E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early non-metastatic breast cancer and therapy-induced bone loss and fractures |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10065687 |
E.1.2 | Term | Bone loss |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006188 |
E.1.2 | Term | Breast cancer female 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 determine whether denosumab compared to placebo will reduce the rate of first clinical fracture (ie, clinically evident fracture with associated symptoms) in women with non-metastatic breast cancer receiving non-steroidal aromatase inhibitor therapy (AIT). |
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E.2.2 | Secondary objectives of the trial |
- To assess the effect of denosumab compared to placebo on the following:
Fracture-related secondary endpoints:
• Bone mineral density (BMD) at lumbar spine, total hip and femoral neck in a subgroup of subjects at pre-selected sites
• Incidence of new vertebral fractures (both clinical and morphometric [ie, a fracture in the vertebral column that is not clinically evident and that is asymptomatic])
• Incidence of new or worsening of pre-existing vertebral fractures (both clinical and morphometric)
Disease outcome-related secondary endpoints:
• Disease-free survival (DFS)
• Bone metastasis-free survival (BMFS)
• Overall survival (OS)
- To assess the safety and tolerability of denosumab in this population |
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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 |
A sub-study has been added in Appendix G to evaluate subjects completing open-label denosumab treatment, to either receive a single dose of ZA, or to be managed according to current standard of care (SOC) for the patient population.
Protocol Am 6, dated 15July2019
Objective: To evaluate the impact of a single intravenous (IV) zoledronic acid (ZA) administration on BMD, fracture incidence (clinical and morphometric), and bone turnover markers (C-terminal telopeptide [CTX] and Osteocalcin) post OL denosumab extension. |
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E.3 | Principal inclusion criteria |
Inclusion criteria:
Histologically or cytologically confirmed adenocarcinoma of the breast
Female subjects with non-metastatic disease who are estrogen receptor (ER) and/or progesterone receptor (PR) positive, and who have completed their treatment pathway (surgery, chemotherapy)
Subjects who are currently on, or will initiate an approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting
Postmenopausal woman (1,2), defined as a woman fulfilling any one of the following criteria:
• Having undergone a bilateral oophorectomy;
• Age > 60 years;
• Aged < 60 years meeting the following requirements:
− FSH and estradiol in the postmenopausal range
− A negative pregnancy test within 7 days prior to randomization. Subjects who have undergone a hysterectomy do not require a pregnancy test.
(1) For subjects previously treated with an LHRH antagonist, the last dose must have been 4 months prior to randomization, and FSH and estradiol must be in the postmenopausal range.
(2) Subjects who have received adjuvant or neoadjuvant chemotherapy must have met 1 of the above criteria for postmenopausal status prior to that chemotherapy.
ECOG performance score of 0 or 1
Before any study-specific procedure is performed, a signed and dated written informed consent must be obtained
Inclusion Criteria for Post Open-label Denosumab Zoledronic Acid Extension (ZA Extension):
- Obtain signed and dated written informed consent prior to performing any study-specific procedure
- Subjects that received OLP denosumab and completed OLP treatment
- Last OLP denosumab administration no longer than 9 months ago |
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E.4 | Principal exclusion criteria |
Exclusion criteria:
Aromatase inhibitor therapy for more than 24 months
Prior or concurrent treatment with Selective Estrogen Receptor Modulators ( SERMS), e. g. tamoxifen.
Evidence of metastatic disease
Current or prior IV bisphosphonate administration
Oral bisphosphonate treatment:
• Greater than or equal to 3 years continuously
• Greater than 3 months but less than 3 years unless subject has had a washout period of at least 1 year
• Any use during the 3- month period prior to randomization
Known liver or renal deficiency as determined by the investigator and indicated by the following criteria:
• AST > 2.5 x ULN
• ALT > 2.5 x ULN
• Serum creatinine > 2 x ULN
Prior administration of denosumab ( AMG 162)
Recurrence of the primary malignancy ( e. g. during the allowed interval of pretreatment with an aromatase inhibitor)
Diagnosis of any second non-breast malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or for in situ carcinoma of the cervix uteri
Known history of any of the following conditions either by subject self report or chart review
• Paget’s disease ( bone), Cushing’s disease, hyperprolactinemia, or other active metabolic bone disease
• Hypercalcemia or hypocalcemia: as defined by calcium outside the normal range (A single value outside the normal range does not necessarily constitute hypercalcemia or hypocalcemia, but should be ‘corrected’ before including the subject. Subjects with a known history of hypercalcemia or hypocalcemia cannot be included)
• Major surgery, or significant traumatic injury occurring within 4 weeks prior to randomization
• Known Human Immunodeficiency Virus ( HIV) infection
• Active infection with hepatitis B or hepatitis C virus
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
Thirty days or less since receiving an investigational product or device in another clinical study
Known sensitivity to any of the products to be administered during the study ( e. g. mammalian derived products, calcium or vitamin D)
Subjects who are pregnant, breastfeeding, or plan to become pregnant during the course of the study. All subjects with reproductive potential must have a negative pregnancy test within 7 days before randomization
Any kind of disorder that compromises the ability to give written informed consent and/ or comply with study procedures
Exclusion Criteria for Post Open-label Denosumab Zoledronic Acid Extension
- Current or prior ZA administration.
- Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase and OL phase
- Known sensitivity or intolerance to any of the products to be administered during the study (eg, ZA, calcium or vitamin D)
- Known history of any of the following conditions either by subject self report or chart review
•Paget's disease (bone), Cushing's disease, hyperprolactinemia or other active metabolic bone disease
•Known history of hypocalcemia
•Major surgery, or significant traumatic injury occurring within 4 weeks prior to randomization
•Parathyroid glands in neck surgically removed
•Any sections of intestine removed
•Known human immunodeficiency virus infection
•Active infection with hepatitis B or hepatitis C virus
- Known liver or renal disease as determined by the investigator and indicated by the following criteria:
•Aspartate aminotransferase ≥ 2.5 x ULN
•Alanine transaminase ≥ 2.5 x ULN
•Serum creatinine ≥ 2 x ULN
•Creatine clearance < 35ml/min- Subjects that are pregnant or breastfeeding
•All subjects with reproductive potential must have a negative pregnancy test within 7 days before randomization
- Subjects who are osteoporotic in baseline BMD |
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E.5 End points |
E.5.1 | Primary end point(s) |
The time to the first clinical fracture
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary analysis - data cut-off date for this primary analysis is event-driven (i.e. when approximately 247 subjects have experienced their first clinical fracture and all subjects have had the opportunity to receive at least 2 doses of IP) |
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E.5.2 | Secondary end point(s) |
Fracture-related secondary endpoints:
• The percent change in total lumbar spine, total hip and femoral neck bone mineral density (BMD) from baseline to 36 months (at pre-selected sites)
• Subject incidence of new vertebral fractures (morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays) at Month 36
• Subject incidence of a new or worsening of pre-existing vertebral fractures (morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by
x-rays) at Month 36
Disease outcome-related secondary endpoints:
• Disease-free survival (DFS) determined by the time from randomization to the first observation of disease recurrence or death from any cause
• Bone metastasis-free survival (BMFS) determined by the time from randomization to the first observation of bone metastasis or death from any cause
• Overall survival (OS) determined by the time from randomization to death from any cause
Exploratory Endpoints:
Subjects who participate in the ZA extension:
•Percent change in lumbar spine, total hip and femoral neck BMD from baseline to months 6, 12, and 18.
•Percent change in bone turnover marker values (CTX and Osteocalcin) from baseline to months 6, 12, and 18.
•New clinical fracture incidence at baseline and then at months 6, 12, and 18 after day 1.
Safety endpoints:
• Subject incidence of treatment-emergent adverse events
• Clinically significant changes in laboratory values
• Subject incidence of anti-denosumab antibody (binding and
neutralizing) formation |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Fracture-related secondary endpoints:all evaluated at the primary analysis - primary analysis data cut-off date (PADCD) is event-driven (i.e. when approximately 247 subjects have experienced their first clinical fracture and all subjects have had the opportunity to receive at least 2 doses of IP)
Disease outcome-related secondary endpoints:
• DFS:evaluated at the interim analysis (i.e. analysis for DFS performed after the PADCD) and final analysis (i.e. analysis performed after long-term follow-up, 18 or 66 months after the PADCD, depending on the interim analysis)
• BMFS and OS:evaluated at the final analysis
Exploratory Endpoints:evaluated at the final analysis
Safety endpoints:evaluated at the final analysis
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 62 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 16 |
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 | 16 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |