ClinicalTrials.gov
ClinicalTrials.gov Menu

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

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.
ClinicalTrials.gov Identifier: NCT01007942
Recruitment Status : Completed
First Posted : November 4, 2009
Results First Posted : April 5, 2017
Last Update Posted : April 5, 2017
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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
Enrollment 569
Recruitment Details DCO ( Data cut-off) for patient disposition is 1-Apr-2015. Each Cycle = 21 days
Pre-assignment Details 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.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab
Hide Arm/Group Description 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) 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)
Period Title: Overall Study
Started 284 285
Completed 3 [1] 7 [1]
Not Completed 281 278
Reason Not Completed
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.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab Total
Hide Arm/Group Description 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) 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 of all reporting groups
Overall Number of Baseline Participants 284 285 569
Hide Baseline Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized patients.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 284 participants 285 participants 569 participants
54.3  (10.98) 53.4  (11.00) 53.8  (10.99)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 284 participants 285 participants 569 participants
Female
284
 100.0%
285
 100.0%
569
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Progressive-free Survival (PFS) Per Investigator Assessment
Hide Description PFS was defined as the time from the date of randomization to the date of first radiologically documented tumor progression or death from any cause, whichever occurs first. PFS primary analysis performed when 415 events were reached. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame Every 6 weeks until disease progression or death which ever occurred first up to about 41 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized patients.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab
Hide Arm/Group Description:
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)
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)
Overall Number of Participants Analyzed 284 285
Median (95% Confidence Interval)
Unit of Measure: months
7.00
(6.74 to 8.18)
5.78
(5.49 to 6.90)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Everolimus + Vinorelbine + Trastuzumab, Placebo + Vinorelbine + Trastuzumab
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0067
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.65 to 0.95
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from date of randomization to the date of death from any cause. Final OS was conducted when 388 deaths occurred.
Time Frame Every 3 months until death up to 41 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized patients.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab
Hide Arm/Group Description:
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)
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)
Overall Number of Participants Analyzed 284 285
Median (95% Confidence Interval)
Unit of Measure: months
23.46
(20.01 to 28.81)
24.08
(21.49 to 27.63)
3.Secondary Outcome
Title Overall Response Rate (ORR)
Hide Description ORR was defined as the percentage of participants whose best overall response was either complete response (CR) or partial response (PR) according to RECIST version 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame Every 6 weeks until disease progression or death which ever occurred first up to about 41 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized patients.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab
Hide Arm/Group Description:
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)
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)
Overall Number of Participants Analyzed 284 285
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
40.8
(35.1 to 46.8)
37.2
(31.6 to 43.1)
4.Secondary Outcome
Title Clinical Benefit Rate (CBR)
Hide Description CBR was defined as the percentage of participants whose best overall response, according to RECIST, was either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
Time Frame Every 6 weeks until disease progression or death which ever occurred first up to about 41 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized patients.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab
Hide Arm/Group Description:
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)
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)
Overall Number of Participants Analyzed 284 285
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
59.2
(53.2 to 64.9)
53.3
(47.4 to 59.2)
5.Secondary Outcome
Title Median Time to Deterioration of the ECOG Performance Status Score
Hide Description Time to deterioration of ECOG performance status score was summarized at time of assessment. ECOG (Eastern Cooperative Oncology Group)performance scale is a standard criteria for measuring how treatment of cancer impacts their level of functioning in terms of their ability to care for themselves, daily activity, & physical ability (walking, working, etc.). Scale score ranges from 0 to 5, 5 being the worst. ECOG scale index: 0 - Fully active, able to carry on all pre-disease performance without restriction. 1 - Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature, e.g., light housework, office work. 2 - Ambulatory & capable of all self-care but unable to carry out any work activities. Up & about more than 50% of waking hours. 3 - Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 - Dead
Time Frame baseline, until disease progression or death up to about 41 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized patients.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab
Hide Arm/Group Description:
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)
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)
Overall Number of Participants Analyzed 284 285
Median (95% Confidence Interval)
Unit of Measure: months
32.66
(17.68 to 32.66)
21.55 [1] 
(12.48 to NA)
[1]
N/A = data could not be analyzed at later time points due to the low number of patients.
6.Secondary Outcome
Title 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%)
Hide Description PRO = patient reported outcomes; Time to deterioration (≥ 10% worsening from baseline), in the global health status of EORTC QLQ-C30 scale was done in the 3 functional scales (emotional, physical, & social functioning [EF, PF, & SF]). It contains 30 items & is composed of multi-item scales & single-item measures. These include 5 functional scales (physical, role, emotional, social & cognitive functioning), 3 symptom scales (fatigue, pain, nausea, & vomiting), a global health status/QoL scale, and 6 single items (dyspnea, diarrhea, constipation, anorexia, insomnia & financial impact). Each of the multi-item scale includes a different set of items - no item occurs in more than 1 scale. Each item in the EORTC QLQ-C30 has 4 response categories (1=Not at all, 2= A little, 3= Quite a bit, 4= Very much) with the higher number representing a worse outcome. The global health domain score of the QLQ-C30 questionnaire was pre-specified as the primary QoL domain of interest & disclosed here.
Time Frame Baseline, until disease progression or death up to about 41 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) consisted of all randomized patients.
Arm/Group Title Everolimus + Vinorelbine + Trastuzumab Placebo + Vinorelbine + Trastuzumab
Hide Arm/Group Description:
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)
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)
Overall Number of Participants Analyzed 284 285
Median (95% Confidence Interval)
Unit of Measure: months
Deterioration - global QoL domain by at least 10%
8.31
(6.93 to 11.53)
7.29
(5.55 to 10.38)
Deterioration in the PF domain by at least 10%
11.96
(8.31 to 14.09)
12.48
(8.31 to 20.86)
Deterioration in the EF domain by at least 10%
15.18
(9.20 to 17.28)
12.45
(9.69 to 16.36)
Deterioration in the SF domain by at least 10%
11.33
(8.18 to 14.52)
13.11
(8.31 to 19.32)
7.Secondary Outcome
Title Everolimus Blood Concentrations by Leading Dose and Time Point
Hide Description Pre-dose (Cmin) and 2 hours post-dose (C2h) everolimus PK blood samples were collected at Cycle 2 Day 1. Only valid everolimus PK blood samples collected at steady state were used in the analyses.
Time Frame Cycle 2, Day 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Safety Set consisted of all patients who received at least one dose of the study treatment and who had at least one valid post-baseline safety assessment.
Arm/Group Title Everolimus 2.5 mg Everolimus
Hide Arm/Group Description:
Oral everolimus of 2.5 mg/day
Oral everolimus of 5 mg/day
Overall Number of Participants Analyzed 10 43
Mean (Standard Deviation)
Unit of Measure: ng/ml
Pre-dose (Cmin) (n: 7, 32) 2.928  (2.6197) 5.652  (4.1006)
2 hours post administration (C2h) (n:10, 43) 13.035  (6.6842) 22.005  (13.3800)
8.Secondary Outcome
Title Vinorelbine Blood Concentrations by Leading Dose and Time Point
Hide Description Pre-infusion (Cmin) and end of infusion (C2h) vinorelbine PK blood samples were collected at Cycle 2 Day 1. Only valid vinorelbine PK blood samples collected at steady state were used in the analyses.
Time Frame Cycle 2, Day 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Safety Set consisted of all patients who received at least one dose of the study treatment and who had at least one valid post-baseline safety assessment.
Arm/Group Title Everolimus Everolimus Placebo
Hide Arm/Group Description:
Oral everolimus of 5 mg/day
Oral placebo everolimus of 5 mg/day
Overall Number of Participants Analyzed 76 64
Mean (Standard Deviation)
Unit of Measure: ng/ml
Pre-infusion - dose (Cmin) (n: 76, 64) 11.085  (66.8551) 0.061  (0.4888)
End of infusion (Cmax) (n: 58, 49) 867.147  (971.3057) 1068.51  (1145.860)
9.Secondary Outcome
Title Trastuzumab Blood Concentrations by Leading Dose and Time Point
Hide Description Pre-infusion (Cmin) and end of infusion (C2h) trastuzumab PK blood samples were collected at Cycle 3 Day 1. Only valid trastuzumab PK blood samples collected at steady state were used in the analyses.
Time Frame Cycle 3, Day 1
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The Safety Set consisted of all patients who received at least one dose of the study treatment and who had at least one valid post-baseline safety assessment.
Arm/Group Title Everolimus Everolimus Placebo
Hide Arm/Group Description:
Oral everolimus of 5 mg/day
Oral placebo everolimus of 5 mg/day
Overall Number of Participants Analyzed 74 59
Mean (Standard Deviation)
Unit of Measure: ng/ml
Pre-infusion - dose (Cmin) (n: 73, 57) 23.351  (6.3344) 24.526  (7.9960)
End of infusion (Cmax) (n: 75, 59) 64.279  (27.8549) 60.576  (15.5198)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Everolimus + Trastuzumab + Vinorelbine Placebo + Trastuzumab + Vinorelbine
Hide Arm/Group Description 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) 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)
All-Cause Mortality
Everolimus + Trastuzumab + Vinorelbine Placebo + Trastuzumab + Vinorelbine
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Everolimus + Trastuzumab + Vinorelbine Placebo + Trastuzumab + Vinorelbine
Affected / at Risk (%) Affected / at Risk (%)
Total   122/280 (43.57%)   58/282 (20.57%) 
Blood and lymphatic system disorders     
Agranulocytosis  1  0/280 (0.00%)  1/282 (0.35%) 
Anaemia  1  10/280 (3.57%)  2/282 (0.71%) 
Febrile neutropenia  1  30/280 (10.71%)  4/282 (1.42%) 
Immune thrombocytopenic purpura  1  1/280 (0.36%)  0/282 (0.00%) 
Leukopenia  1  3/280 (1.07%)  0/282 (0.00%) 
Neutropenia  1  12/280 (4.29%)  3/282 (1.06%) 
Thrombocytopenia  1  4/280 (1.43%)  1/282 (0.35%) 
Cardiac disorders     
Acute myocardial infarction  1  1/280 (0.36%)  0/282 (0.00%) 
Cardiac failure  1  1/280 (0.36%)  0/282 (0.00%) 
Eye disorders     
Cataract  1  2/280 (0.71%)  1/282 (0.35%) 
Cataract subcapsular  1  0/280 (0.00%)  1/282 (0.35%) 
Vision blurred  1  1/280 (0.36%)  0/282 (0.00%) 
Gastrointestinal disorders     
Abdominal pain  1  1/280 (0.36%)  1/282 (0.35%) 
Abdominal pain upper  1  2/280 (0.71%)  1/282 (0.35%) 
Ascites  1  1/280 (0.36%)  0/282 (0.00%) 
Constipation  1  1/280 (0.36%)  0/282 (0.00%) 
Diarrhoea  1  5/280 (1.79%)  2/282 (0.71%) 
Dysphagia  1  1/280 (0.36%)  0/282 (0.00%) 
Gastric perforation  1  0/280 (0.00%)  1/282 (0.35%) 
Gastritis  1  2/280 (0.71%)  0/282 (0.00%) 
Gastrointestinal inflammation  1  0/280 (0.00%)  1/282 (0.35%) 
Haematemesis  1  0/280 (0.00%)  1/282 (0.35%) 
Haematochezia  1  1/280 (0.36%)  0/282 (0.00%) 
Ileus  1  1/280 (0.36%)  0/282 (0.00%) 
Intestinal obstruction  1  1/280 (0.36%)  0/282 (0.00%) 
Nausea  1  3/280 (1.07%)  1/282 (0.35%) 
Neutropenic colitis  1  1/280 (0.36%)  0/282 (0.00%) 
Pancreatitis  1  0/280 (0.00%)  1/282 (0.35%) 
Stomatitis  1  9/280 (3.21%)  1/282 (0.35%) 
Vomiting  1  5/280 (1.79%)  2/282 (0.71%) 
General disorders     
Asthenia  1  0/280 (0.00%)  1/282 (0.35%) 
Chills  1  2/280 (0.71%)  0/282 (0.00%) 
Device dislocation  1  0/280 (0.00%)  1/282 (0.35%) 
Extravasation  1  1/280 (0.36%)  0/282 (0.00%) 
General physical health deterioration  1  3/280 (1.07%)  2/282 (0.71%) 
Hyperpyrexia  1  0/280 (0.00%)  1/282 (0.35%) 
Hyperthermia  1  0/280 (0.00%)  1/282 (0.35%) 
Inflammation  1  0/280 (0.00%)  1/282 (0.35%) 
Non-cardiac chest pain  1  2/280 (0.71%)  0/282 (0.00%) 
Pyrexia  1  13/280 (4.64%)  5/282 (1.77%) 
Systemic inflammatory response syndrome  1  1/280 (0.36%)  0/282 (0.00%) 
Hepatobiliary disorders     
Bile duct obstruction  1  0/280 (0.00%)  2/282 (0.71%) 
Cholecystitis  1  1/280 (0.36%)  0/282 (0.00%) 
Hepatic mass  1  0/280 (0.00%)  1/282 (0.35%) 
Hepatocellular injury  1  1/280 (0.36%)  0/282 (0.00%) 
Infections and infestations     
Abscess jaw  1  0/280 (0.00%)  1/282 (0.35%) 
Aspergillus infection  1  1/280 (0.36%)  0/282 (0.00%) 
Bronchiolitis  1  0/280 (0.00%)  1/282 (0.35%) 
Bronchitis  1  0/280 (0.00%)  1/282 (0.35%) 
Cellulitis  1  4/280 (1.43%)  0/282 (0.00%) 
Clostridium difficile colitis  1  1/280 (0.36%)  0/282 (0.00%) 
Conjunctivitis  1  1/280 (0.36%)  0/282 (0.00%) 
Device related infection  1  3/280 (1.07%)  1/282 (0.35%) 
Device related sepsis  1  1/280 (0.36%)  0/282 (0.00%) 
Escherichia sepsis  1  1/280 (0.36%)  0/282 (0.00%) 
Escherichia urinary tract infection  1  1/280 (0.36%)  0/282 (0.00%) 
Furuncle  1  1/280 (0.36%)  0/282 (0.00%) 
Gastroenteritis  1  2/280 (0.71%)  0/282 (0.00%) 
Gastroenteritis clostridial  1  1/280 (0.36%)  0/282 (0.00%) 
Herpes zoster  1  1/280 (0.36%)  1/282 (0.35%) 
Influenza  1  2/280 (0.71%)  0/282 (0.00%) 
Klebsiella bacteraemia  1  1/280 (0.36%)  0/282 (0.00%) 
Lobar pneumonia  1  1/280 (0.36%)  0/282 (0.00%) 
Lung infection  1  2/280 (0.71%)  0/282 (0.00%) 
Neutropenic infection  1  1/280 (0.36%)  0/282 (0.00%) 
Neutropenic sepsis  1  2/280 (0.71%)  0/282 (0.00%) 
Osteomyelitis  1  1/280 (0.36%)  0/282 (0.00%) 
Parainfluenzae virus infection  1  1/280 (0.36%)  0/282 (0.00%) 
Peritonitis  1  1/280 (0.36%)  0/282 (0.00%) 
Peritonsillar abscess  1  1/280 (0.36%)  0/282 (0.00%) 
Pharyngitis  1  2/280 (0.71%)  0/282 (0.00%) 
Pneumocystis jirovecii infection  1  0/280 (0.00%)  1/282 (0.35%) 
Pneumonia  1  8/280 (2.86%)  1/282 (0.35%) 
Postoperative wound infection  1  1/280 (0.36%)  0/282 (0.00%) 
Pseudomonal sepsis  1  0/280 (0.00%)  1/282 (0.35%) 
Sepsis  1  3/280 (1.07%)  0/282 (0.00%) 
Sinusitis  1  0/280 (0.00%)  1/282 (0.35%) 
Soft tissue infection  1  1/280 (0.36%)  0/282 (0.00%) 
Tuberculosis  1  1/280 (0.36%)  0/282 (0.00%) 
Upper respiratory tract infection  1  0/280 (0.00%)  1/282 (0.35%) 
Urinary tract infection  1  1/280 (0.36%)  2/282 (0.71%) 
Viral upper respiratory tract infection  1  0/280 (0.00%)  1/282 (0.35%) 
Injury, poisoning and procedural complications     
Fall  1  1/280 (0.36%)  0/282 (0.00%) 
Femur fracture  1  1/280 (0.36%)  1/282 (0.35%) 
Fractured sacrum  1  0/280 (0.00%)  1/282 (0.35%) 
Hand fracture  1  0/280 (0.00%)  1/282 (0.35%) 
Humerus fracture  1  2/280 (0.71%)  0/282 (0.00%) 
Pelvic fracture  1  0/280 (0.00%)  1/282 (0.35%) 
Procedural pain  1  0/280 (0.00%)  1/282 (0.35%) 
Spinal compression fracture  1  0/280 (0.00%)  1/282 (0.35%) 
Subdural haematoma  1  1/280 (0.36%)  0/282 (0.00%) 
Thoracic vertebral fracture  1  0/280 (0.00%)  1/282 (0.35%) 
Wound dehiscence  1  1/280 (0.36%)  0/282 (0.00%) 
Investigations     
Neutrophil count decreased  1  1/280 (0.36%)  0/282 (0.00%) 
Metabolism and nutrition disorders     
Cachexia  1  1/280 (0.36%)  0/282 (0.00%) 
Decreased appetite  1  1/280 (0.36%)  1/282 (0.35%) 
Dehydration  1  1/280 (0.36%)  0/282 (0.00%) 
Diabetes mellitus  1  2/280 (0.71%)  1/282 (0.35%) 
Hyperglycaemia  1  1/280 (0.36%)  0/282 (0.00%) 
Hyperkalaemia  1  0/280 (0.00%)  1/282 (0.35%) 
Hypocalcaemia  1  1/280 (0.36%)  0/282 (0.00%) 
Hypokalaemia  1  1/280 (0.36%)  0/282 (0.00%) 
Hyponatraemia  1  2/280 (0.71%)  1/282 (0.35%) 
Type 2 diabetes mellitus  1  1/280 (0.36%)  0/282 (0.00%) 
Musculoskeletal and connective tissue disorders     
Bone pain  1  2/280 (0.71%)  0/282 (0.00%) 
Flank pain  1  1/280 (0.36%)  0/282 (0.00%) 
Musculoskeletal pain  1  0/280 (0.00%)  1/282 (0.35%) 
Neck pain  1  0/280 (0.00%)  1/282 (0.35%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Metastases to central nervous system  1  1/280 (0.36%)  1/282 (0.35%) 
Paraneoplastic syndrome  1  1/280 (0.36%)  0/282 (0.00%) 
Thyroid cancer  1  1/280 (0.36%)  0/282 (0.00%) 
Nervous system disorders     
Brain oedema  1  1/280 (0.36%)  1/282 (0.35%) 
Disturbance in attention  1  1/280 (0.36%)  0/282 (0.00%) 
Dizziness  1  0/280 (0.00%)  1/282 (0.35%) 
Headache  1  2/280 (0.71%)  3/282 (1.06%) 
Hydrocephalus  1  1/280 (0.36%)  0/282 (0.00%) 
Migraine  1  1/280 (0.36%)  0/282 (0.00%) 
Neuralgia  1  1/280 (0.36%)  0/282 (0.00%) 
Neurological symptom  1  0/280 (0.00%)  1/282 (0.35%) 
Neuropathy peripheral  1  1/280 (0.36%)  0/282 (0.00%) 
Seizure  1  3/280 (1.07%)  1/282 (0.35%) 
Somnolence  1  0/280 (0.00%)  1/282 (0.35%) 
Syncope  1  1/280 (0.36%)  0/282 (0.00%) 
Psychiatric disorders     
Suicide attempt  1  0/280 (0.00%)  1/282 (0.35%) 
Renal and urinary disorders     
Acute kidney injury  1  3/280 (1.07%)  0/282 (0.00%) 
Dysuria  1  1/280 (0.36%)  0/282 (0.00%) 
Reproductive system and breast disorders     
Breast pain  1  1/280 (0.36%)  0/282 (0.00%) 
Ovarian cyst  1  1/280 (0.36%)  1/282 (0.35%) 
Pelvic pain  1  1/280 (0.36%)  0/282 (0.00%) 
Uterine haemorrhage  1  1/280 (0.36%)  0/282 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/280 (0.36%)  0/282 (0.00%) 
Cough  1  1/280 (0.36%)  2/282 (0.71%) 
Dyspnoea  1  3/280 (1.07%)  3/282 (1.06%) 
Dyspnoea exertional  1  0/280 (0.00%)  1/282 (0.35%) 
Epistaxis  1  3/280 (1.07%)  0/282 (0.00%) 
Haemothorax  1  0/280 (0.00%)  1/282 (0.35%) 
Hypoxia  1  1/280 (0.36%)  1/282 (0.35%) 
Interstitial lung disease  1  3/280 (1.07%)  0/282 (0.00%) 
Oropharyngeal pain  1  0/280 (0.00%)  1/282 (0.35%) 
Pleural effusion  1  1/280 (0.36%)  5/282 (1.77%) 
Pneumonitis  1  2/280 (0.71%)  3/282 (1.06%) 
Pneumothorax  1  0/280 (0.00%)  1/282 (0.35%) 
Pulmonary arterial hypertension  1  0/280 (0.00%)  1/282 (0.35%) 
Pulmonary embolism  1  3/280 (1.07%)  5/282 (1.77%) 
Respiratory failure  1  0/280 (0.00%)  3/282 (1.06%) 
Tachypnoea  1  0/280 (0.00%)  1/282 (0.35%) 
Skin and subcutaneous tissue disorders     
Rash  1  1/280 (0.36%)  0/282 (0.00%) 
Skin ulcer  1  1/280 (0.36%)  0/282 (0.00%) 
Vascular disorders     
Deep vein thrombosis  1  1/280 (0.36%)  0/282 (0.00%) 
Haematoma  1  0/280 (0.00%)  1/282 (0.35%) 
Haemorrhage  1  0/280 (0.00%)  1/282 (0.35%) 
Hypotension  1  1/280 (0.36%)  2/282 (0.71%) 
Shock  1  0/280 (0.00%)  1/282 (0.35%) 
Thrombosis  1  0/280 (0.00%)  1/282 (0.35%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA V18.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Everolimus + Trastuzumab + Vinorelbine Placebo + Trastuzumab + Vinorelbine
Affected / at Risk (%) Affected / at Risk (%)
Total   280/280 (100.00%)   280/282 (99.29%) 
Blood and lymphatic system disorders     
Anaemia  1  137/280 (48.93%)  85/282 (30.14%) 
Febrile neutropenia  1  17/280 (6.07%)  7/282 (2.48%) 
Leukopenia  1  126/280 (45.00%)  105/282 (37.23%) 
Neutropenia  1  226/280 (80.71%)  196/282 (69.50%) 
Thrombocytopenia  1  39/280 (13.93%)  6/282 (2.13%) 
Gastrointestinal disorders     
Abdominal pain  1  45/280 (16.07%)  52/282 (18.44%) 
Abdominal pain upper  1  34/280 (12.14%)  40/282 (14.18%) 
Constipation  1  84/280 (30.00%)  88/282 (31.21%) 
Diarrhoea  1  108/280 (38.57%)  88/282 (31.21%) 
Dry mouth  1  14/280 (5.00%)  7/282 (2.48%) 
Dyspepsia  1  21/280 (7.50%)  25/282 (8.87%) 
Mouth ulceration  1  32/280 (11.43%)  6/282 (2.13%) 
Nausea  1  98/280 (35.00%)  105/282 (37.23%) 
Stomatitis  1  174/280 (62.14%)  78/282 (27.66%) 
Vomiting  1  57/280 (20.36%)  59/282 (20.92%) 
General disorders     
Asthenia  1  74/280 (26.43%)  57/282 (20.21%) 
Chills  1  18/280 (6.43%)  18/282 (6.38%) 
Fatigue  1  124/280 (44.29%)  119/282 (42.20%) 
Non-cardiac chest pain  1  11/280 (3.93%)  20/282 (7.09%) 
Oedema peripheral  1  39/280 (13.93%)  23/282 (8.16%) 
Pain  1  20/280 (7.14%)  20/282 (7.09%) 
Pyrexia  1  107/280 (38.21%)  65/282 (23.05%) 
Infections and infestations     
Nasopharyngitis  1  37/280 (13.21%)  29/282 (10.28%) 
Upper respiratory tract infection  1  38/280 (13.57%)  26/282 (9.22%) 
