E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adjuvant treatment for women with early-stage breast cancer at high risk of disease recurrence receiving standard of care adjuvant/neoadjuvant cancer therapy. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006187 |
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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 disease 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) • Overall survival (OS) • Distant recurrence-free survival (DRFS) |
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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 |
FARMACOGENETICA: Versione:NA Data:2010/01/11 Titolo:Pharmacogenetic sub-study, 11 January 2010. Obiettivi: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.
FARMACOCINETICA/FARMACODINAMICA: Versione:NA Data:2010/01/11 Titolo:Pharmacokinetic sub-study, 11 January 2010. Obiettivi: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.
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E.3 | Principal inclusion criteria |
• Histologically confirmed, AJCC stage II or III breast cancer See Appendix E 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: o Biopsy evidence of breast cancer in regional LN (node positive disease) o Tumor size > 5 cm (T3) or locally advanced disease (T4) See Appendix E for breast cancer grading and staging information. • Documented pathological evaluation of the breast cancer for hormone receptor (ER and PR) status and HER-2 status • Subjects must be receiving or be scheduled to receive standard of care adjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER-2 targeted therapy • For subjects receiving adjuvant therapy only: o 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 resection of the primary tumor with curative intent after completion of chemotherapy. Definitive treatment must be planned to be completed within 9 months of randomization o Time between definitive surgery and randomization must be ≤ 8 weeks Definitive surgery may include secondary interventions (e.g. to clear inadequate surgical margins) o 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 after completion of chemotherapy. Definitive treatment must be planned to be completed within 9 months of randomization o 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: o Subjects must have tumor size > 5 cm (T3) or locally advanced disease (T4) or biopsy-proven lymph node involvement o Time between start of neoadjuvant treatment and randomization must be ≤ 4 weeks o Subjects must be scheduled to undergo definitive surgery and/or radical radiotherapy with curative intent within 6 months of starting neoadjuvant treatment Definitive surgery may include secondary interventions (e.g. to clear inadequate surgical margins) • Female subjects with age ≥ 18 years • 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) • 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 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 • 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: o 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 o 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) • Prior history or current evidence of osteomyelitis or 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 • 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) • Subject is pregnant or breast feeding, or planning to become pregnant within 7 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 7 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 may 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) |
BMFS (determined by the time from randomization to the first observation of bone metastasis or death from any cause). |
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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.8.3 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 181 |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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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If Dmab results superior and with a + benefit/risk profile compared with Placebo,the end of the clinical study is approx. 12 weeks after the last dose of dmab in the open-label treatment phase;otherwise 4 weeks after the last dose of Dmab in blind. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
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 |