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

Breast Cancer Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00556374
• Other study ID #: 20050209
• Secondary ID: ABCSG-182005-005
• Status: Completed
• Phase: Phase 3
• Start date: December 18, 2006
• Est. completion date: July 26, 2022

Study information

• Verified date: June 2023
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3420
• Est. completion date: July 26, 2022
• Est. primary completion date: October 7, 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years to 100 Years

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Placebo

Biological:
• Denosumab
Administered as a subcutaneous injection

Drug:
• Non-steroidal aromatase inhibitor therapy
An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting
• Zoledronic Acid
5 mg zoledronic acid administered at a constant infusion rate

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.

Locations

Country	Name	City	State
Austria	Research Site	Baden
Austria	Research Site	Braunau
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	Schärding
Austria	Research Site	St Poelten
Austria	Research Site	St Veit an der Glan
Austria	Research Site	St. Poelten
Austria	Research Site	Steyr
Austria	Research Site	Villach
Austria	Research Site	Villach
Austria	Research Site	Voecklabruck
Austria	Research Site	Weiz
Austria	Research Site	Wels
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wien
Austria	Research Site	Wiener Neustadt
Austria	Research Site	Wolfsberg
Sweden	Research Site	Gävle
Sweden	Research Site	Göteborg
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Sweden	Research Site	Uppsala

Sponsors (2)

Lead Sponsor	Collaborator
Amgen	Austrian Breast and Colorectal Cancer Study Group

Countries where clinical trial is conducted

Austria,  Sweden, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites	Bone mineral density was assessed by dual x-ray absorptiometry.	Baseline and Month 36
Secondary	Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites	Bone mineral density was assessed by dual x-ray absorptiometry.	Baseline and Month 36
Secondary	Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites	Bone mineral density was assessed by dual x-ray absorptiometry.	Baseline and Month 36
Secondary	Number of Participants With New Vertebral Fractures	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.	36 months
Secondary	Number of Participants With New or Worsening Vertebral Fractures	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.	36 months
Secondary	Disease-free Survival (DFS)	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.	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
Secondary	Bone Metastases-free Survival (BMFS)	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.	From randomization until end of main study, maximum time on main study was 152 months
Secondary	Overall Survival (OS)	OS was defined as the time from randomization to death from any cause.	Randomization until end of main study, maximum duration of main study was 152 months

External Links

•   AmgenTrials clinical trials website