Clinical Trial Results:
A Randomized, 3 Arm, Multicenter, Phase III Study to Evaluate the Efficacy and the Safety of T-DM1 Combined With Pertuzumab or T-DM1 Combined With Pertuzumab-Placebo (Blinded for Pertuzumab), Versus the Combination of Trastuzumab Plus Taxane, as First Line Treatment in HER2 Positive Progressive or Recurrent Locally Advanced or Metastatic Breast Cancer (MBC)
|
Summary
|
|
EudraCT number |
2009-017905-13 |
Trial protocol |
AT ES DE FR SE DK HU CZ GB IT BE PT GR |
Global end of trial date |
16 Sep 2016
|
|
Results information
|
|
Results version number |
v2(current) |
This version publication date |
30 Aug 2017
|
First version publication date |
07 Jan 2017
|
Other versions |
v1 |
Version creation reason |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
BO22589
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT01120184 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Hoffmann-La Roche
|
||
Sponsor organisation address |
Grenzacherstrasse 124, CH, Basel, Switzerland, Switzerland, 4070
|
||
Public contact |
Medical Communications, Hoffmann-La Roche, +41 8008218590, genentech@druginfo.com
|
||
Scientific contact |
Medical Communications, Hoffmann-La Roche, +41 8008218590, genentech@druginfo.com
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
15 May 2016
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
16 Sep 2016
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
This randomized, three-arm, multicenter, Phase III study was designed to evaluate the efficacy and safety of trastuzumab emtansine with and without pertuzumab, versus the combination of trastuzumab with taxane therapy, among subjects with human epidermal growth factor receptor 2 (HER2)-positive locally advanced breast cancer (LABC) or metastatic breast cancer (MBC) who had not received prior chemotherapy for their metastatic disease.
|
||
Protection of trial subjects |
All investigators were trained according to applicable Sponsor Standard Operating Procedures (SOPs). Roche and the investigators strictly adhered to the stated provisions in these guidelines. This was documented by the investigator’s signature on the protocol agreeing to carry out all of its terms in accordance with the applicable regulations and law and to follow International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
29 Jun 2010
|
||
Long term follow-up planned |
Yes
|
||
Long term follow-up rationale |
Efficacy, Safety | ||
Long term follow-up duration |
67 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Germany: 41
|
||
Country: Number of subjects enrolled |
Korea, Republic of: 79
|
||
Country: Number of subjects enrolled |
Belgium: 20
|
||
Country: Number of subjects enrolled |
Bahamas: 6
|
||
Country: Number of subjects enrolled |
Portugal: 6
|
||
Country: Number of subjects enrolled |
Colombia: 5
|
||
Country: Number of subjects enrolled |
Panama: 5
|
||
Country: Number of subjects enrolled |
Switzerland: 4
|
||
Country: Number of subjects enrolled |
Greece: 2
|
||
Country: Number of subjects enrolled |
Turkey: 2
|
||
Country: Number of subjects enrolled |
Sweden: 2
|
||
Country: Number of subjects enrolled |
United States: 131
|
||
Country: Number of subjects enrolled |
Brazil: 88
|
||
Country: Number of subjects enrolled |
Japan: 82
|
||
Country: Number of subjects enrolled |
United Kingdom: 74
|
||
Country: Number of subjects enrolled |
France: 72
|
||
Country: Number of subjects enrolled |
Italy: 53
|
||
Country: Number of subjects enrolled |
Russian Federation: 50
|
||
Country: Number of subjects enrolled |
Spain: 43
|
||
Country: Number of subjects enrolled |
Thailand: 39
|
||
Country: Number of subjects enrolled |
Poland: 31
|
||
Country: Number of subjects enrolled |
Bosnia and Herzegovina: 25
|
||
Country: Number of subjects enrolled |
Canada: 23
|
||
Country: Number of subjects enrolled |
Philippines: 23
|
||
Country: Number of subjects enrolled |
Macedonia, the former Yugoslav Republic of: 21
|
||
Country: Number of subjects enrolled |
Peru: 20
|
||
Country: Number of subjects enrolled |
Czech Republic: 19
|
||
Country: Number of subjects enrolled |
Hungary: 19
|
||
Country: Number of subjects enrolled |
Australia: 18
|
||
Country: Number of subjects enrolled |
Taiwan: 17
|
||
Country: Number of subjects enrolled |
Mexico: 16
|
||
Country: Number of subjects enrolled |
Guatemala: 12
|
||
Country: Number of subjects enrolled |
Austria: 10
|
||
Country: Number of subjects enrolled |
Malaysia: 10
|
||
Country: Number of subjects enrolled |
New Zealand: 8
|
||
Country: Number of subjects enrolled |
Denmark: 7
|
||
Country: Number of subjects enrolled |
Romania: 6
|
||
Country: Number of subjects enrolled |
Argentina: 6
|
||
Worldwide total number of subjects |
1095
|
||
EEA total number of subjects |
405
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
912
|
||
From 65 to 84 years |
179
|
||
85 years and over |
4
|
||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Screening details |
A total of 1629 subjects were screened, of whom 1095 were randomized. There were 534 subjects who failed screening, most often due to non-centrally confirmed HER2 status or abnormal laboratory results. | ||||||||||||||||||||||||||||||||||||||||||||||||
|
Period 1
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
||||||||||||||||||||||||||||||||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||||||||||||||||||||||||||||||||
Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
The study was considered open-label with respect to trastuzumab and trastuzumab emtansine treatment; however, subjects and investigators were blinded with respect to pertuzumab or placebo.
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
Arms
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
Arm title
|
Trastuzumab + Taxane | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy. | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Trastuzumab
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Powder for concentrate for solution for infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Trastuzumab was administered via IV infusion and dosed depending upon the taxane selected. Subjects received either 8 mg/kg on Day 1 of Cycle 1 followed by 6 mg/kg on Day 1 of each subsequent 3-week cycle, or 4 mg/kg on Day 1 of Cycle 1 followed by 2 mg/kg weekly beginning on Day 8 of Cycle 1.
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Docetaxel
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Powder for concentrate for solution for infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Docetaxel was administered via IV infusion as 75 or 100 mg/m^2 on Day 1 of each 3-week cycle.
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Paclitaxel
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Powder for concentrate for solution for infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Paclitaxel was administered via IV infusion as 80 mg/m^2 weekly.
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
Arm title
|
Trastuzumab Emtansine + Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Trastuzumab emtansine
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Powder for concentrate for solution for infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion on Day 1 of each 3-week cycle.
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Powder for concentrate for solution for infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Subjects received the placebo equivalent to pertuzumab via IV infusion on Day 1 of each 3-week cycle.
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
Arm title
|
Trastuzumab Emtansine + Pertuzumab | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pertuzumab
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Powder for concentrate for solution for infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Pertuzumab was administered via IV infusion as 840 mg on Day 1 of Cycle 1, followed by 420 mg on Day 1 of each subsequent 3-week cycle.
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Trastuzumab emtansine
|
||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||||||||||||||||||||||||||||||||
Other name |
|||||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Powder for concentrate for solution for infusion
|
||||||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion on Day 1 of each 3-week cycle.
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trastuzumab + Taxane
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trastuzumab Emtansine + Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Trastuzumab + Taxane
|
||
Reporting group description |
Subjects received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy. | ||
Reporting group title |
Trastuzumab Emtansine + Placebo
|
||
Reporting group description |
Subjects received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||
Reporting group title |
Trastuzumab Emtansine + Pertuzumab
|
||
Reporting group description |
Subjects received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||
Subject analysis set title |
Trastuzumab + Taxane
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy.
|
||
Subject analysis set title |
Trastuzumab Emtansine + Placebo
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
|
||
Subject analysis set title |
Trastuzumab Emtansine + Pertuzumab
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Subjects received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination.
