Clinical trial NCT00556374: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Amgen
Sponsor class: INDUSTRY
Collaborators: name: Austrian Breast and Colorectal Cancer Study Group
First posted: 2007-11-12
Enrollment: 3420
Sex: FEMALE
Minimum age (years): 45
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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).

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

Primary outcomes:
measure: Time to First Clinical Fracture
timeFrame: 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:
measure: Percent Change From Baseline in Total Lumbar Spine Bone Mineral Density (BMD) at Month 36 at Pre-selected Sites
timeFrame: Baseline and Month 36
measure: Percent Change From Baseline in Total Hip BMD at Month 36 at Pre-selected Sites
timeFrame: Baseline and Month 36
measure: Percent Change From Baseline in Femoral Neck BMD at Month 36 at Pre-selected Sites
timeFrame: Baseline and Month 36
measure: Number of Participants With New Vertebral Fractures
timeFrame: 36 months
measure: Number of Participants With New or Worsening Vertebral Fractures
timeFrame: 36 months
measure: Disease-free Survival (DFS)
timeFrame: 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
measure: Bone Metastases-free Survival (BMFS)
timeFrame: From randomization until end of main study, maximum time on main study was 152 months
measure: Overall Survival (OS)
timeFrame: Randomization until end of main study, maximum duration of main study was 152 months
Other outcomes:
Locations:
city: Baden
country: Austria
facility: Research Site
city: Braunau
country: Austria
facility: Research Site
city: Dornbirn
country: Austria
facility: Research Site
city: Feldkirch
country: Austria
facility: Research Site
city: Gmunden
country: Austria
facility: Research Site
city: Graz
country: Austria
facility: Research Site
city: Graz
country: Austria
facility: Research Site
city: Güssing
country: Austria
facility: Research Site
city: Hall in Tirol
country: Austria
facility: Research Site
city: Innsbruck
country: Austria
facility: Research Site
city: Klagenfurt
country: Austria
facility: Research Site
city: Krems
country: Austria
facility: Research Site
city: Kufstein
country: Austria
facility: Research Site
city: Leoben
country: Austria
facility: Research Site
city: Lienz
country: Austria
facility: Research Site
city: Linz
country: Austria
facility: Research Site
city: Linz
country: Austria
facility: Research Site
city: Oberpullendorf
country: Austria
facility: Research Site
city: Ried
country: Austria
facility: Research Site
city: Rottenmann
country: Austria
facility: Research Site
city: Salzburg
country: Austria
facility: Research Site
city: Schärding
country: Austria
facility: Research Site
city: St Poelten
country: Austria
facility: Research Site
city: St Veit an der Glan
country: Austria
facility: Research Site
city: St. Poelten
country: Austria
facility: Research Site
city: Steyr
country: Austria
facility: Research Site
city: Villach
country: Austria
facility: Research Site
city: Villach
country: Austria
facility: Research Site
city: Voecklabruck
country: Austria
facility: Research Site
city: Weiz
country: Austria
facility: Research Site
city: Wels
country: Austria
facility: Research Site
city: Wiener Neustadt
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wien
country: Austria
facility: Research Site
city: Wolfsberg
country: Austria
facility: Research Site
city: Gävle
country: Sweden
facility: Research Site
city: Göteborg
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Stockholm
country: Sweden
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.