Clinical trial NCT03324932: Efficacy of Denosumab on Normal BMD in Women Receiving Adjuvant Aromatase Inhibitors for Early Breast Cancer
Official title: A Multicenter, Randomized, Comparative Study Regarding the Efficacy of Denosumab on Normal Bone Mineral Density in Women Receiving Adjuvant Aromatase Inhibitors for Early Breast Cancer (ENDEAVOR Trial)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: bone health
hormone-sensitive breast cancer
postmenopausal
aromatase inhibitor
bone mineral density
Lead sponsor: Kyoto Prefectural University of Medicine
Sponsor class: OTHER
First posted: 2017-10-30
Enrollment: 160
Sex: FEMALE
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This multicenter, randomized, comparative study will evaluate the efficacy of denosumab to prevent the adjuvant therapy of aromatase inhibitors-induced loss of bone mineral density (BMD) in breast cancer patients with normal BMD. Investigators will compare the inhibitory effects of denosumab on bone loss between participants with normal BMD to whom Letrozole or Arimidex will be administered as postoperative endocrine therapy for stage I-IIIA postmenopausal hormone-sensitive breast cancer and controls.

Detailed description: Normal BMD means T score is ≥-1.0 for the lumbar vertebrae (L1-L4) and/or the femoral neck.

Eligibility criteria: Inclusion Criteria:

Patients must meet all of the following items at the time of case registration:

1. Patients with infiltrative breast cancer, aged ≥20 years, meeting the following definitions:

   * Those pathologically diagnosed with stage I, II, or IIIA breast cancer (Cancer Management Regulations, 11th version)
   * Those who underwent appropriate surgery, such as mastectomy and breast-preserving surgery
2. Estrogen receptor (ER)- or progesterone receptor (PgR)-positive patients on immunohistochemical (IHC) staining
3. Females meeting one of the following criteria for menopause:

   * Those, aged ≥55 years, without menstruation
   * Those, aged \<55 years, with amenorrhea for ≥12 months, or those diagnosed with menopause by attending physicians based on the FSH and estradiol levels
   * Those who underwent bilateral oophorectomy
4. Patients in whom the BMD for the lumbar vertebrae (L1-L4) on DXA before the start of this study is ≥-1.0SD of the mean value of young adult females (YAM), and the BMD for the femoral neck is ≥-1.0SD of YAM
5. Patients without lumbar vertebral or femoral fracture
6. Those with an ECOG PS of 0-2
7. Those with adequate organ functions (laboratory data within 4 weeks before case registration)

   * Leukocyte count, ≥3,000/mm3 or Neutrophil count, ≥1,500/mm3
   * AST, ALT, ≤1.5-fold of the upper limit of the institutional reference range
   * Serum creatinine, ≤1.5-fold of the upper limit of the institutional reference range
8. Case registration should be performed before the following point:Twelve weeks after the completion of surgery or postoperative chemotherapy (The completion of chemotherapy refers to the completion of the final course, involving the recovery phase.)
9. Patients with an interval of ≥4 weeks after the discontinuation of therapy with bisphosphonates (oral preparations), estrogen preparations, raloxifene, calcitonin preparations, vitamin K preparations, active vitamin D preparations, or ipriflavone preparations, which influence bones
10. Those from whom written informed consent regarding study participation was obtained

Exclusion Criteria:

Whether each patient meets any of the following items must be checked on case registration:

1. Patients in whom distant metastasis was confirmed clinically or using imaging procedures at the time of case registration
2. Those with bilateral breast cancer
3. Those for whom postoperative hormonal therapy was started before consenting to study participation
4. Those who received endocrine therapy within 52 weeks before consenting to study participation
5. Those to whom bisphosphonate preparations were intravenously administered within 52 weeks before consenting to study participation
6. Those with the following diseases that may affect DXA

   * Severe scoliosis, immobility, hyperostosis or osteosclerosis of the lumbar vertebrae, calcification of the abdominal aorta, and vertebral disease
7. Those with a history of malignant tumors other than breast cancer within 260 weeks before consenting to study participation
8. Those with dental diseases, such as infectious diseases of the teeth or jaw and tooth trauma. Those for whom tooth or jaw surgery is scheduled within 6 weeks after consenting to study participation (tooth extraction, implantation)
9. Others who are considered to be ineligible by the chief investigator

Primary outcomes:
measure: percentage change in the bone mineral density (BMD) for the lumbar vertebrae (L1-L4) on dual-energy X-ray absorptiometry (DXA)
timeFrame: 12 months after the start of this study
Secondary outcomes:
measure: percentage change in the BMD for the lumbar vertebrae (L1-L4) on DXA
timeFrame: after 2, 3, 4, and 5 years
measure: percentage change in the BMD for the femoral neck
timeFrame: after 12 months and 2/3/4/5 years
measure: percentage change in the BMD for the radius (an ultrasonic bone densimeter is used)institutions in which ultrasonic bone densimeters are used)
timeFrame: after 2 and 4 weeks, every 4 weeks thereafter (for 2 years after registration)(only
measure: Changes in Ca and bone metabolism markers
timeFrame: after 24 weeks
measure: Appearance rate of morbid fracture in all participants
timeFrame: up to 3 years
measure: Disease-free survival
timeFrame: at least 5 year
measure: Overall survival
timeFrame: at least 5 year
measure: Appearance of adverse events
timeFrame: at least 5 year
measure: Quality of life (QOL)
timeFrame: after 24 weeks
Other outcomes:
Locations:
city: Kyoto
country: Japan
facility: Hisako Ono
Study officials:
affiliation: Kyoto Prefectural University of Medicine
name: Hisako Ono, PhD
role: STUDY_DIRECTOR
affiliation: Kyoto Prefectural University of Medicine
name: Tetsuya Taguchi, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nakatsukasa K, Koyama H, Ouchi Y, Ono H, Sakaguchi K, Matsuda T, Kato M, Ishikawa T, Yamada K, Yoshimura M, Koizumi K, Sakurai T, Shigematsu H, Takahashi S, Taira S, Suzuki M, Narui K, Niikura N, Hasegawa Y, Miura D, Konishi E, Taguchi T; Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society. Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results. Breast Cancer. 2019 Jan;26(1):106-112. doi: 10.1007/s12282-018-0896-y. Epub 2018 Jul 27.
citation: Sakaguchi K, Ono H, Nakatsukasa K, Ishikawa T, Hasegawa Y, Takahashi M, Niikura N, Koizumi K, Sakurai T, Shigematsu H, Takahashi S, Taira S, Suzuki M, Narui K, Miura D, Yamada K, Yoshimura M, Shioya H, Konishi E, Isao Y, Imai K, Fujikawa K, Taguchi T; Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society. Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer. Medicine (Baltimore). 2019 Aug;98(32):e16770. doi: 10.1097/MD.0000000000016770.