Urinary tract infection  1  26/280 (9.29%)  18/282 (6.38%) 
Investigations     
Alanine aminotransferase increased  1  37/280 (13.21%)  26/282 (9.22%) 
Aspartate aminotransferase increased  1  33/280 (11.79%)  22/282 (7.80%) 
Ejection fraction decreased  1  17/280 (6.07%)  5/282 (1.77%) 
Gamma-glutamyltransferase increased  1  29/280 (10.36%)  23/282 (8.16%) 
Haemoglobin decreased  1  22/280 (7.86%)  18/282 (6.38%) 
Neutrophil count decreased  1  14/280 (5.00%)  8/282 (2.84%) 
Weight decreased  1  83/280 (29.64%)  47/282 (16.67%) 
White blood cell count decreased  1  17/280 (6.07%)  23/282 (8.16%) 
Metabolism and nutrition disorders     
Decreased appetite  1  94/280 (33.57%)  49/282 (17.38%) 
Hypercholesterolaemia  1  26/280 (9.29%)  12/282 (4.26%) 
Hyperglycaemia  1  26/280 (9.29%)  15/282 (5.32%) 
Hypertriglyceridaemia  1  23/280 (8.21%)  9/282 (3.19%) 
Hypokalaemia  1  34/280 (12.14%)  19/282 (6.74%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  48/280 (17.14%)  36/282 (12.77%) 
Back pain  1  37/280 (13.21%)  46/282 (16.31%) 
Bone pain  1  28/280 (10.00%)  24/282 (8.51%) 
Muscle spasms  1  31/280 (11.07%)  47/282 (16.67%) 
Musculoskeletal chest pain  1  16/280 (5.71%)  12/282 (4.26%) 
Musculoskeletal pain  1  14/280 (5.00%)  14/282 (4.96%) 
Myalgia  1  39/280 (13.93%)  31/282 (10.99%) 
Pain in extremity  1  42/280 (15.00%)  44/282 (15.60%) 
Nervous system disorders     
Dizziness  1  31/280 (11.07%)  24/282 (8.51%) 
Dysgeusia  1  32/280 (11.43%)  17/282 (6.03%) 
Headache  1  74/280 (26.43%)  62/282 (21.99%) 
Hypoaesthesia  1  15/280 (5.36%)  7/282 (2.48%) 
Neuropathy peripheral  1  27/280 (9.64%)  41/282 (14.54%) 
Paraesthesia  1  21/280 (7.50%)  21/282 (7.45%) 
Peripheral sensory neuropathy  1  25/280 (8.93%)  17/282 (6.03%) 
Psychiatric disorders     
Anxiety  1  13/280 (4.64%)  18/282 (6.38%) 
Insomnia  1  34/280 (12.14%)  27/282 (9.57%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  84/280 (30.00%)  55/282 (19.50%) 
Dyspnoea  1  51/280 (18.21%)  40/282 (14.18%) 
Epistaxis  1  64/280 (22.86%)  38/282 (13.48%) 
Oropharyngeal pain  1  27/280 (9.64%)  27/282 (9.57%) 
Pneumonitis  1  17/280 (6.07%)  9/282 (3.19%) 
Rhinorrhoea  1  17/280 (6.07%)  14/282 (4.96%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  22/280 (7.86%)  29/282 (10.28%) 
Pruritus  1  16/280 (5.71%)  29/282 (10.28%) 
Rash  1  71/280 (25.36%)  54/282 (19.15%) 
Vascular disorders     
Hot flush  1  4/280 (1.43%)  16/282 (5.67%) 
Hypertension  1  24/280 (8.57%)  10/282 (3.55%) 
Phlebitis  1  14/280 (5.00%)  18/282 (6.38%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA V18.0
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.
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 terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
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