ABCSG 50 / BRCA-P Details

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.

Start:: 07/2019
Status:: open
Sample size:: 2.918 (international)

Design:

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Primary Objective:

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

Secondary Objectives:

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.
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.
To determine the reduction in the risk of ovarian, fallopian and peritoneal cancers (in women who have not undergone PBSO) in women with germline BRCA1 mutation who are treated with denosumab compared to placebo.
To determine the reduction in the risk of other (i.e. non-breast and non-ovarian) 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.
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.
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.

Safety Objective:

To determine the safety profile of denosumab delivered at the study dose compared to placebo in pre- and postmenopausal women with germline BRCA1 mutation.

Exploratory Objectives:

To determine the reduction in the risk of osteopenia and osteoporosis in pre- and postmenopausal women with germline BRCA1 mutation during denosumab treatment compared to placebo at sites/ countries where DXA is SoC or funded.
To identify serological and other markers that allow early diagnosis of breast cancer in BRCA1 mutation carriers.
To study the genetic, epigenetic, and phenotypic characteristics of cancers that occur during denosumab/placebo treatment.
To study changes in bone turnover markers in pre- and postmenopausal women during denosumab/placebo treatment.
To study changes in hormone biomarkers including RANKL, OPG, LH, FSH, E2 and progesterone.
To study changes in breast mammographic density, or breast background parenchymal enhancement on MRI using a BIRADs score.
To evaluate SNPs that have been associated with altered breast cancer risk, mammographic density, bone mineral density and any relationship to treatment effect.
To study the incidence of serous tubal in situ carcinoma (STIC), other precursor lesions and occult neoplasia in women who undergo risk-reducing bilateral salpingo-oophorectomy during the clinical trial.
To study differences in arms in Quality of Life in all subjects, as well as menopausal symptoms in perimenopausal and postmenopausal subjects through questionaires.
To study additional research questions / to perform additional analyses from biological material and / or clinical data that have been collected within this trial (upon decision of the steering committee and in alignment with the national study sponsors).

Inclusion criteria:

Women with a confirmed deleterious or likely deleterious BRCA 1 germline mutation (Variant class 4 or 5)
Age ≥ 25 years and ≤ 55 years at randomization
No evidence of breast cancer by MRI or MG and clinical breast examination within the last 6 months prior to randomization
No clinical evidence of ovarian cancer at randomization
Negative pregnancy test at randomization for women of childbearing potential
No preventive breast surgery planned at time of randomization
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Written informed consent before any study-specific procedure is performed

Exclusion criteria:

Prior bilateral mastectomy
History of ovarian cancer (including fallopian and peritoneal cancer)
History of breast cancer
History of invasive cancer except for basal cell or squamous cell skin cancer or carcinoma in situ of the cervix, stage 1 papillary or follicular thyroid cancer, atypical hyperplasia or LCIS (Lobular Carcinoma In Situ)
Pregnant or lactating women (within the last 2 months prior to randomization)
Unwillingness to use highly effective contraception method during and within at least 5 months after cessation of denosumab/placebo therapy in women of childbearing potential. (Note: Women of childbearing potential should be monitored for pregnancy prior to each denosumab/placebo injection)
Clinically relevant hypocalcaemia (history and current condition), or serum calcium <2.0 mmol/L (<8.0 mg/dL)
Hypocalcemia defined by calcium below the normal range (a single value below the normal range does not necessarily constitute hypocalcemia, but should be ‘corrected’ before dosing the subject). Monitoring of calcium level in regular intervals (usually prior to IP administration) is highly recommended
Tamoxifen, raloxifene or aromatase inhibitor use during the last 3 months prior to randomization or for a duration of more than 3 years in total (current and prior HRT is permitted)
Prior use of denosumab
Subject has a known prior history or current evidence of osteonecrosis or osteomyelitis of the jaw, or an active dental/jaw condition which requires oral surgery including tooth extraction within 3 months of enrollment
Concurrent treatment with a bisphosphonate or an anti-angiogenic agent
Any major medical or psychiatric condition that may prevent the subject from completing the study
Known active infection with Hepatitis B virus or Hepatitis C virus
Known infection with human immunodeficiency virus (HIV)
Use of any other investigational product (current or prior Aspirin or NSAIDs are permitted)

* studyinformation based on protocol version 1.1

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