will be analyzed in the overall group and in different strata (oral contraceptive use, hormone replacement therapy use, and menopausal status).

May be recommended as part of care based on a finding on mammogram, MRI, ultrasound or physical exam performed as part of monitoring for breast cancer. Will be compared between the two treatment arms via chi-square analysis.

Overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment will be reported per treatment arm.

National Cancer Institute (NCI)

Austrian Breast & Colorectal Cancer Study Group (ABCSG)

Alliance for Clinical Trials in Oncology

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Diabetes Mellitus

Diabetes Mellitus, Type 2

Micronutrients

Vitamins

Vitamin D

Cholecalciferol

Ergocalciferols

Trace Elements

Hormones

Calcium

Calcium, Dietary

Vitamin D3

Calciferol

Ergocalciferol

Vitamin D2

Vitamin D3 80 micrograms (3200 IU) per day

Vitamin D3 40 micrograms (1600 IU) per day

Tomi-Pekka Tuomainen, MD, PhD

Jyrki K Virtanen, PhD

Sari Voutilainen, PhD

The Finnish Vitamin D Trial (FIND) is a randomized, double-blind, placebo-controlled, 5-year supplementation study of the benefits and risks of vitamin D in the primary prevention of cardiovascular (CVD) and cancer among 18000 men 60 years or older and women 65 years or older.

\[Edit 25.3.2015: Due to difficulties in recruitment and funding, the study size is approximately 2500 subjects, with a 550 subject subgroup with more detailed examinations\]

The participants will be randomized to 3 groups with 6000 in each, with daily supplementation of either: 1) 40 µg/day (1600 IU) of vitamin D3, 2) 80 µg/day (3200 IU) of vitamin D3, or 3) placebo.

\[Edit 15.3.2015: The 2500 subjects are randomized in 3 groups, approximately 830 subjects per group.\]

Compliance, use of non-study drugs or supplements, diet, development of endpoints, and CVD and cancer risk factors will be assessed by questionnaires. Blood samples will be collected for assessment of effect modification by baseline 25-hydroxyvitamin D, as well as for future ancillary studies of genetic/biochemical hypotheses. Event data will be obtained by record linkage from the national computerized hospitalization registry.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Studying the Effect of Denosumab on Preventing Breast Cancer in Women With a BRCA1 Germline Mutation	NCT04711109	BRCA1 Mutation Breast Cancer Breast Diseases Breast Neoplasm... Breast Carcinom... Neoplasms	Denosumab Placebo Quality-of-Life...	25 Years - 55 Years	Alliance for Clinical Trials in Oncology
Finnish Vitamin D Trial (FIND)	NCT01463813	Cardiovascular ... Cancer	Vitamin D3 Vitamin D3 Placebo	60 Years -	University of Eastern Finland

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