|
||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Death or Disease Progression According to Independent Review Facility (IRF) Assessment [1] | ||||||||||||||||
End point description |
Tumor assessments were performed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and 5-millimeter (mm) increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of subjects with death or disease progression was calculated as [number of subjects with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics only |
|||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Progression-Free Survival (PFS) According to IRF Assessment | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding confidence intervals (CIs) were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Primary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo versus Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
732
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
[2] | ||||||||||||||||
P-value |
= 0.3125 [3] | ||||||||||||||||
Method |
Logrank | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.91
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.73 | ||||||||||||||||
upper limit |
1.13 | ||||||||||||||||
| Notes [2] - The study was powered for superiority with target hazard ratio (HR) equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was less than (<) 1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00. [3] - Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab versus Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
728
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
[4] | ||||||||||||||||
P-value |
= 0.1407 [5] | ||||||||||||||||
Method |
Logrank | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.87
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.69 | ||||||||||||||||
upper limit |
1.08 | ||||||||||||||||
| Notes [4] - The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. Non-inferiority was established if the upper bound of the 97.5% CI was <1.1765. Superiority was achieved if the upper bound of the 97.5% CI was <1.00. [5] - Test and p-value apply for superiority test. Two-sided significance level of 2.5% was used to adjust for independent comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. |
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab versus Trastuzumab Emtansine + Placebo. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab Emtansine + Placebo v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
730
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
[6] | ||||||||||||||||
P-value |
= 0.3075 [7] | ||||||||||||||||
Method |
Logrank | ||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.91
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.73 | ||||||||||||||||
upper limit |
1.13 | ||||||||||||||||
| Notes [6] - Formal comparison planned depending on superiority for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane. The study was powered for superiority with target HR equal to 0.75, as well as for non-inferiority with HR equal to 1.1765 for comparison between each of the trastuzumab emtansine-containing arms and the trastuzumab + taxane arm. [7] - Test and p-value apply for superiority test. Primary endpoint did not meet superiority of PFS for trastuzumab emtansine + pertuzumab versus trastuzumab + taxane (two-sided significance level 2.5%); thus, tests and p-value are considered descriptive. |
|||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects Who Died Prior to Clinical Cutoff | ||||||||||||||||
End point description |
The percentage of subjects who died prior to clinical cutoff was calculated as [number of subjects with event divided by the number analyzed multiplied by 100]. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Overall Survival (OS) at Clinical Cutoff | ||||||||||||||||
End point description |
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Here, "9999" represents that the value is not applicable because Median duration of OS was not reached due to insufficient follow-up. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab versus Trastuzmab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
728
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.86
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.67 | ||||||||||||||||
upper limit |
1.11 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo versus Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
732
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.93
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.73 | ||||||||||||||||
upper limit |
1.2 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Death or Disease Progression According to Investigator Assessment | ||||||||||||||||
End point description |
Tumor assessments were performed by the investigator according to RECIST version 1.1. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of subjects with death or disease progression was calculated as [number of subjects with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
PFS According to Investigator Assessment | ||||||||||||||||
End point description |
Tumor assessments were performed by the investigator according to RECIST version 1.1. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo versus Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
732
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.85
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.69 | ||||||||||||||||
upper limit |
1.04 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab versus Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
728
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.77
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.63 | ||||||||||||||||
upper limit |
0.95 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects Experiencing Treatment Failure | ||||||||||||||||
End point description |
Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or subject withdrawal. The percentage of subjects with treatment failure was calculated as [number of subjects with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Time to Treatment Failure (TTF) | ||||||||||||||||
End point description |
Treatment failure was defined as the discontinuation of all study medications in the treatment arm for any reason including disease progression, treatment toxicity, death, physician decision, or subject withdrawal. TTF was defined as the time from randomization to treatment failure. Median TTF was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab versus Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
728
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.78
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.65 | ||||||||||||||||
upper limit |
0.95 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo versus Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
732
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.8
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.66 | ||||||||||||||||
upper limit |
0.97 | ||||||||||||||||
|
|||||||||||||||||
End point title |
One-Year Survival Rate | ||||||||||||||||
End point description |
The percentage of subjects alive at 1 year after randomization was estimated as the one-year survival rate using Kaplan-Meier analysis, and corresponding CIs were computed using Greenwood's estimate of the standard error. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
From randomization until 1 year
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Grade ≥3 Adverse Events | ||||||||||||||||
End point description |
Adverse events were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Grade 5: Death. Analysis was performed on safety population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose ]
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects Who Died at 2 Years | ||||||||||||||||
End point description |
Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
From randomization until 2 years
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Overall Survival Truncated at 2 Years | ||||||||||||||||
End point description |
Overall Survival truncated at 2 years was defined as the time from the date of randomization to the date of death from any cause. Subjects who were alive at 2 years had been censored at 2 years. Overall survival truncated at 2 years was estimated using Kaplan-Meier analyses. Here, "9999" represents that data was not applicable because median was not reached at 2 years as most of the subjects were alive at that time point. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
From randomization until 2 years
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Grade 5 Adverse Events | ||||||||||||||||
End point description |
Adverse events were graded according to NCI CTCAE version 4.0. Grade 5 adverse events are those events which led to death. Analysis was performed on safety population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects with Grade 3-4 Laboratory Parameters | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Laboratory results were graded according to NCI CTCAE version 4.0. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activity of daily living with inability to perform bathing, dressing and undressing, feeding self, using the toilet, taking medications but not bedridden. Grade 4: An immediate threat to life. Urgent medical intervention is required in order to maintain survival. Analysis was performed on ITT population (all subjects randomized in the study).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1, 8, and 15 of Cycle 1–3 and on Day 1 of each subsequent cycle up to 50 months from randomization until clinical cutoff of 16-Sept-2014
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Decline of ≥2 points from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status | ||||||||||||||||
End point description |
The ECOG performance status is a scale used to quantify cancer subjects' general well-being and activities of daily life. The scale ranges from 0 to 5, with 0 denoting perfect health and 5 indicating death. The 6 categories are 0=Asymptomatic (Fully active, able to carry on all predisease activities without restriction), 1=Symptomatic but completely ambulatory (Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature), 2=Symptomatic, < 50% in bed during the day (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours), 3=Symptomatic, > 50% in bed, but not bedbound (Capable of only limited self-care, confined to bed or chair 50% or more of waking hours), 4=Bedbound (Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair), 5=Death. Analysis was performed on safety population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline, Day 1 of every Cycle up to Clinical Data Cut (up to 48 months)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Hospitalization Days | ||||||||||||||||
End point description |
Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Reported values represent number of days admitted per subjects. Analysis was performed on safety population. Number of subjects analyzed=subjects with hospitalization and data available for calculation of the parameter.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Hospitalization | ||||||||||||||||
End point description |
Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment. Analysis was performed on safety population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Objective Response According to IRF Assessment | ||||||||||||||||
End point description |
