Early non-metastatic breast cancer and therapy-induced bone loss and fractures MedDRA version: 21.1 Level: PT Classification code 10065687 Term: Bone loss System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders MedDRA version: 21.1 Level: LLT Classification code 10006188 Term: Breast cancer female NOS System Organ Class: 100000004864
Conditions
Sponsors
Amgen Limited
Eligibility
Sex/Gender
All
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 1908
Exclusion criteria
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 indica
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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).;Secondary Objective: - 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 ;Primary end point(s): The time to the first clinical fracture ;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) | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;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 endpoint | — |
Countries
Austria, Sweden
Contacts
Public ContactMedical Information
Amgen GmbH
Outcome results
None listed