Study to Determine Treatment Effects of Denosumab in Patients With Breast Cancer Receiving Aromatase Inhibitor Therapy
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Placebo; Denosumab; Non-steroidal aromatase inhibitor therapy; Zoledronic Acid; Standard of Care
Intervention description: Administered as a subcutaneous injection; An approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting; 5 mg zoledronic acid administered at a constant infusion rate; 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 MeSH terms: Zoledronic Acid; Denosumab; Aromatase Inhibitors
Phase: Phase 3
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 3420.0
Sex: Female
Minimum age: 45 Years
Maximum age: 100 Years
Healthy volunteers: No
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

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.
    

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