E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prevention of breast cancer in women with a BRCA1 germline mutation |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036898 |
E.1.2 | Term | Prophylaxis |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006187 |
E.1.2 | Term | Breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071980 |
E.1.2 | Term | BRCA1 gene mutation |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
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E.2.2 | Secondary objectives of the trial |
• To determine the reduction in risk of invasive breast cancer • To determine the reduction in risk of invasive triple negative breast cancer (TNBC) • To determine the reduction in risk of ovarian, fallopian tube cancers (in women who have not undergone PBSO) and primary peritoneal cancers 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 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 • 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal exclusion criteria |
• Prior bilateral mastectomy • History of ovarian cancer (including fallopian tube and primary peritoneal cancer) • History of breast cancer • History of invasive cancer except for basal cell or squamous cell skin cancer. History of the following are also allowed: 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. • Clinically relevant hypocalcaemia (history and current condition), or serum calcium <2.0 mmol/L (<8.0 mg/dL) or corrected calcium (<2.1mmol/L) 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 participant). 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) • Any prior use of denosumab • Participant 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 ≤ 3 months prior enrollment • Concurrent treatment with a bisphosphonate or an anti-angiogenic agent (wash out period for bisphosphonates (e.g. Zoledronic Acid) is up to 6 months, therefore these medications need to be stopped ≥ 6 months before first IP administration the latest) • Concurrent therapy with other Investigational Products (at enrollment or during trial treatment) • Any major medical or psychiatric condition that may prevent the participant from completing the study • Known active infection with Hepatitis B virus or Hepatitis C virus • Known infection with human immunodeficiency virus (HIV) • Hypersensitivity to the active substance or to any of the excipients • Known rare hereditary problems of fructose intolerance |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Time to the occurrence of any breast cancer (invasive or DCIS) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time from randomization to the occurrence of breast cancer (invasive or DCIS) |
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E.5.2 | Secondary end point(s) |
• Time to invasive breast cancer • Time to invasive triple negative breast cancer • Time to ovarian, fallopian tube or primary peritoneal cancer (in women who have not undergone PBSO) • Time to other (non breast or ovarian cancer) malignancies, including those known to be associated with BRCA1 mutations • Time to clinical fractures in pre- and postmenopausal women • Frequency of breast biopsies and frequency of benign breast lesions |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Israel |
United States |
Austria |
Spain |
Germany |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study is the date when the last patient has completed their end of study visit, all data have been collected, and all queries have been resolved. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 14 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 14 |