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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

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Placebo Biological: Denosumab Drug: Non-steroidal aromatase inhibitor therapy Drug: Zoledronic Acid Other: Standard of Care Phase 3

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3420 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: 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.
Actual Study Start Date : December 18, 2006
Actual Primary Completion Date : October 7, 2014
Estimated Study Completion Date : August 2, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
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.
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

Placebo Comparator: Placebo
Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.
Drug: Placebo
Other Name: Administered as a subcutaneous injection

Drug: Non-steroidal aromatase inhibitor therapy
An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting

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.
Drug: Zoledronic Acid
5 mg zoledronic acid administered at a constant infusion rate
Other Names:
  • Reclast
  • Zometa

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.
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.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.


  5. 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.

  6. 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.


  7. 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.

  8. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   45 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00556374


Locations
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Austria
Research Site
Baden, Austria, 2500
Research Site
Braunau, Austria, 5280
Research Site
Dornbirn, Austria, 6850
Research Site
Feldkirch, Austria, 6807
Research Site
Gmunden, Austria, 4810
Research Site
Graz, Austria, 8020
Research Site
Graz, Austria, 8036
Research Site
Güssing, Austria, 7540
Research Site
Hall in Tirol, Austria, 6060
Research Site
Innsbruck, Austria, 6020
Research Site
Klagenfurt, Austria, 9026
Research Site
Krems, Austria, 3500
Research Site
Kufstein, Austria, 6330
Research Site
Leoben, Austria, 8700
Research Site
Lienz, Austria, 9900
Research Site
Linz, Austria, 4010
Research Site
Linz, Austria, 4020
Research Site
Oberpullendorf, Austria, 7350
Research Site
Ried, Austria, 4910
Research Site
Rottenmann, Austria, 8786
Research Site
Salzburg, Austria, 5020
Research Site
Schärding, Austria, 4780
Research Site
St Poelten, Austria, 3100
Research Site
St Veit an der Glan, Austria, 9300
Research Site
St. Poelten, Austria, 3100
Research Site
Steyr, Austria, 4400
Research Site
Villach, Austria, 9500
Research Site
Villach, Austria, 9504
Research Site
Voecklabruck, Austria, 4840
Research Site
Weiz, Austria, 8160
Research Site
Wels, Austria, 4600
Research Site
Wiener Neustadt, Austria, 2700
Research Site
Wien, Austria, 1010
Research Site
Wien, Austria, 1020
Research Site
Wien, Austria, 1050
Research Site
Wien, Austria, 1090
Research Site
Wien, Austria, 1130
Research Site
Wien, Austria, 1140
Research Site
Wien, Austria, 1160
Research Site
Wien, Austria, 1180
Research Site
Wien, Austria, 1220
Research Site
Wolfsberg, Austria, 9400
Sweden
Research Site
Gävle, Sweden, 801 87
Research Site
Göteborg, Sweden
Research Site
Stockholm, Sweden, 112 81
Research Site
Stockholm, Sweden, 171 76
Research Site
Uppsala, Sweden, 751 85
Sponsors and Collaborators
Amgen
Austrian Breast and Colorectal Cancer Study Group
Investigators
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Study Director: MD Amgen
Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT00556374    
Other Study ID Numbers: 20050209
ABCSG-18 ( Other Identifier: Austrian Breast and Colorectal Cancer Study Group )
2005-005275-15 ( EudraCT Number )
First Posted: November 12, 2007    Key Record Dates
Results First Posted: November 6, 2015
Last Update Posted: January 13, 2020
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
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
Keywords provided by Amgen:
confirmed adenocarcinoma
non-metastatic breast cancer
estrogen receptor positive
progesterone receptor positive
non-steroidal aromatase
aromatase inhibitor therapy
postmenopausal woman
adjuvant chemotherapy
neoadjuvant chemotherapy
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Zoledronic Acid
Denosumab
Aromatase Inhibitors
Bone Density Conservation Agents
Physiological Effects of Drugs
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists