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

• ClinicalTrials.gov Identifier: NCT00556374
• Recruitment Status: Completed
• First Posted: November 12, 2007
• Results First Posted: November 6, 2015
• Last Update Posted: July 27, 2023
• Sponsor: Amgen
• Collaborator: Austrian Breast and Colorectal Cancer Study Group
• Information provided by (Responsible Party): Amgen

Tracking Information

• First Submitted Date: November 8, 2007
• First Posted Date: November 12, 2007
• Results First Submitted Date: October 6, 2015
• Results First Posted Date: November 6, 2015
• Last Update Posted Date: July 27, 2023
• Actual Study Start Date: December 18, 2006
• Actual Primary Completion Date: October 7, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 19, 2023)

Time to First Clinical Fracture [ Time Frame: From randomization until the primary analysis cut-off date of 26 March 2014; maximum time on main study at the cut-off was 87 months ]

The time to first on-study clinical fracture was 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 (submitted: November 8, 2007): The time to the first clinical fracture.

Current Secondary Outcome Measures (submitted: July 19, 2023)

• 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 was 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 was 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 was defined as an increase in fracture severity of at least 1 grade on the semiquantitative scale.
• Disease-free Survival (DFS) [ Time Frame: From randomization until the DFS data cut-off date of 15 September 2015; maximum time on main study at the cut-off was 102 months ]
  DFS was 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.
• Bone Metastases-free Survival (BMFS) [ Time Frame: From randomization until end of main study, maximum time on main study was 152 months ]
  BMFS was defined as the time interval from randomization to first occurrence of bone metastasis or death from any cause, whichever comes first. Participants last known to be alive, who did not experience bone metastasis, were censored at their last assessment (i.e., bone scan) date or at the last contact date, whichever comes first.
• Overall Survival (OS) [ Time Frame: Randomization until end of main study, maximum duration of main study was 152 months ]
  OS was defined as the time from randomization to death from any cause.

Original Secondary Outcome Measures (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: Study to Determine Treatment Effects of Denosumab in Patients With Breast Cancer Receiving Aromatase Inhibitor Therapy
• 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.
• 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Supportive Care
• Condition: Breast Cancer

Intervention

• 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

• 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 *

• Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Aug 1;386(9992):433-43. doi: 10.1016/S0140-6736(15)60995-3. Epub 2015 May 31.
• Minichsdorfer C, Fuereder T, Leutner M, Singer CF, Kacerovsky-Strobl S, Egle D, Greil R, Balic M, Fitzal F, Pfeiler G, Frantal S, Bartsch R, Gnant M. Effect of concomitant statin treatment in postmenopausal patients with hormone receptor-positive early-stage breast cancer receiving adjuvant denosumab or placebo: a post hoc analysis of ABCSG-18. ESMO Open. 2022 Apr;7(2):100426. doi: 10.1016/j.esmoop.2022.100426. Epub 2022 Mar 22.
• Gnant M, Pfeiler G, Steger GG, Egle D, Greil R, Fitzal F, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Jakesz R, Marth C, Sevelda P, Mlineritsch B, Exner R, Fesl C, Frantal S, Singer CF; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 Mar;20(3):339-351. doi: 10.1016/S1470-2045(18)30862-3. Epub 2019 Feb 19.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 29, 2015): 3420
• Original Enrollment (submitted: November 8, 2007): 2800
• Actual Study Completion Date: July 26, 2022
• Actual Primary Completion Date: October 7, 2014 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 45 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Sweden

Administrative Information

• NCT Number: NCT00556374
• Other Study ID Numbers: 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

• 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

• Current Responsible Party: Amgen
• Original Responsible Party: Not Provided
• Current Study Sponsor: Amgen
• Original Study Sponsor: Same as current
• Collaborators: Austrian Breast and Colorectal Cancer Study Group

Investigators

• Study Director: MD; Amgen

• PRS Account: Amgen
• Verification Date: June 2023