ABCSG 18 Details

A randomized, doubleblind, placebo-controlled, multi-center phase-3-study to determine the treatment effect of denosumab in subjects with non-metastatic breast cancer receiving non-steroidal aromatase inhibitor therapy


Contact ABCSG-Trial office

E-mail: info@abcsg.at
Phone: +43 1 408 92 30
Fax: +43 1 409 09 90

Design

ABCSG-18 Design
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Primary objectives:

  • To determine whether denosumab compared to placebo will reduce the rate of first (on-study) clinical fracture (ie, clinically evident fracture with associated symptoms) in women with non-metastatic breast cancer receiving non-steroidal aromatase inhibitor therapy (AIT).

Secondary objectives:

  • To assess the effect of denosumab compared to placebo on the following:
  • Fracture-related secondary endpoints:
  • Bone mineral density (BMD) at lumbar spine, total hip and femoral neck in a subgroup of subjects at pre-selected sites
  • Incidence of new vertebral fractures (both clinical and morphometric [ie, a fracture in the vertebral column that is not clinically evident and that is asymptomatic])
  • Incidence of new or worsening of pre-existing vertebral fractures (both clinical and morphometric)
  • Disease outcome-related secondary endpoints:
  • Disease-free survival (DFS)
  • Bone metastasis-free survival (BMFS)
  • Overall survival (OS)

Inclusion criteria:

  1. Histologically or cytologically confirmed adenocarcinoma of the breast
  2. Female subjects with non-metastatic disease who are estrogen receptor (ER) and/or progesterone receptor (PR) positive, and who have completed their treatment pathway (surgery, chemotherapy)
  3. Subjects who are currently on, or will initiate an approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting
  4. Postmenopausal woman1,2, defined as a woman fulfilling any 1 of the following criteria:
    • Having undergone a bilateral oophorectomy;
    • Age ≥ 60 years;
    • Aged < 60 years meeting the following requirements:
    • 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.
  5. ECOG performance score of 0 or 1
  6. Before any study-specific procedure is performed, a signed and dated written informed consent must be obtained

Exclusion criteria:

  1. Aromatase inhibitor therapy for more than 24 months
  2. Prior or concurrent treatment with Selective Estrogen Receptor Modulators (SERMs) (eg, tamoxifen)
  3. Evidence of metastatic disease
  4. Current or prior IV bisphosphonate administration
  5. 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
    • Any use during the 3-month period prior to randomization
  6. Known liver or renal deficiency as determined by the investigator and indicated by the following criteria:
    • AST ≥ 2.5 x ULN
    • ALT ≥ 2.5 x ULN
    • Serum creatinine ≥ 2 x ULN
  7. Prior administration of denosumab (AMG 162)
  8. Recurrence of the primary malignancy (eg, during the allowed interval of pretreatment with an aromatase inhibitor)
  9. 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
  10. 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
    • Hypercalcemia or hypocalcemia: as defined by calcium outside the normal range (A single value outside the normal range does not necessarily constitute hypercalcemia or hypocalcemia, but should be ‘corrected’ before including the subject. Subjects with a known history of hypercalcemia or hypocalcemia cannot be included)
    • Major surgery, or significant traumatic injury occurring within 4 weeks prior to randomization
    • Known Human Immunodeficiency Virus (HIV) infection
    • Active infection with hepatitis B or hepatitis C virus
  11. Any major medical or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results
  12. Thirty days or less since receiving an investigational product or device in another clinical study
  13. Known sensitivity to any of the products to be administered during the study (eg, mammalian-derived products, calcium or vitamin D)
  14. Subjects who are pregnant, breastfeeding, or plan to become pregnant during the course of the study. All subjects with reproductive potential must have a negative pregnancy test within 7 days before randomization
  15. Any kind of disorder that compromises the ability to give written informed consent and/or comply with study procedures