Objective response was defined as having complete response (CR) or partial response (PR), assessed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of subjects with a best overall response of CR or PR (ie, the objective response rate [ORR]) was calculated as [number of subjects meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs computed using the Blyth-Still-Casella exact method. Analysis performed on ITT population with measurable disease by IRF at Baseline.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo versus Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
590
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Response Rate | ||||||||||||||||
Point estimate |
-8.2
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-15.9 | ||||||||||||||||
upper limit |
-0.5 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
586
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Response Rate | ||||||||||||||||
Point estimate |
-3.7
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-11.4 | ||||||||||||||||
upper limit |
3.9 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Comparison groups |
Trastuzumab Emtansine + Placebo v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
602
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Response Rate | ||||||||||||||||
Point estimate |
4.5
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.3 | ||||||||||||||||
upper limit |
12.2 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Objective Response According to Investigator Assessment | ||||||||||||||||
End point description |
Objective response was defined as having CR or PR, assessed according to RECIST version 1.1, by investigator. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of subjects with a best overall response of CR or PR (ie, the ORR) was calculated as [number of subjects meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method. Analysis was performed on ITT population (all subjects randomized in the study). Only subjects with measurable disease by investigator at Baseline were included.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
607
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Response Rate | ||||||||||||||||
Point estimate |
-4.6
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-12.1 | ||||||||||||||||
upper limit |
2.8 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
604
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Response Rate | ||||||||||||||||
Point estimate |
-1.8
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-9.2 | ||||||||||||||||
upper limit |
5.7 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Comparison groups |
Trastuzumab Emtansine + Placebo v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
625
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Response Rate | ||||||||||||||||
Point estimate |
2.9
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-4.5 | ||||||||||||||||
upper limit |
10.3 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Duration of Response According to IRF Assessment | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Duration of response was defined as the time from confirmed PR or CR to first documented disease progression or death from any cause. CR was defined as the disappearance of all target lesions and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. Median duration of response was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on ITT population. Only subjects achieving CR or PR were included in the analysis.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
376
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.6
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.43 | ||||||||||||||||
upper limit |
0.84 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
387
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.62
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.45 | ||||||||||||||||
upper limit |
0.85 | ||||||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects with a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment | ||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient (20%) increase to qualify for disease progression. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of subjects with a best overall response of CR, PR, or SD was calculated as [number of subjects meeting the respective criteria divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||
|
|||||||||||||
| Notes [8] - This outcome was removed because it was redundant to another prespecified secondary endpoint. [9] - This outcome was removed because it was redundant to another prespecified secondary endpoint. [10] - This outcome was removed because it was redundant to another prespecified secondary endpoint. |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects Experiencing a Clinically Significant Increase in Taxane-Related Treatment Symptoms as Measured by Taxane Subscale of the Functional Assessment of Cancer Therapy (FACT) Taxane (FACT-TaxS) Score | ||||||||||||||||
End point description |
The FACT-Taxane is a self-reported instrument which measures the health-related quality of life (HRQOL) of subjects receiving taxane-containing chemotherapy. The FACT-TaxS consists of 16 items including 11 neurotoxicity-related questions and 5 additional questions assessing arthralgia, myalgia, and skin discoloration. Items are rated from 0 (not at all) to 4 (very much) and a total score is inversely derived. Scores may range from 0 to 64, with higher scores indicating fewer/no symptoms. A minimally clinically important difference in treatment-related symptoms was defined as a ≥5% decrease (ie, 3.2 points) in FACT-TaxS score from Baseline. The percentage of subjects with treatment-related symptoms was calculated using following formula: [number of subjects meeting the above threshold divided by the number analyzed] multiplied by 100. Corresponding CIs computed using the Blyth-Still-Casella exact method. Analysis included randomized subjects who entered after Protocol Amendment C.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
344
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Symptom Rate | ||||||||||||||||
Point estimate |
-32.2
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-40 | ||||||||||||||||
upper limit |
-24 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab v Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Symptom Rate | ||||||||||||||||
Point estimate |
-24.2
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-32 | ||||||||||||||||
upper limit |
-16 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab v Trastuzumab Emtansine + Placebo. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab Emtansine + Placebo v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
325
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Difference in Symptom Rate | ||||||||||||||||
Point estimate |
8
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.3 | ||||||||||||||||
upper limit |
18.4 | ||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module | ||||||||||||||||||||||||||||||||
End point description |
The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of subjects with nausea was calculated using following formula: [number of subjects with any level of either symptom divided by the number analyzed] multiplied by 100. Analyses were performed on the Protocol Amendment C Subpopulation. Only subjects with a FACTC score at the designated visit (n) were included in the analysis.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
Percentage of Subjects Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module | ||||||||||||||||||||||||||||||||
End point description |
The FACT-C is a self-reported instrument which measures HRQOL pertaining to colorectal cancer. Response options on each question may range from 0 (not at all) to 4 (very much). The percentage of subjects with diarrhea was calculated using following formula: [number of subjects with any level of either symptom divided by the number analyzed] multiplied by 100. Analyses were performed on the Protocol Amendment C Subpopulation. Only subjects with a FACTC score at the designated visit (n) were included in the analysis.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with a Clinically Significant Deterioration in Health Related Quality of Life (HRQoL) as measured by FACT Breast (FACT-B) Trial Outcome Index-Physical Function Breast (TOI-PFB) Score | ||||||||||||||||
End point description |
The FACT-B is a self-reported instrument which measures HRQOL of subjects with breast cancer. It consists of 5 subscales including physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a breast cancer subscale (BCS). The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. The percentage of subjects with deterioration was calculated as [number of subjects meeting the above threshold divided by the number analyzed] multiplied by 100. Analysis was performed on the ITT population with baseline and at least one post baseline FACT-B TOI-PFB score.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 39 months from randomization until clinical cutoff of 16-Sept-2014 (at Baseline, on Day 1 of Cycles 2 to 8 and every even-numbered cycle thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score | ||||||||||||||||
End point description |
The FACT-B is a self-reported instrument which measures HRQOL of subjects with breast cancer. It consists of 5 subscales including PWB, SWB, EWB, FWB, and BCS. The TOI-PFB score is taken by adding the scores from the PWB (7 items), FWB (7 items), and BCS (9 items) subscales. Items are rated from 0 (not at all) to 4 (very much) and a total score is derived. Scores may range from 0 to 92, with higher scores indicating better HRQOL. A 5 point change has been identified as the clinically minimal important difference (CMID) on the FACT-TOI-PFB scale. Time to deterioration was defined as the time from Baseline until the first decrease in FACT-B TOI-PFB score. Median time to deterioration was estimated using Kaplan-Meier analysis, and corresponding CIs were computed using the Brookmeyer-Crowley method. Analysis was performed on the ITT population with baseline and at least one post baseline FACT-B TOI-PFB score.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline up to 39 months from randomization until clinical cutoff of 16-Sept-2014
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Pertuzumab vs Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||
Number of subjects included in analysis |
665
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.68
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.55 | ||||||||||||||||
upper limit |
0.84 | ||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo vs Trastuzumab + Taxane. Stratified Analysis: Stratification factors included world region (United States, Western Europe/Canada/Australia-Pacific, Eastern Europe, Asia, others); prior adjuvant/neoadjuvant therapy (no, yes [trastuzumab and/or lapatinib], yes [no trastuzumab and/or lapatinib]), and visceral disease (present, absent).
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
679
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.7
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.57 | ||||||||||||||||
upper limit |
0.86 | ||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change from Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score | ||||||||||||||||||||||||
End point description |
The RSCL is a self-reported instrument which consists of 4 domains including physical symptom distress, psychological distress, activity level, and overall global life quality. Only the activity level scale was collected and assessed. Scores may range from 0 to 100, with higher scores indicating increased burden of disease. Mean RSCL activity scale score changes were calculated as [mean score at the assessment visit minus mean score at Baseline]. The higher the score, the higher the level of impairment or burden. Analysis was performed on ITT population. Only subjects with available data at baseline and Cycle 7 (Week 18) were included.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Cycle 7 (Week 18)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score | ||||||||||||||||||||||||||||||||||||||||
