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Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer (BOLERO-3)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01007942
First Posted: November 4, 2009
Last Update Posted: April 5, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
Results First Submitted: June 10, 2016  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions: HER2/Neu Over-expressing Locally Advanced Breast Cancer
Metastatic Breast Cancer
Interventions: Drug: everolimus
Drug: Placebo
Drug: vinorelbine
Drug: trastuzumab

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
DCO ( Data cut-off) for patient disposition is 1-Apr-2015. Each Cycle = 21 days

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
284 patients randomized to the Everolimus + trastuzumab + vinorelbine arm, 280 took drug. 285 patients randomized to the placebo + trastuzumab + vinorelbine arm, 282 too drug. A total of 569 were comprised to randomized total and 562 to safety.

Reporting Groups
  Description
Everolimus + Vinorelbine + Trastuzumab Oral everolimus (5 mg/day) + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)
Placebo + Vinorelbine + Trastuzumab Oral daily matching placebo + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

Participant Flow:   Overall Study
    Everolimus + Vinorelbine + Trastuzumab   Placebo + Vinorelbine + Trastuzumab
STARTED   284   285 
COMPLETED   3 [1]   7 [1] 
NOT COMPLETED   281   278 
Adverse Event                29                14 
Abnormal test procedure                0                1 
Disease progression                217                242 
New cancer therapy                5                1 
Protocol Violation                1                1 
Withdrawal by Subject                19                14 
Lost to Follow-up                1                0 
Administrative problems                2                0 
Death                3                2 
Patients untreated                4                3 
[1] Pts completed= on treatment at time of DCO. Not Completed = ended treatment as per protocol.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
The Full Analysis Set (FAS) consisted of all randomized patients.

Reporting Groups
  Description
Everolimus + Vinorelbine + Trastuzumab Oral everolimus (5 mg/day) + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)
Placebo + Vinorelbine + Trastuzumab Oral daily matching placebo + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)
Total Total of all reporting groups

Baseline Measures
   Everolimus + Vinorelbine + Trastuzumab   Placebo + Vinorelbine + Trastuzumab   Total 
Overall Participants Analyzed 
[Units: Participants]
 284   285   569 
Age 
[Units: Years]
Mean (Standard Deviation)
 54.3  (10.98)   53.4  (11.00)   53.8  (10.99) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      284 100.0%      285 100.0%      569 100.0% 
Male      0   0.0%      0   0.0%      0   0.0% 


  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Progressive-free Survival (PFS) Per Investigator Assessment   [ Time Frame: Every 6 weeks until disease progression or death which ever occurred first up to about 41 months ]

2.  Secondary:   Overall Survival (OS)   [ Time Frame: Every 3 months until death up to 41 months ]

3.  Secondary:   Overall Response Rate (ORR)   [ Time Frame: Every 6 weeks until disease progression or death which ever occurred first up to about 41 months ]

4.  Secondary:   Clinical Benefit Rate (CBR)   [ Time Frame: Every 6 weeks until disease progression or death which ever occurred first up to about 41 months ]

5.  Secondary:   Median Time to Deterioration of the ECOG Performance Status Score   [ Time Frame: baseline, until disease progression or death up to about 41 months ]

6.  Secondary:   PRO: Time to Deterioration in Global Health Status/QoL Domain Score of the European Organization for the Research and Treatment of Cancer (EORTC)–Core Quality of Life Questionnaire (QLQ-C30) (by at Least 10%)   [ Time Frame: Baseline, until disease progression or death up to about 41 months ]

7.  Secondary:   Everolimus Blood Concentrations by Leading Dose and Time Point   [ Time Frame: Cycle 2, Day 1 ]

8.  Secondary:   Vinorelbine Blood Concentrations by Leading Dose and Time Point   [ Time Frame: Cycle 2, Day 1 ]

9.  Secondary:   Trastuzumab Blood Concentrations by Leading Dose and Time Point   [ Time Frame: Cycle 3, Day 1 ]


  Serious Adverse Events


  Other Adverse Events
  Hide Other Adverse Events

Time Frame No text entered.
Additional Description No text entered.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Everolimus + Trastuzumab + Vinorelbine Oral everolimus (5 mg/day) + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)
Placebo + Trastuzumab + Vinorelbine Oral daily matching placebo + intravenous vinorelbine (25 mg/m2 weekly) + intravenous trastuzumab (2 mg/kg weekly following a 4 mg/kg loading dose on Day 1 of Cycle 1 only)

Other Adverse Events
    Everolimus + Trastuzumab + Vinorelbine   Placebo + Trastuzumab + Vinorelbine
Total, Other (not including serious) Adverse Events     
# participants affected / at risk   280/280 (100.00%)   280/282 (99.29%) 
Blood and lymphatic system disorders     
Anaemia † 1     
# participants affected / at risk   137/280 (48.93%)   85/282 (30.14%) 
Febrile neutropenia † 1     
# participants affected / at risk   17/280 (6.07%)   7/282 (2.48%) 
Leukopenia † 1     
# participants affected / at risk   126/280 (45.00%)   105/282 (37.23%) 
Neutropenia † 1     
# participants affected / at risk   226/280 (80.71%)   196/282 (69.50%) 
Thrombocytopenia † 1     
# participants affected / at risk   39/280 (13.93%)   6/282 (2.13%) 
Gastrointestinal disorders     
Abdominal pain † 1     
# participants affected / at risk   45/280 (16.07%)   52/282 (18.44%) 
Abdominal pain upper † 1     
# participants affected / at risk   34/280 (12.14%)   40/282 (14.18%) 
Constipation † 1     
# participants affected / at risk   84/280 (30.00%)   88/282 (31.21%) 
Diarrhoea † 1     
# participants affected / at risk   108/280 (38.57%)   88/282 (31.21%) 
Dry mouth † 1     
# participants affected / at risk   14/280 (5.00%)   7/282 (2.48%) 
Dyspepsia † 1     
# participants affected / at risk   21/280 (7.50%)   25/282 (8.87%) 
Mouth ulceration † 1     
# participants affected / at risk   32/280 (11.43%)   6/282 (2.13%) 
Nausea † 1     
# participants affected / at risk   98/280 (35.00%)   105/282 (37.23%) 
Stomatitis † 1     
# participants affected / at risk   174/280 (62.14%)   78/282 (27.66%) 
Vomiting † 1     
# participants affected / at risk   57/280 (20.36%)   59/282 (20.92%) 
General disorders     
Asthenia † 1     
# participants affected / at risk   74/280 (26.43%)   57/282 (20.21%) 
Chills † 1     
# participants affected / at risk   18/280 (6.43%)   18/282 (6.38%) 
Fatigue † 1     
# participants affected / at risk   124/280 (44.29%)   119/282 (42.20%) 
Non-cardiac chest pain † 1     
# participants affected / at risk   11/280 (3.93%)   20/282 (7.09%) 
Oedema peripheral † 1     
# participants affected / at risk   39/280 (13.93%)   23/282 (8.16%) 
Pain † 1     
# participants affected / at risk   20/280 (7.14%)   20/282 (7.09%) 
Pyrexia † 1     
# participants affected / at risk   107/280 (38.21%)   65/282 (23.05%) 
Infections and infestations     
Nasopharyngitis † 1     
# participants affected / at risk   37/280 (13.21%)   29/282 (10.28%) 
Upper respiratory tract infection † 1     
# participants affected / at risk   38/280 (13.57%)   26/282 (9.22%) 
Urinary tract infection † 1     
# participants affected / at risk   26/280 (9.29%)   18/282 (6.38%) 
Investigations     
Alanine aminotransferase increased † 1     
# participants affected / at risk   37/280 (13.21%)   26/282 (9.22%) 
Aspartate aminotransferase increased † 1     
# participants affected / at risk   33/280 (11.79%)   22/282 (7.80%) 
Ejection fraction decreased † 1     
# participants affected / at risk   17/280 (6.07%)   5/282 (1.77%) 
Gamma-glutamyltransferase increased † 1     
# participants affected / at risk   29/280 (10.36%)   23/282 (8.16%) 
Haemoglobin decreased † 1     
# participants affected / at risk   22/280 (7.86%)   18/282 (6.38%) 
Neutrophil count decreased † 1     
# participants affected / at risk   14/280 (5.00%)   8/282 (2.84%) 
Weight decreased † 1     
# participants affected / at risk   83/280 (29.64%)   47/282 (16.67%) 
White blood cell count decreased † 1     
# participants affected / at risk   17/280 (6.07%)   23/282 (8.16%) 
Metabolism and nutrition disorders     
Decreased appetite † 1     
# participants affected / at risk   94/280 (33.57%)   49/282 (17.38%) 
Hypercholesterolaemia † 1     
# participants affected / at risk   26/280 (9.29%)   12/282 (4.26%) 
Hyperglycaemia † 1     
