E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early-stage non-metastatic breast cancer |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006190 |
E.1.2 | Term | Breast cancer invasive NOS |
E.1.2 | System Organ Class | 100000004864 |
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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 compare the treatment effect of denosumab with that of placebo on prolonging bone metastasis-free survival (BMFS) in subjects with early-stage breast cancer at high risk of recurrence |
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E.2.2 | Secondary objectives of the trial |
To compare the treatment effect of denosumab with that of placebo on:
• Disease-free survival (DFS) in the full study population
•DFS in the postmenopausal subset
• Overall survival (OS)
• Distant recurrence-free survival (DRFS)
Safety Objectives
• To assess the safety and tolerability of denosumab compared with placebo |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Pharmacokinetic sub-study, 11 January 2010: This sub-study will be carried out on a subset of approximately 120 subjects at selected sites. These subjects will be required to sign an additional optional informed consent to participate in this sub-study. Samples for serum denosumab concentration levels will be obtained as outlined in the Schedule of Assessments (Appendix A) of the protocol.
The purpose of this sub-study is to evaluate the pharmacokinetic profile of denosumab when given as a monthly (QM) regimen for 6 months followed by every-three-month (Q3M) dosing in patients with early-stage breast cancer who are at high risk of disease recurrence.
- Pharmacogenetic sub-study, 11 January 2010:If a subject signs the additional optional informed consent (Pharmacogenetic Consent), DNA extracted from blood samples collected for biomarker development (as per the Schedule of Assessments in Appendix A of the protocol) may be analyzed for optional, exploratory pharmacogenetic analyses.
These optional analyses focus on inherited genetic variations, to evaluate their possible correlation to breast cancer and/or responsiveness to denosumab. The goals of these optional studies include the use of genetic markers to help in the investigation of breast cancer and/or to identify persons who may have the best possible response to denosumab. |
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E.3 | Principal inclusion criteria |
Disease related
• Histologically confirmed, AJCC stage II or III breast cancer
See Appendix D of protocol for breast cancer grading and staging information.
• High risk of breast cancer recurrence, defined as documented evidence of one or more of the following criteria:
- Biopsy evidence of breast cancer in regional lymph node(s) (LN) (node-positive disease)
Nodal micrometastases only are not considered node positive
- Tumor size > 5 cm or locally advanced disease (T4)
See Appendix D of protocol for breast cancer grading and staging information.
• Documented pathological evaluation of the breast cancer for hormone receptor (estrogen receptor [ER] and progesterone receptor [PR]) status and HER-2 status
• Subjects must be receiving or be scheduled to receive standard of care systemic adjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER-2 targeted therapy
• For subjects receiving adjuvant therapy only:
- Subjects must have undergone complete resection of the primary tumor with clean surgical margins, or
- Subjects must have undergone resection of the primary tumor and be scheduled for further treatment of the primary tumor with curative intent. Definitive treatment must be planned to be completed within approximately 9 months of randomization
- Time between definitive surgery and randomization must be ≤ 12 weeks
Definitive surgery may include secondary interventions (e.g. to clear inadequate surgical margins)
- Subjects with node positive disease must have undergone radical treatment of axillary LN with curative intent, or
Subjects must be scheduled for further treatment of regional lymph nodes with curative intent. Definitive treatment must be planned to be completed within approximately 9 months of randomization
- Subjects must not have received prior neoadjuvant treatment
Endocrine treatment for less than 30 days prior to surgery is not
considered prior neoadjuvant treatment
• For subjects receiving neoadjuvant therapy only:
- Time between start of neoadjuvant treatment and randomization must be ≤ 8 weeks
- Subjects must be scheduled to undergo definitive treatment (including surgery and/or radiotherapy) with curative intent within approximately 9 months of starting neoadjuvant treatment
Demographic
• Female subjects with age ≥ 18 years
Laboratory
• Subjects with reproductive potential must have a negative pregnancy test within 14 days before randomization
• Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL)
General
• 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 |
Disease related
• Prior or current evidence of any metastatic involvement of any distant site
• History of breast cancer (other than ductal carcinoma in situ [DCIS] or lobular carcinoma in situ [LCIS]) prior to the current diagnosis
Medical Conditions
• Osteoporosis requiring treatment at the time of randomization or treatment considered likely to become necessary within the subsequent six months
• Any prior or synchronous malignancy (other than breast cancer), except:
- Malignancy treated with curative intent and with no evidence of disease for ≥ 5 years prior to enrollment and considered to be at low risk for recurrence by the treating physician
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Active infection with Hepatitis B virus or Hepatitis C virus
• Known infection with human immunodeficiency virus (HIV)
Oral/ Dental Conditions
• Prior history or current evidence of osteomyelitis/osteonecrosis of the jaw
• Active dental or jaw condition which requires oral surgery
• Planned invasive dental procedure for the course of the study
• Non-healed dental or oral surgery
Medications/ Treatments
• Use of oral bisphosphonates within the past 1 year
• Prior or current IV bisphosphonate administration
• Prior administration of denosumab
• Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or investigational drug study(s), or subject is receiving other investigational agent(s)
General
• Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment.
• Subject is of child bearing potential and is not willing to use, in combination with her partner, 2 highly effective methods of contraception or abstinence during treatment and for 5 months after the end of treatment
• Subject has known sensitivity to any of the products to be administered during the study (e.g., mammalian derived products, calcium, or vitamin D)
• Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.
• Any major medical or psychiatric disorder that in the opinion of the investigator might prevent the subject from completing the study or interfere with the interpretation of the study results |
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E.5 End points |
E.5.1 | Primary end point(s) |
Bone metastasis-free survival (BMFS) (please note that disease-free survival also contributes to event-driven data cut-off date [please see E.5.1.1 below])
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be conducted after all enrolled subjects have had the opportunity to complete 5 years of treatment from Study Day 1 |
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E.5.2 | Secondary end point(s) |
• Disease-free survival (DFS) in the full study population
•DFS in the postmenopausal subset
• Overall survival (OS)
• Distant recurrence-free survival (DRFS)
• Subject incidence of treatment-emergent adverse events
• Changes in laboratory values
• Subject incidence of anti-denosumab neutralizing antibody formation |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis will be conducted after all enrolled subjects have had the opportunity to complete 5 years of treatment from Study Day 1 |
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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 | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
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 | Yes |
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 | 190 |
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 |
Argentina |
Australia |
Brazil |
Canada |
Chile |
European Union |
Hong Kong |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Mexico |
Peru |
Philippines |
Russian Federation |
Serbia |
South Africa |
Taiwan |
Turkey |
United States |
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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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The End of Study (End of the Clinical Study) is defined as the date that the last subject is assessed in the follow-up phase. |
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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 | 12 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 12 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |