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Study to Determine Treatment Effects of Denosumab in Patients With Breast Cancer Receiving Aromatase Inhibitor Therapy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00556374
Recruitment Status : Active, not recruiting
First Posted : November 12, 2007
Results First Posted : November 6, 2015
Last Update Posted : January 13, 2020
Sponsor:
Collaborator:
Austrian Breast and Colorectal Cancer Study Group
Information provided by (Responsible Party):
Amgen

Tracking Information
First Submitted Date  ICMJE November 8, 2007
First Posted Date  ICMJE November 12, 2007
Results First Submitted Date  ICMJE October 6, 2015
Results First Posted Date  ICMJE November 6, 2015
Last Update Posted Date January 13, 2020
Actual Study Start Date  ICMJE December 18, 2006
Actual Primary Completion Date October 7, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 6, 2015)
Time to First Clinical Fracture [ Time Frame: From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on study was 87 months. ]
The time to first on-study clinical fracture defined as the number of days from randomization to the date of the x-ray confirming the clinical fracture. A clinical fracture is any clinically evident fracture with associated symptoms and confirmed by x-ray. Participants who died or withdrew without experiencing a clinical fracture were censored at the date of last contact or study termination whichever was earlier.
Original Primary Outcome Measures  ICMJE
 (submitted: November 8, 2007)
The time to the first clinical fracture.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
  • Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites [ Time Frame: Baseline and Month 36 ]
    Bone mineral density was assessed by dual x-ray absorptiometry.
  • Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites [ Time Frame: Baseline and Month 36 ]
    Bone mineral density was assessed by dual x-ray absorptiometry.
  • Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites [ Time Frame: Baseline and Month 36 ]
    Bone mineral density was assessed by dual x-ray absorptiometry.
  • Number of Participants With New Vertebral Fractures [ Time Frame: 36 months ]
    Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture is defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays.
  • Number of Participants With New or Worsening Vertebral Fractures [ Time Frame: 36 months ]
    Assessment of vertebral fractures was performed by an expert radiologist at the central imaging center using a semiquantitative grading scale: Grade 1, 20% to 25% reduction in vertebral height (anterior, middle, or posterior); Grade 2, 25% to 40% reduction in height; Grade 3, greater than 40% reduction in height. A new vertebral fracture is defined as a fracture in a previously undeformed vertebrae including new compression fractures, defined as those compression fractures having a decrease in total anterior or posterior height of at least 25% from baseline. New vertebral fractures includes morphometric vertebral fractures identified from on study x-rays and clinical vertebral fractures confirmed by x-rays. Worsening of pre-existing fractures is defined as an increase in fracture severity of at least 1 grade on the semiquantitative scale.
  • Disease-free Survival [ Time Frame: From randomization until the DFS data cut-off date of 15 September 2015; maximum time on study was 102 months. ]
    Disease-free survival (DFS) is defined as the time interval from the randomization date to the date of first evidence of local or distant metastases, contra-lateral breast cancer, secondary carcinoma, or death from any cause (whichever occurred first). Participants last known to be alive, who did not experience recurrence of disease, were censored at their last contact date or at the data cut-off date whichever came first. DFS was initially specified to be analyzed after completion of the long-term follow-up period, however after analysis of the primary results was completed the data monitoring committee recommended that the analysis be conducted 18 months after the primary analysis data cut-off date.
  • Bone Metastases-free Survival [ Time Frame: Participants will be followed for bone metastasis-free survival once every 12 months for 66 months after primary completion date. ]
    Bone metastasis-free survival (BMFS) determined by the time from randomization to the first observation of bone metastasis or death from any cause. BMFS will be analyzed after long-term follow-up is complete.
  • Overall Survival [ Time Frame: Participants will be followed for overall survival once every 12 months for 66 months after primary completion date. ]
    Overall survival (OS) determined by the time from randomization to death from any cause. OS will be analyzed after long-term follow-up is complete.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 8, 2007)
  • The incidence of new vertebral fractures at Months 12, 24, and 36months /End of study.
  • The incidence of a new or worsening of pre-existing vertebral fractures at Months 12, 24, and 36 months/End of Study visit
  • The percentage change in total lumbar spine, total hip and femoral neck bone mineral bone density frm baseline to 12, 24 and 36 months/End of study (at pre-selected sites)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Determine Treatment Effects of Denosumab in Patients With Breast Cancer Receiving Aromatase Inhibitor Therapy
Official Title  ICMJE A Randomised, Double-Blind, Placebo-Controlled, Multi-Centre Phase 3 Study to Determine the Treatment Effect of Denosumab in Subjects With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor Therapy.
Brief Summary The purpose of this study is to determine whether denosumab compared to placebo, will reduce the rate of first clinical fracture in women with non-metastatic breast cancer receiving (non-steroidal) aromatase inhibitor therapy.
Detailed Description

Participants will remain on treatment until the required number of events (where an event is defined as first clinical fracture) is reached and all participants have had the opportunity to receive a minimum of at least 2 doses of study drug, whichever occurs later. The primary analysis data cut-off date (PADCD) is defined as the time at which the required number of events is reached and all participants have had the opportunity to receive at least 2 doses of study drug. When the PADCD is reached, all participants will discontinue study drug.

Following the study PADCD, participants will be followed every 12 months starting from their last study visit until a maximum of 66 months after PADCD.

After approval of Amendment 4, willing and eligible participants randomized to placebo during the double-blind phase may participate in an open-label phase (OLP) and receive denosumab 60 mg Q6M for up to 36 months (maximum of 7 doses).

After approval of Amendment 6 in 2019 a zoledronic acid (ZA) substudy was added to the protocol. Willing and eligible participants who participated in the OLP of the study and completed open-label denosumab may opt in to this ZA substudy and either receive a single dose of ZA (Therapy Arm), or be managed according to the current standard of care for this patient population (Control Arm).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Placebo
    Other Name: Administered as a subcutaneous injection
  • Biological: Denosumab
    Administered as a subcutaneous injection
    Other Name: Prolia®
  • Drug: Non-steroidal aromatase inhibitor therapy
    An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting
  • Drug: Zoledronic Acid
    5 mg zoledronic acid administered at a constant infusion rate
    Other Names:
    • Reclast
    • Zometa
  • Other: Standard of Care
    Standard of care (SoC) as recommended by the treating physician, depending on individual factors such as bone density, lifestyle recommendations by the Investigator such as diet, physical activities and sun exposure, as well as local treatment standards.
Study Arms  ICMJE
  • Experimental: Denosumab
    Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
    Interventions:
    • Biological: Denosumab
    • Drug: Non-steroidal aromatase inhibitor therapy
  • Placebo Comparator: Placebo
    Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
    Interventions:
    • Drug: Placebo
    • Drug: Non-steroidal aromatase inhibitor therapy
  • Experimental: SubStudy: Zoledronic Acid
    Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive a single 5 mg intravenous dose of zoledronic acid 8 months after the last open-label dose of denosumab.
    Intervention: Drug: Zoledronic Acid
  • Substudy: Standard of Care
    Eligible participants who completed the open-label phase could be enrolled into the zoledronic acid substudy and randomized to receive standard of care 8 months after the last open-label dose of denosumab.
    Intervention: Other: Standard of Care
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 29, 2015)
3420
Original Enrollment  ICMJE
 (submitted: November 8, 2007)
2800
Estimated Study Completion Date  ICMJE August 2, 2022
Actual Primary Completion Date October 7, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for Double Blinded Phase:

  • 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;
  • Subjects who are currently on, or will initiate an approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting;
  • Postmenopausal woman, 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:
  • Follicle-stimulating hormone (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.
  • More criteria may apply.

Exclusion Criteria for Double Blinded Phase:

  • Aromatase inhibitor therapy for more than 24 months;
  • Prior or concurrent treatment with Selective Estrogen Receptor Modulators (eg, tamoxifen);
  • Evidence of metastatic disease;
  • Current or prior intravenous (IV) bisphosphonate administration;
  • Oral bisphosphonate treatment greater than or equal to 3 years continuously OR greater than 3 months but less than 3 years unless there was a washout period of at least 1 year prior to randomization OR any use during the 3-month period prior to randomization;
  • Prior administration of denosumab;
  • Known liver or renal deficiency;
  • Recurrence of the primary malignancy (e.g., during the allowed interval of pretreatment with 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;
  • Any kind of disorder that compromises the ability to give written informed consent and/or comply with study procedures.

Inclusion Criteria to Receive Open-label Phase Denosumab:

  • Obtain signed and dated written informed consent prior to performing any study-specific procedure;
  • Subjects currently taking an approved non-steroidal AIT (eg, anastrazole) or who have completed or discontinued AIT within 12 months prior to participation in the OLP;
  • Randomized to placebo arm during the double-blind phase (as determined by unblinding procedures);

Exclusion Criteria to Receive Open-label Phase Denosumab:

  • Current or prior IV bisphosphonate administration;
  • Subjects meeting the following criteria for 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 prior to participation in the OLP,
    • Any use during the 3-month period prior to participation in the OLP;
  • Prior or concurrent treatment with SERMs (eg, tamoxifen);
  • Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase; Treatment with commercial denosumab (Prolia or Xgeva) prior to participation in the OLP.

Eligibility for ZA substudy Inclusion Criteria

  • Obtain signed and dated written informed consent prior to performing any substudy-specific procedure
  • Subjects that received OLP denosumab and completed OLP treatment
  • Last OLP denosumab administration no longer than 9 months ago Exclusion Criteria
  • 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 substudy (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
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 45 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00556374
Other Study ID Numbers  ICMJE 20050209
ABCSG-18 ( Other Identifier: Austrian Breast and Colorectal Cancer Study Group )
2005-005275-15 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
URL: https://www.amgen.com/datasharing
Responsible Party Amgen
Study Sponsor  ICMJE Amgen
Collaborators  ICMJE Austrian Breast and Colorectal Cancer Study Group
Investigators  ICMJE
Study Director: MD Amgen
PRS Account Amgen
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP