Clinical trial NCT01077154: Study of Denosumab as Adjuvant Treatment for Women With High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)
Official title: A Randomized, Double-Blind, Placebo-Controlled, Multi-Center Phase 3 Study of Denosumab as Adjuvant Treatment for Women With Early-Stage Breast Cancer at High Risk of Recurrence (D-CARE)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Breast Cancer
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
Lead sponsor: Amgen
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
First posted: 2010-02-26
Enrollment: 4509
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: Eligible participants were randomized in a 1:1 ratio to receive denosumab 120 mg or placebo subcutaneously (SC) for up to 5 years. Randomization was stratified based on:

1. Breast cancer therapy/lymph node (LN) status: neoadjuvant therapy/any LN status versus adjuvant therapy/LN negative (based on axillary LN dissection, or based on sentinel node status) versus adjuvant therapy/LN positive
2. Hormone receptor (estrogen receptor \[ER\]/progesterone receptor \[PR\]) status: ER and/or PR positive versus ER and PR negative
3. Human epidermal growth factor receptor 2 (HER-2) status: HER-2 positive versus HER-2 negative
4. Age: \< 50 years versus ≥ 50 years
5. Geographic Region: Japan versus Other regions.

The primary analysis was conducted after all enrolled participants had the opportunity to complete 5 years of treatment from study day 1.

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

Primary outcomes:
measure: Bone Metastasis-free Survival (BMFS)
timeFrame: From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
Secondary outcomes:
measure: Disease-free Survival (DFS)
timeFrame: From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
measure: Disease-free Survival (DFS) in the Postmenopausal Subset
timeFrame: From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
measure: Overall Survival
timeFrame: From randomization until the end of study; median (minimum, maximum) time on study was 72.7 (0, 92) and 72.3 (0, 92) months in each treatment group respectively.
measure: Distant Recurrence-free Survival
timeFrame: From randomization until the primary analysis data cut-off date of 31 August 2017; median (minimum, maximum) time on study was 67.2 (0.0, 85.9) and 67.0 (0.0, 86.6) months in each treatment group respectively.
Other outcomes:
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state: SÃ£o Paulo
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city: Brampton
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country: Hungary
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country: Hungary
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country: India
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country: India
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country: India
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country: India
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country: India
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country: India
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city: Rehovot
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Ancona
country: Italy
facility: Research Site
city: Bari
country: Italy
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Meldola FC
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Monza (MB)
country: Italy
facility: Research Site
city: Palermo
country: Italy
facility: Research Site
city: Parma
country: Italy
facility: Research Site
city: San Giovanni Rotondo FG
country: Italy
facility: Research Site
city: Treviglio (BG)
country: Italy
facility: Research Site
city: Varese
country: Italy
facility: Research Site
city: Nagoya-shi
country: Japan
facility: Research Site
state: Aichi
city: Nagoya-shi
country: Japan
facility: Research Site
state: Aichi
city: Matsuyama-shi
country: Japan
facility: Research Site
state: Ehime
city: Fukuoka-shi
country: Japan
facility: Research Site
state: Fukuoka
city: Kitakyushu-shi
country: Japan
facility: Research Site
state: Fukuoka
city: Kurume-shi
country: Japan
facility: Research Site
state: Fukuoka
city: Kure-shi
country: Japan
facility: Research Site
state: Hiroshima
city: Akashi-shi
country: Japan
facility: Research Site
state: Hyogo
city: Kagoshima-shi
country: Japan
facility: Research Site
state: Kagoshima
city: Isehara-shi
country: Japan
facility: Research Site
state: Kanagawa
city: Kumamoto-shi
country: Japan
facility: Research Site
state: Kumamoto
city: Kyoto-shi
country: Japan
facility: Research Site
state: Kyoto
city: Miyazaki-shi
country: Japan
facility: Research Site
state: Miyazaki
city: Niigata-shi
country: Japan
facility: Research Site
state: Niigata
city: Kurashiki-shi
country: Japan
facility: Research Site
state: Okayama
city: Osaka-shi
country: Japan
facility: Research Site
state: Osaka
city: Osaka-shi
country: Japan
facility: Research Site
state: Osaka
city: Suita-shi
country: Japan
facility: Research Site
state: Osaka
city: Hidaka-Shi
country: Japan
facility: Research Site
state: Saitama
city: Kitaadachi-gun
country: Japan
facility: Research Site
state: Saitama
city: Suntou-gun
country: Japan
facility: Research Site
state: Shizuoka
city: Shimotsuke-shi
country: Japan
facility: Research Site
state: Tochigi
city: Utsunomiya-shi
country: Japan
facility: Research Site
state: Tochigi
city: Chuo-ku
country: Japan
facility: Research Site
state: Tokyo
city: Tokyo
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
city: Goyang-si, Gyeonggi-do
country: Korea, Republic of
facility: Research Site
city: Incheon
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Daugavpils
country: Latvia
facility: Research Site
city: Liepaja
country: Latvia
facility: Research Site
city: Riga
country: Latvia
facility: Research Site
city: Kota Bharu
country: Malaysia
facility: Research Site
state: Kelantan
city: Subang Jaya
country: Malaysia
facility: Research Site
state: Selangor (incl. Putrajaya)
city: Kuala Lumpur
country: Malaysia
facility: Research Site
state: Wilayah Persekutuan
city: Kuala Lumpur
country: Malaysia
facility: Research Site
state: Wilayah Persekutuan
city: Mexico City
country: Mexico
facility: Research Site
state: Distrito Federal
city: Mexico City
country: Mexico
facility: Research Site
state: Distrito Federal
city: Mexico
country: Mexico
facility: Research Site
state: Distrito Federal
city: Leon
country: Mexico
facility: Research Site
state: Guanajuato
city: Pachuca de Soto
country: Mexico
facility: Research Site
state: Hidalgo
city: Monterrey
country: Mexico
facility: Research Site
state: Nuevo LeÃ³n
city: Queretaro
country: Mexico
facility: Research Site
state: QuerÃ©taro
city: San Luis Potosi
country: Mexico
facility: Research Site
state: San Luis PotosÃ-
city: Colima
country: Mexico
facility: Research Site
city: Distrito Federal
country: Mexico
facility: Research Site
city: Durango
country: Mexico
facility: Research Site
city: Toluca
country: Mexico
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Bergen op Zoom
country: Netherlands
facility: Research Site
city: Breda
country: Netherlands
facility: Research Site
city: Capelle aan den ijssel
country: Netherlands
facility: Research Site
city: Den Haag
country: Netherlands
facility: Research Site
city: Dordrecht
country: Netherlands
facility: Research Site
city: Hoofddorp
country: Netherlands
facility: Research Site
city: Leiden
country: Netherlands
facility: Research Site
city: Nieuwegein
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Schiedam
country: Netherlands
facility: Research Site
city: Sittard-Geleen
country: Netherlands
facility: Research Site
city: Tiel
country: Netherlands
facility: Research Site
city: Tilburg
country: Netherlands
facility: Research Site
city: Venlo
country: Netherlands
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Cebu City
country: Philippines
facility: Research Site
city: Manila
country: Philippines
facility: Research Site
city: Manila
country: Philippines
facility: Research Site
city: Metro Manila
country: Philippines
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Krakow
country: Poland
facility: Research Site
city: Olsztyn
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Rzeszow
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Porto
country: Portugal
facility: Research Site
city: Porto
country: Portugal
facility: Research Site
city: Santa Maria da Feira
country: Portugal
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Craiova
country: Romania
