Study of Denosumab as Adjuvant Treatment for Women With High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)

Inclusion Criteria:

• Histologically confirmed, American Joint Committee on Cancer (AJCC) stage II or IIIbreast cancer
• High risk of breast cancer recurrence, defined as documented evidence of one or moreof the following criteria: i) Biopsy evidence of breast cancer in regional lymph node(s) (LN) (node-positivedisease); Nodal micrometastases only are not considered node positive ii) Tumor size > 5 cm (T3) or locally advanced disease (T4)
• Documented pathological evaluation of the breast cancer for hormone receptor (estrogenreceptor [ER] and progesterone receptor [PR]) status and HER-2 status
• Subjects must be receiving or be scheduled to receive standard of care systemicadjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER-2 targetedtherapy
• For subjects receiving adjuvant therapy only:
• subjects must have undergone complete resection of the primary tumor with cleansurgical margins, or subjects must have undergone resection of the primary tumor andbe scheduled for further treatment of the primary tumor with curative intent.Definitive treatment must be planned to be completed within approximately 9 months ofrandomization
• Time between definitive surgery and randomization must be ≤ 12 weeks. Definitivesurgery may include secondary interventions (e.g. to clear inadequate surgicalmargins)
• Subjects with node positive disease must have undergone treatment of axillary LN withcurative intent, or subjects must be scheduled for further treatment of regional lymphnodes with curative intent. Definitive treatment must be planned to be completedwithin approximately 9 months of randomization
• Subjects must not have received prior neoadjuvant treatment. Endocrine treatment forless than 30 days prior to surgery is not considered prior neoadjuvant treatment
• For subjects receiving neoadjuvant therapy only:
• Time between start of neoadjuvant treatment and randomization must be ≤ 8 weeks andsubjects must be scheduled to undergo definitive treatment (including surgery and/orradiotherapy) with curative intent within approximately 9 months of startingneoadjuvant treatment
• Female subjects with age ≥ 18 years
• Subjects with reproductive potential must have a negative pregnancy test within 14days before randomization
• Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9mmol/L (11.5 mg/dL)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Written informed consent before any study-specific procedure is performed

Exclusion Criteria:

• Prior or current evidence of any metastatic involvement of any distant site
• History of breast cancer (other than ductal carcinoma in situ [DCIS] or lobularcarcinoma in situ [LCIS]) prior to the current diagnosis
• Osteoporosis requiring treatment at the time of randomization or treatment consideredlikely to become necessary within the subsequent six months
• Any prior or synchronous malignancy (other than breast cancer), except i) Malignancytreated with curative intent and with no evidence of disease for ≥ 5 years prior toenrollment and considered to be at low risk for recurrence by the treating physicianii) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence ofdisease
• Active infection with Hepatitis B virus or Hepatitis C virus
• Known infection with human immunodeficiency virus (HIV)
• Prior history or current evidence of osteomyelitis/osteonecrosis of the jaw
• Active dental or jaw condition which requires oral surgery
• Planned invasive dental procedure for the course of the study
• Non-healed dental or oral surgery
• Use of oral bisphosphonates within the past 1 year
• Prior or current IV bisphosphonate administration
• Prior administration of denosumab
• Subject currently is enrolled in or has not yet completed at least 30 days sinceending other investigational device or investigational drug study(s), or subject isreceiving other investigational agent(s)
• Subject is pregnant or breast feeding, or planning to become pregnant within 7 monthsafter the end of treatment.
• Subject is of child bearing potential and is not willing to use, in combination withher partner, 2 highly effective methods of contraception or abstinence duringtreatment and for 5 months after the end of treatment
• Subject has known sensitivity to any of the products to be administered during thestudy (e.g., mammalian derived products, calcium, or vitamin D)
• Subject has any kind of disorder that compromises the ability of the subject to givewritten informed consent and/or to comply with study procedures.
• Any major medical or psychiatric disorder that in the opinion of the investigatorprevent the subject from completing the study or interfere with the interpretation ofthe study results