End point description |
The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks subjects to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of subjects reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect). Analysis was performed on ITT population.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Cycle 7 (Week 18)
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score | ||||||||||||||||||||||||
End point description |
The WPAI is a patient-reported measure which assesses the effect of general health and symptom severity on work productivity and regular activities. The General Health questionnaire asks subjects to estimate the number of hours missed from work due to reasons related and unrelated to their health problems, as well as the total number of hours actually worked in the preceding 7-day period. The percentage of subjects reporting that they were employed (working for pay) was assessed at baseline was assessed along with Absenteeism (work time missed), Presenteeism (impairment at work / reduced on-the-job effectiveness), Work productivity loss (overall work impairment / absenteeism plus presenteeism), and Activity Impairment. The reported changes represent change from baseline at Cycle 7. The score range for the scales of the WPAI is between 0 (no effect) to 100% (max effect). Analysis was performed on ITT population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline, Cycle 7 (Week 18)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with a Best Overall Response of CR or PR According to IRF Assessment Among Those with High Human Epidermal Growth Factor Receptor 2 (HER2) Messenger Ribonucleic Acid (mRNA) Levels | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of subjects with a best overall response of CR or PR (ie, the ORR) was calculated as [number of subjects meeting the respective criteria divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population with above the median HER2 mRNA expression (value greater than [>] 59.71). Only subjects with measurable disease at Baseline were included in the analysis.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
268
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
0.67
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.4 | ||||||||||||||||
upper limit |
1.15 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with a Best Overall Response of CR or PR According to IRF Assessment Among Those with Low HER2 mRNA Levels | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. CR was defined as the disappearance of all target and non-target lesions and short-axis reduction in pathological lymph nodes to <10 mm. PR was defined as a ≥30% decrease in sum of diameters of target lesions, taking as reference the Baseline sum. Response was determined using 2 consecutive tumor assessments at least 4 weeks apart. The percentage of subjects with a best overall response of CR or PR (ie, the ORR) was calculated as [number of subjects meeting the respective criteria divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population with below the median HER2 mRNA expression (value less than or equal to [≤] 59.71). Only subjects with measurable disease at Baseline were included in the analysis.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 46 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo" vs Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
273
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
0.66
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.41 | ||||||||||||||||
upper limit |
1.07 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Death or Disease Progression According to IRF Assessment Among Those with High HER2 mRNA Levels | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of subjects with death or disease progression was calculated as [number of subjects with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT Population (High HER2 mRNA Subpopulation).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
PFS According to IRF Assessment Among Those with High HER2 mRNA Levels | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis. Analysis was performed on ITT Population (High HER2 mRNA Subpopulation).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
325
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
0.9
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.65 | ||||||||||||||||
upper limit |
1.25 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects with Death or Disease Progression According to IRF Assessment Among Those with Low HER2 mRNA Levels | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). The percentage of subjects with death or disease progression was calculated as [number of subjects with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT Population (Low HER2 mRNA Subpopulation).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
PFS According to IRF Assessment Among Those with Low HER2 mRNA Levels | ||||||||||||||||
End point description |
Tumor assessments were performed according to RECIST version 1.1, using radiographic images submitted to the IRF up to and including the confirmatory tumor assessment 4 to 6 weeks after study drug discontinuation. PFS was defined as the time from randomization to first documented disease progression or death from any cause. Disease progression was defined as a ≥20% and 5-mm increase in sum of diameters of target lesions, taking as reference the smallest sum obtained during the study, or appearance of new lesion(s). Median duration of PFS was estimated using Kaplan-Meier analysis. Analysis was performed on ITT Population (Low HER2 mRNA Subpopulation).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 (at Screening, every 9 weeks for 81 weeks, then every 12 weeks thereafter and/or up to 42 days after last dose)