facility: Research Site
city: Sibiu
country: Romania
facility: Research Site
city: Suceava
country: Romania
facility: Research Site
city: Timisoara
country: Romania
facility: Research Site
city: Barnaul
country: Russian Federation
facility: Research Site
city: Chelyabinsk
country: Russian Federation
facility: Research Site
city: Ivanovo
country: Russian Federation
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Belgrade
country: Serbia
facility: Research Site
city: Nis
country: Serbia
facility: Research Site
city: Bardejov
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Michalovce
country: Slovakia
facility: Research Site
city: Poprad
country: Slovakia
facility: Research Site
city: Presov
country: Slovakia
facility: Research Site
city: Spisska Nova Ves
country: Slovakia
facility: Research Site
city: Trebisov
country: Slovakia
facility: Research Site
city: Ljublijana
country: Slovenia
facility: Research Site
city: Maribor
country: Slovenia
facility: Research Site
city: Groenkloof
country: South Africa
facility: Research Site
state: Gauteng
city: Johannesburg
country: South Africa
facility: Research Site
state: Gauteng
city: Cape Town
country: South Africa
facility: Research Site
city: Pietermaritzburg
country: South Africa
facility: Research Site
city: Port Elizabeth
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: Pretoria
country: South Africa
facility: Research Site
city: CÃ¡diz
country: Spain
facility: Research Site
state: AndalucÃ-a
city: CÃ³rdoba
country: Spain
facility: Research Site
state: AndalucÃ-a
city: JaÃ©n
country: Spain
facility: Research Site
state: AndalucÃ-a
city: MÃ¡laga
country: Spain
facility: Research Site
state: AndalucÃ-a
city: Sevilla
country: Spain
facility: Research Site
state: AndalucÃ-a
city: Zaragoza
country: Spain
facility: Research Site
state: AragÃ³n
city: Santander
country: Spain
facility: Research Site
state: Cantabria
city: Badalona
country: Spain
facility: Research Site
state: CataluÃ±a
city: Barcelona
country: Spain
facility: Research Site
state: CataluÃ±a
city: Barcelona
country: Spain
facility: Research Site
state: CataluÃ±a
city: Barcelona
country: Spain
facility: Research Site
state: CataluÃ±a
city: Barcelona
country: Spain
facility: Research Site
state: CataluÃ±a
city: Girona
country: Spain
facility: Research Site
state: CataluÃ±a
city: Lleida
country: Spain
facility: Research Site
state: CataluÃ±a
city: Sabadell
country: Spain
facility: Research Site
state: CataluÃ±a
city: Elche
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Research Site
state: Comunidad Valenciana
city: A CoruÃ±a
country: Spain
facility: Research Site
state: Galicia
city: A CoruÃ±a
country: Spain
facility: Research Site
state: Galicia
city: AlcorcÃ³n
country: Spain
facility: Research Site
state: Madrid
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Putzu City
country: Taiwan
facility: Research Site
state: Chiayi
city: Keelung City
country: Taiwan
facility: Research Site
state: Keelung
city: Tainan
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Bornova-Izmir
country: Turkey
facility: Research Site
city: Ä°zmir
country: Turkey
facility: Research Site
city: Bebington
country: United Kingdom
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Brighton
country: United Kingdom
facility: Research Site
city: Bristol
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Dorset
country: United Kingdom
facility: Research Site
city: Guildford
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle
country: United Kingdom
facility: Research Site
city: Peterborough
country: United Kingdom
facility: Research Site
city: Plymouth
country: United Kingdom
facility: Research Site
city: Poole
country: United Kingdom
facility: Research Site
city: Portsmouth
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
city: Truro
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Perianez AM, Tonkin K, Deleu I, Sohn J, Crown J, Delaloge S, Dai T, Zhou Y, Jandial D, Chan A. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):60-72. doi: 10.1016/S1470-2045(19)30687-4. Epub 2019 Dec 2.
citation: Coleman R, Zhou Y, Jandial D, Cadieux B, Chan A. Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer. Adv Ther. 2021 Aug;38(8):4569-4580. doi: 10.1007/s12325-021-01812-9. Epub 2021 Jun 29.