Trial Outcomes & Findings for Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer (NCT NCT01007942)
NCT ID: NCT01007942
Last Updated: 2017-04-05
Results Overview
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.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
569 participants
Primary outcome timeframe
Every 6 weeks until disease progression or death which ever occurred first up to about 41 months
Results posted on
2017-04-05
Participant Flow
DCO ( Data cut-off) for patient disposition is 1-Apr-2015. Each Cycle = 21 days
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.
Participant milestones
| Measure |
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)
|
|---|---|---|
|
Overall Study
STARTED
|
284
|
285
|
|
Overall Study
COMPLETED
|
3
|
7
|
|
Overall Study
NOT COMPLETED
|
281
|
278
|
Reasons for withdrawal
| Measure |
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)
|
|---|---|---|
|
Overall Study
Adverse Event
|
29
|
14
|
|
Overall Study
Abnormal test procedure
|
0
|
1
|
|
Overall Study
Disease progression
|
217
|
242
|
|
Overall Study
New cancer therapy
|
5
|
1
|
|
Overall Study
Protocol Violation
|
1
|
1
|
|
Overall Study
Withdrawal by Subject
|
19
|
14
|
|
Overall Study
Lost to Follow-up
|
1
|
0
|
|
Overall Study
Administrative problems
|
2
|
0
|
|
Overall Study
Death
|
3
|
2
|
|
Overall Study
Patients untreated
|
4
|
3
|
Baseline Characteristics
Daily Everolimus in Combination With Trastuzumab and Vinorelbine in HER2/Neu Positive Women With Locally Advanced or Metastatic Breast Cancer
Baseline characteristics by cohort
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=284 Participants
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
n=285 Participants
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
n=569 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
54.3 years
STANDARD_DEVIATION 10.98 • n=5 Participants
|
53.4 years
STANDARD_DEVIATION 11.00 • n=7 Participants
|
53.8 years
STANDARD_DEVIATION 10.99 • n=5 Participants
|
|
Sex: Female, Male
Female
|
284 Participants
n=5 Participants
|
285 Participants
n=7 Participants
|
569 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: Every 6 weeks until disease progression or death which ever occurred first up to about 41 monthsPopulation: The Full Analysis Set (FAS) consisted of all randomized patients.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=284 Participants
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
n=285 Participants
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)
|
|---|---|---|
|
Progressive-free Survival (PFS) Per Investigator Assessment
|
7.00 months
Interval 6.74 to 8.18
|
5.78 months
Interval 5.49 to 6.9
|
SECONDARY outcome
Timeframe: Every 3 months until death up to 41 monthsPopulation: The Full Analysis Set (FAS) consisted of all randomized patients.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=284 Participants
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
n=285 Participants
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 Survival (OS)
|
23.46 months
Interval 20.01 to 28.81
|
24.08 months
Interval 21.49 to 27.63
|
SECONDARY outcome
Timeframe: Every 6 weeks until disease progression or death which ever occurred first up to about 41 monthsPopulation: The Full Analysis Set (FAS) consisted of all randomized patients.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=284 Participants
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
n=285 Participants
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 Response Rate (ORR)
|
40.8 Percentage of participants
Interval 35.1 to 46.8
|
37.2 Percentage of participants
Interval 31.6 to 43.1
|
SECONDARY outcome
Timeframe: Every 6 weeks until disease progression or death which ever occurred first up to about 41 monthsPopulation: The Full Analysis Set (FAS) consisted of all randomized patients.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=284 Participants
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
n=285 Participants
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)
|
|---|---|---|
|
Clinical Benefit Rate (CBR)
|
59.2 Percentage of participants
Interval 53.2 to 64.9
|
53.3 Percentage of participants
Interval 47.4 to 59.2
|
SECONDARY outcome
Timeframe: baseline, until disease progression or death up to about 41 monthsPopulation: The Full Analysis Set (FAS) consisted of all randomized patients.
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
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=284 Participants
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
n=285 Participants
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)
|
|---|---|---|
|
Median Time to Deterioration of the ECOG Performance Status Score
|
32.66 months
Interval 17.68 to 32.66
|
21.55 months
Interval 12.48 to
N/A = data could not be analyzed at later time points due to the low number of patients.
|
SECONDARY outcome
Timeframe: Baseline, until disease progression or death up to about 41 monthsPopulation: The Full Analysis Set (FAS) consisted of all randomized patients.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=284 Participants
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
n=285 Participants
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)
|
|---|---|---|
|
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%)
Deterioration - global QoL domain by at least 10%
|
8.31 months
Interval 6.93 to 11.53
|
7.29 months
Interval 5.55 to 10.38
|
|
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%)
Deterioration in the PF domain by at least 10%
|
11.96 months
Interval 8.31 to 14.09
|
12.48 months
Interval 8.31 to 20.86
|
|
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%)
Deterioration in the EF domain by at least 10%
|
15.18 months
Interval 9.2 to 17.28
|
12.45 months
Interval 9.69 to 16.36
|
|
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%)
Deterioration in the SF domain by at least 10%
|
11.33 months
Interval 8.18 to 14.52
|
13.11 months
Interval 8.31 to 19.32
|
SECONDARY outcome
Timeframe: Cycle 2, Day 1Population: 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.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=10 Participants
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
n=43 Participants
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)
|
|---|---|---|
|
Everolimus Blood Concentrations by Leading Dose and Time Point
Pre-dose (Cmin) (n: 7, 32)
|
2.928 ng/ml
Standard Deviation 2.6197
|
5.652 ng/ml
Standard Deviation 4.1006
|
|
Everolimus Blood Concentrations by Leading Dose and Time Point
2 hours post administration (C2h) (n:10, 43)
|
13.035 ng/ml
Standard Deviation 6.6842
|
22.005 ng/ml
Standard Deviation 13.3800
|
SECONDARY outcome
Timeframe: Cycle 2, Day 1Population: 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.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=76 Participants
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
n=64 Participants
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)
|
|---|---|---|
|
Vinorelbine Blood Concentrations by Leading Dose and Time Point
Pre-infusion - dose (Cmin) (n: 76, 64)
|
11.085 ng/ml
Standard Deviation 66.8551
|
0.061 ng/ml
Standard Deviation 0.4888
|
|
Vinorelbine Blood Concentrations by Leading Dose and Time Point
End of infusion (Cmax) (n: 58, 49)
|
867.147 ng/ml
Standard Deviation 971.3057
|
1068.51 ng/ml
Standard Deviation 1145.860
|
SECONDARY outcome
Timeframe: Cycle 3, Day 1Population: 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.
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.
Outcome measures
| Measure |
Everolimus + Vinorelbine + Trastuzumab
n=74 Participants
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
n=59 Participants
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)
|
|---|---|---|
|
Trastuzumab Blood Concentrations by Leading Dose and Time Point
Pre-infusion - dose (Cmin) (n: 73, 57)
|
23.351 ng/ml
Standard Deviation 6.3344
|
24.526 ng/ml
Standard Deviation 7.9960
|
|
Trastuzumab Blood Concentrations by Leading Dose and Time Point
End of infusion (Cmax) (n: 75, 59)
|
64.279 ng/ml
Standard Deviation 27.8549
|
60.576 ng/ml
Standard Deviation 15.5198
|
Adverse Events
Everolimus + Trastuzumab + Vinorelbine
Serious events: 122 serious events
Other events: 280 other events
Deaths: 0 deaths
Placebo + Trastuzumab + Vinorelbine
Serious events: 58 serious events
Other events: 280 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Everolimus + Trastuzumab + Vinorelbine
n=280 participants at risk
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
n=282 participants at risk
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)
|
|---|---|---|
|
Blood and lymphatic system disorders
Agranulocytosis
|
0.00%
0/280
|
0.35%
1/282
|
|
Blood and lymphatic system disorders
Anaemia
|
3.6%
10/280
|
0.71%
2/282
|
|
Blood and lymphatic system disorders
Febrile neutropenia
|
10.7%
30/280
|
1.4%
4/282
|
|
Blood and lymphatic system disorders
Immune thrombocytopenic purpura
|
0.36%
1/280
|
0.00%
0/282
|
|
Blood and lymphatic system disorders
Leukopenia
|
1.1%
3/280
|
0.00%
0/282
|
|
Blood and lymphatic system disorders
Neutropenia
|
4.3%
12/280
|
1.1%
3/282
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
1.4%
4/280
|
0.35%
1/282
|
|
Cardiac disorders
Acute myocardial infarction
|
0.36%
1/280
|
0.00%
0/282
|
|
Cardiac disorders
Cardiac failure
|
0.36%
1/280
|
0.00%
0/282
|
|
Eye disorders
Cataract
|
0.71%
2/280
|
0.35%
1/282
|
|
Eye disorders
Cataract subcapsular
|
0.00%
0/280
|
0.35%
1/282
|
|
Eye disorders
Vision blurred
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Abdominal pain
|
0.36%
1/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Abdominal pain upper
|
0.71%
2/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Ascites
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Constipation
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Diarrhoea
|
1.8%
5/280
|
0.71%
2/282
|
|
Gastrointestinal disorders
Dysphagia
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Gastric perforation
|
0.00%
0/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Gastritis
|
0.71%
2/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Gastrointestinal inflammation
|
0.00%
0/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Haematemesis
|
0.00%
0/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Haematochezia
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Ileus
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Intestinal obstruction
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Nausea
|
1.1%
3/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Neutropenic colitis
|
0.36%
1/280
|
0.00%
0/282
|
|
Gastrointestinal disorders
Pancreatitis
|
0.00%
0/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Stomatitis
|
3.2%
9/280
|
0.35%
1/282
|
|
Gastrointestinal disorders
Vomiting
|
1.8%
5/280
|
0.71%
2/282
|
|
General disorders
Asthenia
|
0.00%
0/280
|
0.35%
1/282
|
|
General disorders
Chills
|
0.71%
2/280
|
0.00%
0/282
|
|
General disorders
Device dislocation
|
0.00%
0/280
|
0.35%
1/282
|
|
General disorders
Extravasation
|
0.36%
1/280
|
0.00%
0/282
|
|
General disorders
General physical health deterioration
|
1.1%
3/280
|
0.71%
2/282
|
|
General disorders
Hyperpyrexia
|
0.00%
0/280
|
0.35%
1/282
|
|
General disorders
Hyperthermia
|
0.00%
0/280
|
0.35%
1/282
|
|
General disorders
Inflammation
|
0.00%
0/280
|
0.35%
1/282
|
|
General disorders
Non-cardiac chest pain
|
0.71%
2/280
|
0.00%
0/282
|
|
General disorders
Pyrexia
|
4.6%
13/280
|
1.8%
5/282
|
|
General disorders
Systemic inflammatory response syndrome
|
0.36%
1/280
|
0.00%
0/282
|
|
Hepatobiliary disorders
Bile duct obstruction
|
0.00%
0/280
|
0.71%
2/282
|
|
Hepatobiliary disorders
Cholecystitis
|
0.36%
1/280
|
0.00%
0/282
|
|
Hepatobiliary disorders
Hepatic mass
|
0.00%
0/280
|
0.35%
1/282
|
|
Hepatobiliary disorders
Hepatocellular injury
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Abscess jaw
|
0.00%
0/280
|
0.35%
1/282
|
|
Infections and infestations
Aspergillus infection
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Bronchiolitis
|
0.00%
0/280
|
0.35%
1/282
|
|
Infections and infestations
Bronchitis
|
0.00%
0/280
|
0.35%
1/282
|
|
Infections and infestations
Cellulitis
|
1.4%
4/280
|
0.00%
0/282
|
|
Infections and infestations
Clostridium difficile colitis
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Conjunctivitis
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Device related infection
|
1.1%
3/280
|
0.35%
1/282
|
|
Infections and infestations
Device related sepsis
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Escherichia sepsis
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Escherichia urinary tract infection
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Furuncle
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Gastroenteritis
|
0.71%
2/280
|
0.00%
0/282
|
|
Infections and infestations
Gastroenteritis clostridial
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Herpes zoster
|
0.36%
1/280
|
0.35%
1/282
|
|
Infections and infestations
Influenza
|
0.71%
2/280
|
0.00%
0/282
|
|
Infections and infestations
Klebsiella bacteraemia
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Lobar pneumonia
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Lung infection
|
0.71%
2/280
|
0.00%
0/282
|
|
Infections and infestations
Neutropenic infection
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Neutropenic sepsis
|
0.71%
2/280
|
0.00%
0/282
|
|
Infections and infestations
Osteomyelitis
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Parainfluenzae virus infection
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Peritonitis
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Peritonsillar abscess
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Pharyngitis
|
0.71%
2/280
|
0.00%
0/282
|
|
Infections and infestations
Pneumocystis jirovecii infection
|
0.00%
0/280
|
0.35%
1/282
|
|
Infections and infestations
Pneumonia
|
2.9%
8/280
|
0.35%
1/282
|
|
Infections and infestations
Postoperative wound infection
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Pseudomonal sepsis
|
0.00%
0/280
|
0.35%
1/282
|
|
Infections and infestations
Sepsis
|
1.1%
3/280
|
0.00%
0/282
|
|
Infections and infestations
Sinusitis
|
0.00%
0/280
|
0.35%
1/282
|
|
Infections and infestations
Soft tissue infection
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Tuberculosis
|
0.36%
1/280
|
0.00%
0/282
|
|
Infections and infestations
Upper respiratory tract infection
|
0.00%
0/280
|
0.35%
1/282
|
|
Infections and infestations
Urinary tract infection
|
0.36%
1/280
|
0.71%
2/282
|
|
Infections and infestations
Viral upper respiratory tract infection
|
0.00%
0/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Fall
|
0.36%
1/280
|
0.00%
0/282
|
|
Injury, poisoning and procedural complications
Femur fracture
|
0.36%
1/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Fractured sacrum
|
0.00%
0/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Hand fracture
|
0.00%
0/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Humerus fracture
|
0.71%
2/280
|
0.00%
0/282
|
|
Injury, poisoning and procedural complications
Pelvic fracture
|
0.00%
0/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Procedural pain
|
0.00%
0/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Spinal compression fracture
|
0.00%
0/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Subdural haematoma
|
0.36%
1/280
|
0.00%
0/282
|
|
Injury, poisoning and procedural complications
Thoracic vertebral fracture
|
0.00%
0/280
|
0.35%
1/282
|
|
Injury, poisoning and procedural complications
Wound dehiscence
|
0.36%
1/280
|
0.00%
0/282
|
|
Investigations
Neutrophil count decreased
|
0.36%
1/280
|
0.00%
0/282
|
|
Metabolism and nutrition disorders
Cachexia
|
0.36%
1/280
|
0.00%
0/282
|
|
Metabolism and nutrition disorders
Decreased appetite
|
0.36%
1/280
|
0.35%
1/282
|
|
Metabolism and nutrition disorders
Dehydration
|
0.36%
1/280
|
0.00%
0/282
|
|
Metabolism and nutrition disorders
Diabetes mellitus
|
0.71%
2/280
|
0.35%
1/282
|
|
Metabolism and nutrition disorders
Hyperglycaemia
|
0.36%
1/280
|
0.00%
0/282
|
|
Metabolism and nutrition disorders
Hyperkalaemia
|
0.00%
0/280
|
0.35%
1/282
|
|
Metabolism and nutrition disorders
Hypocalcaemia
|
0.36%
1/280
|
0.00%
0/282
|
|
Metabolism and nutrition disorders
Hypokalaemia
|
0.36%
1/280
|
0.00%
0/282
|
|
Metabolism and nutrition disorders
Hyponatraemia
|
0.71%
2/280
|
0.35%
1/282
|
|
Metabolism and nutrition disorders
Type 2 diabetes mellitus
|
0.36%
1/280
|
0.00%
0/282
|
|
Musculoskeletal and connective tissue disorders
Bone pain
|
0.71%
2/280
|
0.00%
0/282
|
|
Musculoskeletal and connective tissue disorders
Flank pain
|
0.36%
1/280
|
0.00%
0/282
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
|
0.00%
0/280
|
0.35%
1/282
|
|
Musculoskeletal and connective tissue disorders
Neck pain
|
0.00%
0/280
|
0.35%
1/282
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system
|
0.36%
1/280
|
0.35%
1/282
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Paraneoplastic syndrome
|
0.36%
1/280
|
0.00%
0/282
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid cancer
|
0.36%
1/280
|
0.00%
0/282
|
|
Nervous system disorders
Brain oedema
|
0.36%
1/280
|
0.35%
1/282
|
|
Nervous system disorders
Disturbance in attention
|
0.36%
1/280
|
0.00%
0/282
|
|
Nervous system disorders
Dizziness
|
0.00%
0/280
|
0.35%
1/282
|
|
Nervous system disorders
Headache
|
0.71%
2/280
|
1.1%
3/282
|
|
Nervous system disorders
Hydrocephalus
|
0.36%
1/280
|
0.00%
0/282
|
|
Nervous system disorders
Migraine
|
0.36%
1/280
|
0.00%
0/282
|
|
Nervous system disorders
Neuralgia
|
0.36%
1/280
|
0.00%
0/282
|
|
Nervous system disorders
Neurological symptom
|
0.00%
0/280
|
0.35%
1/282
|
|
Nervous system disorders
Neuropathy peripheral
|
0.36%
1/280
|
0.00%
0/282
|
|
Nervous system disorders
Seizure
|
1.1%
3/280
|
0.35%
1/282
|
|
Nervous system disorders
Somnolence
|
0.00%
0/280
|
0.35%
1/282
|
|
Nervous system disorders
Syncope
|
0.36%
1/280
|
0.00%
0/282
|
|
Psychiatric disorders
Suicide attempt
|
0.00%
0/280
|
0.35%
1/282
|
|
Renal and urinary disorders
Acute kidney injury
|
1.1%
3/280
|
0.00%
0/282
|
|
Renal and urinary disorders
Dysuria
|
0.36%
1/280
|
0.00%
0/282
|
|
Reproductive system and breast disorders
Breast pain
|
0.36%
1/280
|
0.00%
0/282
|
|
Reproductive system and breast disorders
Ovarian cyst
|
0.36%
1/280
|
0.35%
1/282
|
|
Reproductive system and breast disorders
Pelvic pain
|
0.36%
1/280
|
0.00%
0/282
|
|
Reproductive system and breast disorders
Uterine haemorrhage
|
0.36%
1/280
|
0.00%
0/282
|
|
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
|
0.36%
1/280
|
0.00%
0/282
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
0.36%
1/280
|
0.71%
2/282
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
1.1%
3/280
|
1.1%
3/282
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional
|
0.00%
0/280
|
0.35%
1/282
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis
|
1.1%
3/280
|
0.00%
0/282
|
|
Respiratory, thoracic and mediastinal disorders
Haemothorax
|
0.00%
0/280
|
0.35%
1/282
|
|
Respiratory, thoracic and mediastinal disorders
Hypoxia
|
0.36%
1/280
|
0.35%
1/282
|
|
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
|
1.1%
3/280
|
0.00%
0/282
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
0.00%
0/280
|
0.35%
1/282
|
|
Respiratory, thoracic and mediastinal disorders
Pleural effusion
|
0.36%
1/280
|
1.8%
5/282
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonitis
|
0.71%
2/280
|
1.1%
3/282
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
0.00%
0/280
|
0.35%
1/282
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary arterial hypertension
|
0.00%
0/280
|
0.35%
1/282
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
|
1.1%
3/280
|
1.8%
5/282
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
0.00%
0/280
|
1.1%
3/282
|
|
Respiratory, thoracic and mediastinal disorders
Tachypnoea
|
0.00%
0/280
|
0.35%
1/282
|
|
Skin and subcutaneous tissue disorders
Rash
|
0.36%
1/280
|
0.00%
0/282
|
|
Skin and subcutaneous tissue disorders
Skin ulcer
|
0.36%
1/280
|
0.00%
0/282
|
|
Vascular disorders
Deep vein thrombosis
|
0.36%
1/280
|
0.00%
0/282
|
|
Vascular disorders
Haematoma
|
0.00%
0/280
|
0.35%
1/282
|
|
Vascular disorders
Haemorrhage
|
0.00%
0/280
|
0.35%
1/282
|
|
Vascular disorders
Hypotension
|
0.36%
1/280
|
0.71%
2/282
|
|
Vascular disorders
Shock
|
0.00%
0/280
|
0.35%
1/282
|
|
Vascular disorders
Thrombosis
|
0.00%
0/280
|
0.35%
1/282
|
Other adverse events
| Measure |
Everolimus + Trastuzumab + Vinorelbine
n=280 participants at risk
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
n=282 participants at risk
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)
|
|---|---|---|
|
Blood and lymphatic system disorders
Anaemia
|
48.9%
137/280
|
30.1%
85/282
|
|
Blood and lymphatic system disorders
Febrile neutropenia
|
6.1%
17/280
|
2.5%
7/282
|
|
Blood and lymphatic system disorders
Leukopenia
|
45.0%
126/280
|
37.2%
105/282
|
|
Blood and lymphatic system disorders
Neutropenia
|
80.7%
226/280
|
69.5%
196/282
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
13.9%
39/280
|
2.1%
6/282
|
|
Gastrointestinal disorders
Abdominal pain
|
16.1%
45/280
|
18.4%
52/282
|
|
Gastrointestinal disorders
Abdominal pain upper
|
12.1%
34/280
|
14.2%
40/282
|
|
Gastrointestinal disorders
Constipation
|
30.0%
84/280
|
31.2%
88/282
|
|
Gastrointestinal disorders
Diarrhoea
|
38.6%
108/280
|
31.2%
88/282
|
|
Gastrointestinal disorders
Dry mouth
|
5.0%
14/280
|
2.5%
7/282
|
|
Gastrointestinal disorders
Dyspepsia
|
7.5%
21/280
|
8.9%
25/282
|
|
Gastrointestinal disorders
Mouth ulceration
|
11.4%
32/280
|
2.1%
6/282
|
|
Gastrointestinal disorders
Nausea
|
35.0%
98/280
|
37.2%
105/282
|
|
Gastrointestinal disorders
Stomatitis
|
62.1%
174/280
|
27.7%
78/282
|
|
Gastrointestinal disorders
Vomiting
|
20.4%
57/280
|
20.9%
59/282
|
|
General disorders
Asthenia
|
26.4%
74/280
|
20.2%
57/282
|
|
General disorders
Chills
|
6.4%
18/280
|
6.4%
18/282
|
|
General disorders
Fatigue
|
44.3%
124/280
|
42.2%
119/282
|
|
General disorders
Non-cardiac chest pain
|
3.9%
11/280
|
7.1%
20/282
|
|
General disorders
Oedema peripheral
|
13.9%
39/280
|
8.2%
23/282
|
|
General disorders
Pain
|
7.1%
20/280
|
7.1%
20/282
|
|
General disorders
Pyrexia
|
38.2%
107/280
|
23.0%
65/282
|
|
Infections and infestations
Nasopharyngitis
|
13.2%
37/280
|
10.3%
29/282
|
|
Infections and infestations
Upper respiratory tract infection
|
13.6%
38/280
|
9.2%
26/282
|
|
Infections and infestations
Urinary tract infection
|
9.3%
26/280
|
6.4%
18/282
|
|
Investigations
Alanine aminotransferase increased
|
13.2%
37/280
|
9.2%
26/282
|
|
Investigations
Aspartate aminotransferase increased
|
11.8%
33/280
|
7.8%
22/282
|
|
Investigations
Ejection fraction decreased
|
6.1%
17/280
|
1.8%
5/282
|
|
Investigations
Gamma-glutamyltransferase increased
|
10.4%
29/280
|
8.2%
23/282
|
|
Investigations
Haemoglobin decreased
|
7.9%
22/280
|
6.4%
18/282
|
|
Investigations
Neutrophil count decreased
|
5.0%
14/280
|
2.8%
8/282
|
|
Investigations
Weight decreased
|
29.6%
83/280
|
16.7%
47/282
|
|
Investigations
White blood cell count decreased
|
6.1%
17/280
|
8.2%
23/282
|
|
Metabolism and nutrition disorders
Decreased appetite
|
33.6%
94/280
|
17.4%
49/282
|
|
Metabolism and nutrition disorders
Hypercholesterolaemia
|
9.3%
26/280
|
4.3%
12/282
|
|
Metabolism and nutrition disorders
Hyperglycaemia
|
9.3%
26/280
|
5.3%
15/282
|
|
Metabolism and nutrition disorders
Hypertriglyceridaemia
|
8.2%
23/280
|
3.2%
9/282
|
|
Metabolism and nutrition disorders
Hypokalaemia
|
12.1%
34/280
|
6.7%
19/282
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
17.1%
48/280
|
12.8%
36/282
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
13.2%
37/280
|
16.3%
46/282
|
|
Musculoskeletal and connective tissue disorders
Bone pain
|
10.0%
28/280
|
8.5%
24/282
|
|
Musculoskeletal and connective tissue disorders
Muscle spasms
|
11.1%
31/280
|
16.7%
47/282
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
|
5.7%
16/280
|
4.3%
12/282
|
|
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
|
5.0%
14/280
|
5.0%
14/282
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
13.9%
39/280
|
11.0%
31/282
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
15.0%
42/280
|
15.6%
44/282
|
|
Nervous system disorders
Dizziness
|
11.1%
31/280
|
8.5%
24/282
|
|
Nervous system disorders
Dysgeusia
|
11.4%
32/280
|
6.0%
17/282
|
|
Nervous system disorders
Headache
|
26.4%
74/280
|
22.0%
62/282
|
|
Nervous system disorders
Hypoaesthesia
|
5.4%
15/280
|
2.5%
7/282
|
|
Nervous system disorders
Neuropathy peripheral
|
9.6%
27/280
|
14.5%
41/282
|
|
Nervous system disorders
Paraesthesia
|
7.5%
21/280
|
7.4%
21/282
|
|
Nervous system disorders
Peripheral sensory neuropathy
|
8.9%
25/280
|
6.0%
17/282
|
|
Psychiatric disorders
Anxiety
|
4.6%
13/280
|
6.4%
18/282
|
|
Psychiatric disorders
Insomnia
|
12.1%
34/280
|
9.6%
27/282
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
30.0%
84/280
|
19.5%
55/282
|
|
Respiratory, thoracic and mediastinal disorders
Dyspnoea
|
18.2%
51/280
|
14.2%
40/282
|
|
Respiratory, thoracic and mediastinal disorders
Epistaxis
|
22.9%
64/280
|
13.5%
38/282
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
9.6%
27/280
|
9.6%
27/282
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonitis
|
6.1%
17/280
|
3.2%
9/282
|
|
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea
|
6.1%
17/280
|
5.0%
14/282
|
|
Skin and subcutaneous tissue disorders
Alopecia
|
7.9%
22/280
|
10.3%
29/282
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
5.7%
16/280
|
10.3%
29/282
|
|
Skin and subcutaneous tissue disorders
Rash
|
25.4%
71/280
|
19.1%
54/282
|
|
Vascular disorders
Hot flush
|
1.4%
4/280
|
5.7%
16/282
|
|
Vascular disorders
Hypertension
|
8.6%
24/280
|
3.5%
10/282
|
|
Vascular disorders
Phlebitis
|
5.0%
14/280
|
6.4%
18/282
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee 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.
- Publication restrictions are in place
Restriction type: OTHER