Efficacy of Denosumab on Normal BMD in Women Receiving Adjuvant Aromatase Inhibitors for Early Breast Cancer

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Denosumab Injection

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Hisako Ono, PhD; Phone Number: 81 0752515534; Email: hisako-o@koto.kpu-m.ac.jp
• Study Contact Backup: Name: Tetsuya Taguchi, PhD; Phone Number: 81 0752515534; Email: ttaguchi@koto.kpu-m.ac.jp

Study Locations

• Japan
  • Kyoto, Japan, 6028566
    • Hisako Ono

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: AI+denosumab VS only AI; We compare AI intake+denosumab injection and AI intake only in patients with normal BMD to whom Letrozole or Arimidex will be administered as postoperative endocrine therapy, and we assess the efficacy of denosumab injection on bone loss by adjuvant endocrine therapy.	Drug: Denosumab Injection; AI intake + denosumab injection per 6 months VS only AI intake; Other Names: pralia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage change in the bone mineral density (BMD) for the lumbar vertebrae (L1-L4) on dual-energy X-ray absorptiometry (DXA)	The change is a value obtained by subtracting 1 from the BMD after 12 months/baseline BMD is expressed as a percentage	12 months after the start of this study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage change in the BMD for the lumbar vertebrae (L1-L4) on DXA	percentage change in the BMD for the femoral neck: After 2/3/4/5 years	after 2, 3, 4, and 5 years
percentage change in the BMD for the femoral neck	percentage change in the BMD for the femoral neck: After 12 months and 2/3/4/5 years	after 12 months and 2/3/4/5 years
percentage change in the BMD for the radius (an ultrasonic bone densimeter is used)institutions in which ultrasonic bone densimeters are used)	percentage change in the BMD for the radius (an ultrasonic bone densimeter is used): After 2 and 4 weeks, every 4 weeks thereafter (for 2 years after registration)(only institutions in which ultrasonic bone densimeters are used)	after 2 and 4 weeks, every 4 weeks thereafter (for 2 years after registration)(only
Changes in Ca and bone metabolism markers	Changes in Ca (mg/dL corrected by albumin level) and bone metabolism markers such as TRAP5b, bone-specific alkaline phosphatase (BSAP), blood pentosidine) by blood sampling at every 6 months	after 24 weeks
Appearance rate of morbid fracture in all participants	Appearance rate of morbid fracture up to 3 years in all participants. Morbid fractures include all types of fractures.	up to 3 years
Disease-free survival	Disease-free survival at the end of the study	at least 5 year
Overall survival	Overall survival at the end of the study	at least 5 year
Appearance of adverse events	Appearance rate of adverse events (such as hypocalcemia and necrosis of the jaw)	at least 5 year
Quality of life (QOL)	Quality of life(QOL), Japanese version Euro-Qol (EQ-5D-5L) evaluated by questionnaire at every 6 months	after 24 weeks

Collaborators and Investigators

• Sponsor: Kyoto Prefectural University of Medicine
• Investigators: Study Director: Hisako Ono, PhD, Kyoto Prefectural University of Medicine; Principal Investigator: Tetsuya Taguchi, PhD, Kyoto Prefectural University of Medicine

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2017
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: September 21, 2017
• First Submitted That Met QC Criteria: October 24, 2017
• First Posted (Actual): October 30, 2017

Study Record Updates

• Last Update Posted (Actual): October 6, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: postmenopausal; bone mineral density; aromatase inhibitor; bone health; hormone-sensitive breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: CQARD-EBS-160402; jRCTs051180211 (Registry Identifier: jRCT)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes