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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01077154




Registration number
NCT01077154
Ethics application status
Date submitted
4/02/2010
Date registered
26/02/2010
Date last updated
12/02/2020

Titles & IDs
Public title
Study of Denosumab as Adjuvant Treatment for Women With High Risk Early Breast Cancer Receiving Neoadjuvant or Adjuvant Therapy (D-CARE)
Scientific 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)
Secondary ID [1] 0 0
2009-011299-32
Secondary ID [2] 0 0
20060359
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast Cancer 0 0
Condition category
Condition code
Cancer 0 0 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Placebo
Treatment: Drugs - Denosumab

Placebo Comparator: Placebo - Participants received placebo subcutaneous injections once every 4 weeks for 6 months followed by placebo subcutaneous injections once every 3 months for 4.5 years.

Experimental: Denosumab - Participants received denosumab 120 mg subcutaneous injections once every 4 weeks for 6 months followed by denosumab 120 mg subcutaneous injections once every 3 months for 4.5 years.


Treatment: Drugs: Placebo
Administered subcutaneously for up to 5 years

Treatment: Drugs: Denosumab
Administered subcutaneously for up to 5 years

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Bone Metastasis-free Survival (BMFS) - BMFS time was defined as the time interval from the randomization date to the first occurrence of bone metastasis or death from any cause, whichever came first. Participants last known to be alive with no bone metastasis were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first occurrence of bone metastasis before randomization were censored at their randomization date.
Bone metastasis must have been confirmed by central imaging analysis or by biopsy, Evidence of disseminated tumor cells in bone marrow was not sufficient for determination of disease recurrence. Development of new primary malignancy in bone was not considered as bone metastasis.
Since the median BMSF time could not be estimated due to low number of events, the percentage of participants with an event (i.e., bone metastasis or death) is reported.
Timepoint [1] 0 0
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 outcome [1] 0 0
Disease-free Survival (DFS) - DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date.
Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence.
Since the median DFS time could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Timepoint [1] 0 0
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 outcome [2] 0 0
Disease-free Survival (DFS) in the Postmenopausal Subset - DFS time was defined as the time interval from the randomization date to the date of first observation of disease recurrence or death from any cause, whichever was first. Participants last known to be alive with no disease recurrence were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first disease recurrence before randomization were censored at their randomization date.
Disease recurrence includes bone metastasis and extraosseous disease (EOD) confirmed by central imaging analysis or by biopsy/cytology. Development of non-breast cancer new primary malignancy was not considered as disease recurrence.
Since the median DFS time in the postmenopausal subset could not be estimated due to low number of events, the percentage of participants with an event (i.e., disease recurrence or death) is reported.
Timepoint [2] 0 0
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 outcome [3] 0 0
Overall Survival - Overall survival (OS) time was defined as the time interval from the randomization date to the date of death from any cause. Participants last known to be alive were censored at their last contact date.
Since the median time to overall survival could not be estimated at the time of the final analysis due to low numbers of events, the percentage of participants with an event (i.e., death) is reported.
Timepoint [3] 0 0
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.
Secondary outcome [4] 0 0
Distant Recurrence-free Survival - Distant recurrence-free survival (DRFS) was defined as the time interval from the randomization date to the date of first observation of distant disease recurrence or death from any cause, whichever came first. Participants last known to be alive, who had not experienced distant disease recurrence, were censored at their last assessment date, or at the primary analysis data cut-off date, whichever was first. Participants who had first distant recurrence before randomization were censored at their randomization date.
Distant disease recurrence includes confirmed bone metastasis and extraosseous disease other than local-regional disease recurrence. Development of non-breast cancer new primary malignancy was not considered as distant disease recurrence.
Since the median time to DRFS could not be estimated due to the low number of events, the percentage of participants with an event (i.e., distant recurrence or death) is reported.
Timepoint [4] 0 0
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.

