Study of Denosumab as Adjuvant Treatment for Women With High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Placebo; Denosumab
Intervention description: Administered subcutaneously for up to 5 years; Administered subcutaneously for up to 5 years
Intervention MeSH terms: Denosumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 4509.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Early Stage Breast Cancer; Bone Metastasis; Adjuvant treatment; Neoadjuvant treatment; Denosumab; Stage II breast cancer; Stage III breast cancer; Stage IIA breast cancer; Stage IIB breast cancer; Stage IIIA breast cancer; Stage IIIB breast cancer; Stage IIIC breast cancer; Early breast cancer; Breast Tumors; Breast Neoplasms

Summary:

      This randomized phase 3 trial is studying the effect of denosumab to see if it can prevent
      disease recurrence in the bone or in any other part of the body, when it is given as adjuvant
      therapy for women with early-stage breast cancer, who are at high risk of disease recurrence.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed, American Joint Committee on Cancer (AJCC) stage II or III
             breast cancer

          -  High risk of breast cancer recurrence, defined as documented evidence of one or more
             of the following criteria:

             i) Biopsy evidence of breast cancer in regional lymph node(s) (LN) (node-positive
             disease); 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 (estrogen
             receptor [ER] and progesterone receptor [PR]) status and HER-2 status

          -  Subjects must be receiving or be scheduled to receive standard of care systemic
             adjuvant or neoadjuvant chemotherapy and/or endocrine therapy and/or HER-2 targeted
             therapy

          -  For subjects receiving adjuvant therapy only:

          -  subjects must have undergone complete resection of the primary tumor with clean
             surgical margins, or subjects must have undergone resection of the primary tumor and
             be scheduled for further treatment of the primary tumor with curative intent.
             Definitive treatment must be planned to be completed within approximately 9 months of
             randomization

          -  Time between definitive surgery and randomization must be ≤ 12 weeks. Definitive
             surgery may include secondary interventions (e.g. to clear inadequate surgical
             margins)

          -  Subjects with node positive disease must have undergone treatment of axillary LN with
             curative intent, or subjects must be scheduled for further treatment of regional lymph
             nodes with curative intent. Definitive treatment must be planned to be completed
             within approximately 9 months of randomization

          -  Subjects must not have received prior neoadjuvant treatment. Endocrine treatment for
             less 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 and
             subjects must be scheduled to undergo definitive treatment (including surgery and/or
             radiotherapy) with curative intent within approximately 9 months of starting
             neoadjuvant treatment

          -  Female subjects with age ≥ 18 years

          -  Subjects with reproductive potential must have a negative pregnancy test within 14
             days before randomization

          -  Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9
             mmol/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 lobular
             carcinoma in situ [LCIS]) prior to the current diagnosis

          -  Osteoporosis requiring treatment at the time of randomization or treatment considered
             likely to become necessary within the subsequent six months

          -  Any prior or synchronous malignancy (other than breast cancer), except i) Malignancy
             treated with curative intent and with no evidence of disease for ≥ 5 years prior to
             enrollment and considered to be at low risk for recurrence by the treating physician
             ii) Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of
             disease

          -  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 since
             ending other investigational device or investigational drug study(s), or subject is
             receiving other investigational agent(s)

          -  Subject is pregnant or breast feeding, or planning to become pregnant within 7 months
             after the end of treatment.

          -  Subject is of child bearing potential and is not willing to use, in combination with
             her partner, 2 highly effective methods of contraception or abstinence during
             treatment and for 5 months after the end of treatment

          -  Subject has known sensitivity to any of the products to be administered during the
             study (e.g., mammalian derived products, calcium, or vitamin D)

          -  Subject has any kind of disorder that compromises the ability of the subject to give
             written informed consent and/or to comply with study procedures.

          -  Any major medical or psychiatric disorder that in the opinion of the investigator
             prevent the subject from completing the study or interfere with the interpretation of
             the study results