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

NCT00556374 | Completed Phase 3 Results DMC

• 3 other identifiers: 20050209ABCSG-182005-005275-15
• Study Type: interventional
• Target: 3,420
• Locations: 2 countries
• Sites: 46

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.

Conditions

Breast Cancer

Keywords

confirmed adenocarcinoma; non-metastatic breast cancer; estrogen receptor positive; progesterone receptor positive; non-steroidal aromatase; aromatase inhibitor therapy; postmenopausal woman; adjuvant chemotherapy; neoadjuvant chemotherapy

Outcome Measures

Primary Outcomes (1)

• Time to First Clinical Fracture

  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.

  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

Secondary Outcomes (8)

• Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites

  Baseline and Month 36

• Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites

  Baseline and Month 36

• Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites

  Baseline and Month 36

• Number of Participants With New Vertebral Fractures

  36 months

• Number of Participants With New or Worsening Vertebral Fractures

  36 months

Study Arms (4)

Denosumab

EXPERIMENTAL

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; Drug: Non-steroidal aromatase inhibitor therapy

Placebo

PLACEBO COMPARATOR

Participants received placebo subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Drug: Placebo; Drug: Non-steroidal aromatase inhibitor therapy

SubStudy: Zoledronic Acid

EXPERIMENTAL

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

Substudy: Standard of Care

OTHER

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

Interventions

Placebo DRUG

Also known as: Administered as a subcutaneous injection

Placebo

Denosumab BIOLOGICAL

Administered as a subcutaneous injection

Also known as: Prolia®

Denosumab

Non-steroidal aromatase inhibitor therapy DRUG

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

Denosumab; Placebo

Zoledronic Acid DRUG

5 mg zoledronic acid administered at a constant infusion rate

Also known as: Reclast, Zometa

SubStudy: Zoledronic Acid

Standard of Care OTHER

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.

Substudy: Standard of Care

Eligibility Criteria

• Age: 45 Years - 100 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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);
• Current or prior IV bisphosphonate administration;
• Subjects meeting the following criteria for oral bisphosphonate treatment:

Sponsors & Collaborators

• Amgen: lead
• Austrian Breast and Colorectal Cancer Study Group: collaborator

Study Sites (46)

Research Site

Baden, 2500, Austria

Location

Research Site

Braunau am Inn, 5280, Austria

Location

Research Site

Dornbirn, 6850, Austria

Location

Research Site

Feldkirch, 6807, Austria

Location

Research Site

Gmunden, 4810, Austria

Location

Research Site

Graz, 8020, Austria

Location

Research Site

Graz, 8036, Austria

Location

Research Site

Güssing, 7540, Austria

Location

Research Site

Hall in Tirol, 6060, Austria

Location

Research Site

Innsbruck, 6020, Austria

Location

Research Site

Klagenfurt, 9026, Austria

Location

Research Site

Krems, 3500, Austria

Location

Research Site

Kufstein, 6330, Austria

Location

Research Site

Leoben, 8700, Austria

Location

Research Site

Lienz, 9900, Austria

Location

Research Site

Linz, 4010, Austria

Location

Research Site

Linz, 4020, Austria

Location

Research Site

Oberpullendorf, 7350, Austria

Location

Research Site

Ried, 4910, Austria

Location

Research Site

Rottenmann, 8786, Austria

Location

Research Site

Salzburg, 5020, Austria

Location

Research Site

Sankt Pölten, 3100, Austria

Location

Research Site

Sankt Veit an der Glan, 9300, Austria

Location

Research Site

Schärding, 4780, Austria

Location

Research Site

Steyr, 4400, Austria

Location

Research Site

Vienna, 1010, Austria

Location

Research Site

Vienna, 1020, Austria

Location

Research Site

Vienna, 1050, Austria

Location

Research Site

Vienna, 1090, Austria

Location

Research Site

Vienna, 1130, Austria

Location

Research Site

Vienna, 1140, Austria

Location

Research Site

Vienna, 1160, Austria

Location

Research Site

Vienna, 1180, Austria

Location

Research Site

Vienna, 1220, Austria

Location

Research Site

Villach, 9500, Austria

Location

Research Site

Villach, 9504, Austria

Location

Research Site

Vöcklabruck, 4840, Austria

Location

Research Site

Weiz, 8160, Austria

Location

Research Site

Wels, 4600, Austria

Location

Research Site

Wiener Neustadt, 2700, Austria

Location

Research Site

Wolfsberg, 9400, Austria

Location

Research Site

Gävle, 801 87, Sweden

Location

Research Site

Gothenburg, Sweden

Location

Research Site

Stockholm, 112 81, Sweden

Location

Research Site

Stockholm, 171 76, Sweden

Location

Research Site

Uppsala, 751 85, Sweden

Location

Related Publications (5)

• 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.

  PMID: 26040499 BACKGROUND

• Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

  PMID: 38979716 DERIVED

• Gnant M, Frantal S, Pfeiler G, Steger GG, Egle D, Greil R, Fitzal F, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Kainberger F, Ritter M, Rinnerthaler G, Sevelda P, Bergh J, Kacerovsky-Strobl S, Suppan C, Brunner C, Deutschmann C, Gampenrieder SP, Fohler H, Jakesz R, Fesl C, Singer C. Long-Term Outcomes of Adjuvant Denosumab in Breast Cancer. NEJM Evid. 2022 Dec;1(12):EVIDoa2200162. doi: 10.1056/EVIDoa2200162. Epub 2022 Nov 18.

  PMID: 38319865 DERIVED

• 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.

  PMID: 35334418 DERIVED

• 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.

  PMID: 30795951 DERIVED

Related Links

• AmgenTrials clinical trials website

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Denosumab; Zoledronic Acid; Standard of Care

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2007
• First Posted: November 12, 2007
• Study Start: December 18, 2006
• Primary Completion: October 7, 2014
• Study Completion: July 26, 2022
• Last Updated: July 27, 2023
• Results First Posted: November 6, 2015

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

AU (41); SE (5)