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC,WA
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Research Site - Bedford Park
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Research Site - Bentleigh East
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Research Site - East Melbourne
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Research Site - Fitzroy
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Research Site - Footscray
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2050 - Camperdown
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2229 - Caringbah
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2217 - Kogarah
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2485 - Tweed Heads
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2076 - Wahroonga
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5042 - Bedford Park
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3165 - Bentleigh East
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3002 - East Melbourne
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3065 - Fitzroy
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3011 - Footscray
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3199 - Frankston
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3084 - Heidelberg
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3121 - Richmond
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3135 - Ringwood East
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3690 - Wodonga
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6000 - Perth
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6008 - Subiaco
Recruitment outside Australia
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Poria Eylit
Country [150] 0 0
Israel
State/province [150] 0 0
Rehovot
Country [151] 0 0
Israel
State/province [151] 0 0
Tel Aviv
Country [152] 0 0
Italy
State/province [152] 0 0
Ancona
Country [153] 0 0
Italy
State/province [153] 0 0
Bari
Country [154] 0 0
Italy
State/province [154] 0 0
Brescia
Country [155] 0 0
Italy
State/province [155] 0 0
Meldola FC
Country [156] 0 0
Italy
State/province [156] 0 0
Milano
Country [157] 0 0
Italy
State/province [157] 0 0
Monza (MB)
Country [158] 0 0
Italy
State/province [158] 0 0
Palermo
Country [159] 0 0
Italy
State/province [159] 0 0
Parma
Country [160] 0 0
Italy
State/province [160] 0 0
San Giovanni Rotondo FG
Country [161] 0 0
Italy
State/province [161] 0 0
Treviglio (BG)
Country [162] 0 0
Italy
State/province [162] 0 0
Varese
Country [163] 0 0
Japan
State/province [163] 0 0
Aichi
Country [164] 0 0
Japan
State/province [164] 0 0
Ehime
Country [165] 0 0
Japan
State/province [165] 0 0
Fukuoka
Country [166] 0 0
Japan
State/province [166] 0 0
Hiroshima
Country [167] 0 0
Japan
State/province [167] 0 0
Hyogo
Country [168] 0 0
Japan
State/province [168] 0 0
Kagoshima
Country [169] 0 0
Japan
State/province [169] 0 0
Kanagawa
Country [170] 0 0
Japan
State/province [170] 0 0
Kumamoto
Country [171] 0 0
Japan
State/province [171] 0 0
Kyoto
Country [172] 0 0
Japan
State/province [172] 0 0
Miyazaki
Country [173] 0 0
Japan
State/province [173] 0 0
Niigata
Country [174] 0 0
Japan
State/province [174] 0 0
Okayama
Country [175] 0 0
Japan
State/province [175] 0 0
Osaka
Country [176] 0 0
Japan
State/province [176] 0 0
Saitama
Country [177] 0 0
Japan
State/province [177] 0 0
Shizuoka
Country [178] 0 0
Japan
State/province [178] 0 0
Tochigi
Country [179] 0 0
Japan
State/province [179] 0 0
Tokyo
Country [180] 0 0
Korea, Republic of
State/province [180] 0 0
Goyang-si, Gyeonggi-do
Country [181] 0 0
Korea, Republic of
State/province [181] 0 0
Incheon
Country [182] 0 0
Korea, Republic of
State/province [182] 0 0
Seoul
Country [183] 0 0
Latvia
State/province [183] 0 0
Daugavpils
Country [184] 0 0
Latvia
State/province [184] 0 0
Liepaja
Country [185] 0 0
Latvia
State/province [185] 0 0
Riga
Country [186] 0 0
Malaysia
State/province [186] 0 0
Kelantan
Country [187] 0 0
Malaysia
State/province [187] 0 0
Selangor (incl. Putrajaya)
Country [188] 0 0
Malaysia
State/province [188] 0 0
Wilayah Persekutuan
Country [189] 0 0
Mexico
State/province [189] 0 0
Distrito Federal
Country [190] 0 0
Mexico
State/province [190] 0 0
Guanajuato
Country [191] 0 0
Mexico
State/province [191] 0 0
Hidalgo
Country [192] 0 0
Mexico
State/province [192] 0 0
Nuevo León
Country [193] 0 0
Mexico
State/province [193] 0 0
Querétaro
Country [194] 0 0
Mexico
State/province [194] 0 0
San Luis PotosÃ-
Country [195] 0 0
Mexico
State/province [195] 0 0
Colima
Country [196] 0 0
Mexico
State/province [196] 0 0
Durango
Country [197] 0 0
Mexico
State/province [197] 0 0
Toluca
Country [198] 0 0
Netherlands
State/province [198] 0 0
Amsterdam
Country [199] 0 0
Netherlands
State/province [199] 0 0
Bergen op Zoom
Country [200] 0 0
Netherlands
State/province [200] 0 0
Breda
Country [201] 0 0
Netherlands
State/province [201] 0 0
Capelle aan den ijssel
Country [202] 0 0
Netherlands
State/province [202] 0 0
Den Haag
Country [203] 0 0
Netherlands
State/province [203] 0 0
Dordrecht
Country [204] 0 0
Netherlands
State/province [204] 0 0
Hoofddorp
Country [205] 0 0
Netherlands
State/province [205] 0 0
Leiden
Country [206] 0 0
Netherlands
State/province [206] 0 0
Nieuwegein
Country [207] 0 0
Netherlands
State/province [207] 0 0
Rotterdam
Country [208] 0 0
Netherlands
State/province [208] 0 0
Schiedam
Country [209] 0 0
Netherlands
State/province [209] 0 0
Sittard-Geleen
Country [210] 0 0
Netherlands
State/province [210] 0 0
Tiel
Country [211] 0 0
Netherlands
State/province [211] 0 0
Tilburg
Country [212] 0 0
Netherlands
State/province [212] 0 0
Venlo
Country [213] 0 0
Peru
State/province [213] 0 0
Lima
Country [214] 0 0
Philippines
State/province [214] 0 0
Cebu City
Country [215] 0 0
Philippines
State/province [215] 0 0
Manila
Country [216] 0 0
Philippines
State/province [216] 0 0
Metro Manila
Country [217] 0 0
Philippines
State/province [217] 0 0
Quezon City
Country [218] 0 0
Poland
State/province [218] 0 0
Gdansk
Country [219] 0 0
Poland
State/province [219] 0 0
Krakow
Country [220] 0 0
Poland
State/province [220] 0 0
Olsztyn
Country [221] 0 0
Poland
State/province [221] 0 0
Poznan
Country [222] 0 0
Poland
State/province [222] 0 0
Rzeszow
Country [223] 0 0
Poland
State/province [223] 0 0
Szczecin
Country [224] 0 0
Portugal
State/province [224] 0 0
Lisboa
Country [225] 0 0
Portugal
State/province [225] 0 0
Porto
Country [226] 0 0
Portugal
State/province [226] 0 0
Santa Maria da Feira
Country [227] 0 0
Romania
State/province [227] 0 0
Bucharest
Country [228] 0 0
Romania
State/province [228] 0 0
Craiova
Country [229] 0 0
Romania
State/province [229] 0 0
Sibiu
Country [230] 0 0
Romania
State/province [230] 0 0
Suceava
Country [231] 0 0
Romania
State/province [231] 0 0
Timisoara
Country [232] 0 0
Russian Federation
State/province [232] 0 0
Barnaul
Country [233] 0 0
Russian Federation
State/province [233] 0 0
Chelyabinsk
Country [234] 0 0
Russian Federation
State/province [234] 0 0
Ivanovo
Country [235] 0 0
Russian Federation
State/province [235] 0 0
Kazan
Country [236] 0 0
Russian Federation
State/province [236] 0 0