# participants affected / at risk   26/280 (9.29%)   15/282 (5.32%) 
Hypertriglyceridaemia † 1     
# participants affected / at risk   23/280 (8.21%)   9/282 (3.19%) 
Hypokalaemia † 1     
# participants affected / at risk   34/280 (12.14%)   19/282 (6.74%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1     
# participants affected / at risk   48/280 (17.14%)   36/282 (12.77%) 
Back pain † 1     
# participants affected / at risk   37/280 (13.21%)   46/282 (16.31%) 
Bone pain † 1     
# participants affected / at risk   28/280 (10.00%)   24/282 (8.51%) 
Muscle spasms † 1     
# participants affected / at risk   31/280 (11.07%)   47/282 (16.67%) 
Musculoskeletal chest pain † 1     
# participants affected / at risk   16/280 (5.71%)   12/282 (4.26%) 
Musculoskeletal pain † 1     
# participants affected / at risk   14/280 (5.00%)   14/282 (4.96%) 
Myalgia † 1     
# participants affected / at risk   39/280 (13.93%)   31/282 (10.99%) 
Pain in extremity † 1     
# participants affected / at risk   42/280 (15.00%)   44/282 (15.60%) 
Nervous system disorders     
Dizziness † 1     
# participants affected / at risk   31/280 (11.07%)   24/282 (8.51%) 
Dysgeusia † 1     
# participants affected / at risk   32/280 (11.43%)   17/282 (6.03%) 
Headache † 1     
# participants affected / at risk   74/280 (26.43%)   62/282 (21.99%) 
Hypoaesthesia † 1     
# participants affected / at risk   15/280 (5.36%)   7/282 (2.48%) 
Neuropathy peripheral † 1     
# participants affected / at risk   27/280 (9.64%)   41/282 (14.54%) 
Paraesthesia † 1     
# participants affected / at risk   21/280 (7.50%)   21/282 (7.45%) 
Peripheral sensory neuropathy † 1     
# participants affected / at risk   25/280 (8.93%)   17/282 (6.03%) 
Psychiatric disorders     
Anxiety † 1     
# participants affected / at risk   13/280 (4.64%)   18/282 (6.38%) 
Insomnia † 1     
# participants affected / at risk   34/280 (12.14%)   27/282 (9.57%) 
Respiratory, thoracic and mediastinal disorders     
Cough † 1     
# participants affected / at risk   84/280 (30.00%)   55/282 (19.50%) 
Dyspnoea † 1     
# participants affected / at risk   51/280 (18.21%)   40/282 (14.18%) 
Epistaxis † 1     
# participants affected / at risk   64/280 (22.86%)   38/282 (13.48%) 
Oropharyngeal pain † 1     
# participants affected / at risk   27/280 (9.64%)   27/282 (9.57%) 
Pneumonitis † 1     
# participants affected / at risk   17/280 (6.07%)   9/282 (3.19%) 
Rhinorrhoea † 1     
# participants affected / at risk   17/280 (6.07%)   14/282 (4.96%) 
Skin and subcutaneous tissue disorders     
Alopecia † 1     
# participants affected / at risk   22/280 (7.86%)   29/282 (10.28%) 
Pruritus † 1     
# participants affected / at risk   16/280 (5.71%)   29/282 (10.28%) 
Rash † 1     
# participants affected / at risk   71/280 (25.36%)   54/282 (19.15%) 
Vascular disorders     
Hot flush † 1     
# participants affected / at risk   4/280 (1.43%)   16/282 (5.67%) 
Hypertension † 1     
# participants affected / at risk   24/280 (8.57%)   10/282 (3.55%) 
Phlebitis † 1     
# participants affected / at risk   14/280 (5.00%)   18/282 (6.38%) 
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA V18.0



  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
All randomized patients were included in the FAS. Seven patients (4 in the everolimus arm & 3 in the placebo arm) were randomized but never received treatment & were therefore excluded from the Safety Set.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862-778-8300
e-mail: trialandresults.registries@novartis.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01007942     History of Changes
Other Study ID Numbers: CRAD001W2301
2008-008697-31 ( EudraCT Number )
First Submitted: November 2, 2009
First Posted: November 4, 2009
Results First Submitted: June 10, 2016
Results First Posted: April 5, 2017
Last Update Posted: April 5, 2017