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
Direction of comparison: Trastuzumab Emtansine + Placebo v Trastuzumab + Taxane
|
||||||||||||||||
Comparison groups |
Trastuzumab + Taxane v Trastuzumab Emtansine + Placebo
|
||||||||||||||||
Number of subjects included in analysis |
344
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
Method |
|||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||
Point estimate |
1
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
97.5% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
0.74 | ||||||||||||||||
upper limit |
1.34 | ||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects Who Died Prior to Clinical Cutoff Among Those with High HER2 mRNA Levels | ||||||||||||||||
End point description |
The percentage of subjects who died prior to clinical cutoff was calculated as [number of subjects with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population (High HER2 mRNA Subpopulation).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
OS at Clinical Cutoff Among Those with High HER2 mRNA Levels | ||||||||||||||||
End point description |
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Here, "9999" represents that the value is not applicable because Median duration of OS was not reached due to insufficient follow up. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects Who Died Prior to Clinical Cutoff Among Those with Low HER2 mRNA Levels | ||||||||||||||||
End point description |
The percentage of subjects who died prior to clinical cutoff was calculated as [number of subjects with event divided by the number analyzed] multiplied by 100. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
OS at Clinical Cutoff Among Those with Low HER2 mRNA Levels | ||||||||||||||||
End point description |
OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis. Reported upper bound of confidence interval for "Trastuzumab Emtansine + Placebo" and confidence interval values for "Trastuzumab + Taxane" and "Trastuzumab Emtansine + Pertuzumab" are censored values. Here, "9999" represents that the value is not applicable because Median duration of OS was not reached due to insufficient follow up. Analysis was performed on ITT population.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Up to 70 months from randomization until clinical cutoff of 15-May-2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Up to 70 months from randomization until clinical cutoff of 16 September 2016 (every 3 months until death, loss to follow-up, withdrawal, or study termination).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety Population: All randomized subjects who received at least one dose of study treatment. Subjects were analyzed based on the treatment received.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trastuzumab Emtansine + Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received trastuzumab emtansine plus pertuzumab-placebo. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the placebo IV infusion, on Day 1 of each 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trastuzumab + Taxane
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received trastuzumab plus either docetaxel or paclitaxel. The regimen was chosen at the investigator's discretion. Option 1: trastuzumab 8 mg/kg via IV infusion on Day 1 of Cycle 1, then 6 mg/kg IV on Day 1 of each subsequent 3-week cycle; plus a minimum of 6 cycles with docetaxel 75 or 100 mg/m^2 IV on Day 1 of each 3-week cycle. Option 2: trastuzumab 4 mg/kg IV on Day 1 of Cycle 1, then 2 mg/kg IV weekly beginning on Day 8 of Cycle 1; plus a minimum of 18 weeks with paclitaxel 80 mg/m^2 IV weekly. Treatment continued until disease progression, unacceptable toxicity, or study termination. If trastuzumab or docetaxel were discontinued for toxicity, the other agent could be continued as monotherapy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Trastuzumab Emtansine + Pertuzumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received trastuzumab emtansine plus pertuzumab. Trastuzumab emtansine was administered as 3.6 mg/kg via IV infusion, following completion of the pertuzumab IV infusion, on Day 1 of each 3-week cycle. Pertuzumab was given as 840 mg IV on Day 1 of Cycle 1, then 420 mg IV on Day 1 of each subsequent 3-week cycle. Treatment continued until disease progression, unacceptable toxicity, or study termination. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
07 Mar 2011 |
Updates to the protocol included truncation of OS at 2 years as a secondary endpoint, addition of several quality of life assessments including FACT instruments, changes in the assessment schedule, clarification of the study population and eligibility criteria, and addition of treatment guidelines for cases of study drug discontinuation. |
||
11 Oct 2011 |
The protocol was amended to remove an interim futility analysis and to specify the new nonproprietary name 'trastuzumab emtansine' (formerly T-DM1). |
||
29 May 2013 |
The protocol was revised in order to allow for formal comparison of both trastuzumab emtansine arms, specify statistical assumptions, evaluate OS within high and low HER2 mRNA subsets, remove the clinical benefit rate (CR/PR/SD) as a redundant secondary endpoint, clarify committee procedures, further update the schedule of assessments, and add the option for subjects to cross over to the best treatment arm if OS was more favorable in one of the trastuzumab emtansine arms. |
||
01 Nov 2013 |
The protocol was modified to add safety guidance on hepatotoxicity, including updated language for hemorrhage and Hy's Law. |
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