Moscow
Country [237] 0 0
Russian Federation
State/province [237] 0 0
Saint Petersburg
Country [238] 0 0
Serbia
State/province [238] 0 0
Belgrade
Country [239] 0 0
Serbia
State/province [239] 0 0
Nis
Country [240] 0 0
Slovakia
State/province [240] 0 0
Bardejov
Country [241] 0 0
Slovakia
State/province [241] 0 0
Kosice
Country [242] 0 0
Slovakia
State/province [242] 0 0
Michalovce
Country [243] 0 0
Slovakia
State/province [243] 0 0
Poprad
Country [244] 0 0
Slovakia
State/province [244] 0 0
Presov
Country [245] 0 0
Slovakia
State/province [245] 0 0
Spisska Nova Ves
Country [246] 0 0
Slovakia
State/province [246] 0 0
Trebisov
Country [247] 0 0
Slovenia
State/province [247] 0 0
Ljublijana
Country [248] 0 0
Slovenia
State/province [248] 0 0
Maribor
Country [249] 0 0
South Africa
State/province [249] 0 0
Gauteng
Country [250] 0 0
South Africa
State/province [250] 0 0
Cape Town
Country [251] 0 0
South Africa
State/province [251] 0 0
Pietermaritzburg
Country [252] 0 0
South Africa
State/province [252] 0 0
Port Elizabeth
Country [253] 0 0
South Africa
State/province [253] 0 0
Pretoria
Country [254] 0 0
Spain
State/province [254] 0 0
AndalucÃ-a
Country [255] 0 0
Spain
State/province [255] 0 0
Aragón
Country [256] 0 0
Spain
State/province [256] 0 0
Cantabria
Country [257] 0 0
Spain
State/province [257] 0 0
Cataluña
Country [258] 0 0
Spain
State/province [258] 0 0
Comunidad Valenciana
Country [259] 0 0
Spain
State/province [259] 0 0
Galicia
Country [260] 0 0
Spain
State/province [260] 0 0
Madrid
Country [261] 0 0
Taiwan
State/province [261] 0 0
Chiayi
Country [262] 0 0
Taiwan
State/province [262] 0 0
Keelung
Country [263] 0 0
Taiwan
State/province [263] 0 0
Tainan
Country [264] 0 0
Taiwan
State/province [264] 0 0
Taipei
Country [265] 0 0
Turkey
State/province [265] 0 0
Ankara
Country [266] 0 0
Turkey
State/province [266] 0 0
Bornova-Izmir
Country [267] 0 0
Turkey
State/province [267] 0 0
Ä°zmir
Country [268] 0 0
United Kingdom
State/province [268] 0 0
Bebington
Country [269] 0 0
United Kingdom
State/province [269] 0 0
Birmingham
Country [270] 0 0
United Kingdom
State/province [270] 0 0
Brighton
Country [271] 0 0
United Kingdom
State/province [271] 0 0
Bristol
Country [272] 0 0
United Kingdom
State/province [272] 0 0
Cambridge
Country [273] 0 0
United Kingdom
State/province [273] 0 0
Dorset
Country [274] 0 0
United Kingdom
State/province [274] 0 0
Guildford
Country [275] 0 0
United Kingdom
State/province [275] 0 0
Leeds
Country [276] 0 0
United Kingdom
State/province [276] 0 0
London
Country [277] 0 0
United Kingdom
State/province [277] 0 0
Manchester
Country [278] 0 0
United Kingdom
State/province [278] 0 0
Newcastle
Country [279] 0 0
United Kingdom
State/province [279] 0 0
Peterborough
Country [280] 0 0
United Kingdom
State/province [280] 0 0
Plymouth
Country [281] 0 0
United Kingdom
State/province [281] 0 0
Poole
Country [282] 0 0
United Kingdom
State/province [282] 0 0
Portsmouth
Country [283] 0 0
United Kingdom
State/province [283] 0 0
Sheffield
Country [284] 0 0
United Kingdom
State/province [284] 0 0
Truro

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Amgen
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Daiichi Sankyo, Inc.
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01077154
Trial related presentations / publications
Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Periañez 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.
Public notes

Contacts
Principal investigator
Name 0 0
MD
Address 0 0
Amgen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT01077154