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

NCT ID: NCT00556374

Last Updated: 2023-07-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 3420 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-12-18
• Study Completion Date: 2022-07-26

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).

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: QUADRUPLE

Study Groups

Denosumab

Participants received 60 mg denosumab subcutaneous injection once every 6 months. All participants continued to receive an approved non-steroidal aromatase inhibitor therapy.

Group Type: EXPERIMENTAL

Denosumab

Intervention Type: BIOLOGICAL

Administered as a subcutaneous injection

Non-steroidal aromatase inhibitor therapy

Intervention Type: DRUG

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

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Non-steroidal aromatase inhibitor therapy

Intervention Type: DRUG

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

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.

Group Type: EXPERIMENTAL

Zoledronic Acid

Intervention Type: DRUG

5 mg zoledronic acid administered at a constant infusion rate

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.

Group Type: OTHER

Standard of Care

Intervention Type: 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.

Interventions

Placebo

Intervention Type: DRUG

Denosumab

Administered as a subcutaneous injection

Intervention Type: BIOLOGICAL

Non-steroidal aromatase inhibitor therapy

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

Intervention Type: DRUG

Zoledronic Acid

5 mg zoledronic acid administered at a constant infusion rate

Intervention Type: DRUG

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.

Intervention Type: OTHER

Other Intervention Names

Administered as a subcutaneous injection; Prolia®; Reclast; Zometa

Eligibility 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;
• 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.

• 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);

• Obtain signed and dated written informed consent prior to performing any substudy-specific procedure
• Subjects that received OLP denosumab and completed OLP treatment

Exclusion Criteria

• 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.

• 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.

• 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

• Minimum Eligible Age: 45 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Austrian Breast and Colorectal Cancer Study Group

UNKNOWN

Sponsor Role: collaborator

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

Research Site

Baden, , Austria

Research Site

Braunau am Inn, , Austria

Research Site

Dornbirn, , Austria

Research Site

Feldkirch, , Austria

Research Site

Gmunden, , Austria

Research Site

Graz, , Austria

Research Site

Graz, , Austria

Research Site

Güssing, , Austria

Research Site

Hall in Tirol, , Austria

Research Site

Innsbruck, , Austria

Research Site

Klagenfurt, , Austria

Research Site

Krems, , Austria

Research Site

Kufstein, , Austria

Research Site

Leoben, , Austria

Research Site

Lienz, , Austria

Research Site

Linz, , Austria

Research Site

Linz, , Austria

Research Site

Oberpullendorf, , Austria

Research Site

Ried, , Austria

Research Site

Rottenmann, , Austria

Research Site

Salzburg, , Austria

Research Site

Sankt Pölten, , Austria

Research Site

Sankt Veit an der Glan, , Austria

Research Site

Schärding, , Austria

Research Site

Steyr, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Vienna, , Austria

Research Site

Villach, , Austria

Research Site

Villach, , Austria

Research Site

Vöcklabruck, , Austria

Research Site

Weiz, , Austria

Research Site

Wels, , Austria

Research Site

Wiener Neustadt, , Austria

Research Site

Wolfsberg, , Austria

Research Site

Gävle, , Sweden

Research Site

Gothenburg, , Sweden

Research Site

Stockholm, , Sweden

Research Site

Stockholm, , Sweden

Research Site

Uppsala, , Sweden

Countries

Austria; Sweden

References

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.

Reference Type: BACKGROUND

PMID: 26040499 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38979716 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 38319865 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35334418 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 30795951 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.amgentrials.com

AmgenTrials clinical trials website

Other Identifiers

ABCSG-18

Identifier Type: OTHER

Identifier Source: secondary_id

2005-005275-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

20050209

Identifier Type: -

Identifier Source: org_study_id