A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician's Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy (TH3RESA)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01419197
First received: August 16, 2011
Last updated: April 3, 2014
Last verified: April 2014
Results First Received: February 7, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Breast Cancer
Interventions: Drug: Trastuzumab emtansine
Drug: Treatment of physician's choice

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Participant Flow:   Overall Study
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
STARTED     404     198  
Crossed-over to Trastuzumab Emtansine     0     44  
COMPLETED     319     125  
NOT COMPLETED     85     73  
Death                 61                 44  
Lost to Follow-up                 2                 0  
Non-compliance                 1                 1  
Withdrawal by Subject                 19                 26  
Physician Decision                 2                 2  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.
Total Total of all reporting groups

Baseline Measures
    Trastuzumab Emtansine     Treatment of Physician’s Choice     Total  
Number of Participants  
[units: participants]
  404     198     602  
Age  
[units: years]
Mean ± Standard Deviation
  53.3  ± 10.4     54.3  ± 10.8     53.6  ± 10.5  
Gender  
[units: participants]
     
Female     401     197     598  
Male     3     1     4  



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Progression-free Survival   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Primary
Measure Title Progression-free Survival
Measure Description Progression-free survival was defined as the time from randomization to the first documented disease progression by investigator assessment using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death from any cause, whichever occurred first.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
Number of Participants Analyzed  
[units: participants]
  404     198  
Progression-free Survival  
[units: Months]
Median ( 95% Confidence Interval )
  6.2  
  ( 5.59 to 6.87 )  
  3.3  
  ( 2.89 to 4.14 )  


Statistical Analysis 1 for Progression-free Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] <.0001
Hazard Ratio (HR) [4] 0.528
95% Confidence Interval ( 0.422 to 0.661 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  The hazard ratio was estimated by Cox regression.



2.  Primary:   Overall Survival   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Primary
Measure Title Overall Survival
Measure Description Overall survival was defined as the time from randomization to death from any cause.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
Number of Participants Analyzed  
[units: participants]
  404     198  
Overall Survival  
[units: Months]
Median ( 95% Confidence Interval )
  NA  
  ( 13.14 to NA ) [1]
  14.9  
  ( 11.27 to NA ) [2]
[1] The median and the upper limit of the confidence interval could not be estimated due to too few events.
[2] The upper limit of the confidence interval could not be estimated due to too few events.


Statistical Analysis 1 for Overall Survival
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.0034
Hazard Ratio (HR) [4] 0.552
95% Confidence Interval ( 0.369 to 0.826 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  The hazard ratio was estimated by Cox regression.



3.  Secondary:   Percentage of Participants With an Objective Response   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Percentage of Participants With an Objective Response
Measure Description An objective response was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study. Only participants with measurable disease at Baseline were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
Number of Participants Analyzed  
[units: participants]
  345     163  
Percentage of Participants With an Objective Response  
[units: Percentage of participants]
Number ( 95% Confidence Interval )
  31.3  
  ( 26.5 to 36.5 )  
  8.6  
  ( 5.1 to 13.8 )  


Statistical Analysis 1 for Percentage of Participants With an Objective Response
Groups [1] All groups
Method [2] Mantel Haenszel
P Value [3] <.0001
Difference in Response Percentage [4] 22.7
95% Confidence Interval ( 16.2 to 29.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Duration of the Objective Response   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Duration of the Objective Response
Measure Description Duration of the objective response was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study. Only participants with an objective response were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
Number of Participants Analyzed  
[units: participants]
  108     14  
Duration of the Objective Response  
[units: Months]
Median ( 95% Confidence Interval )
  9.7  
  ( 6.60 to 10.51 )  
  NA  
  ( 2.40 to NA ) [1]
[1] The median and the upper confidence interval value could not be estimated due to too few events.

No statistical analysis provided for Duration of the Objective Response



5.  Secondary:   6-month and 1-year Survival   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title 6-month and 1-year Survival
Measure Description 6-month and 1-year survival were defined as the percentage of participants who were alive at 6 months and 1 year, respectively.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
Number of Participants Analyzed  
[units: participants]
  404     198  
6-month and 1-year Survival  
[units: Percentage of participants]
Number ( 95% Confidence Interval )
   
6-Month Survival     90.9  
  ( 87.79 to 94.01 )  
  78.3  
  ( 71.49 to 85.19 )  
1-Year Survival     68.6  
  ( 59.91 to 77.28 )  
  56.9  
  ( 42.22 to 71.63 )  


Statistical Analysis 1 for 6-month and 1-year Survival
Groups [1] All groups
Method [2] z-test
P Value [3] 0.0011
Difference in Survival Percentage [4] 12.6
95% Confidence Interval ( 5.03 to 20.09 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  6-month survival
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value for the difference in survival rate was derived from the z-test using the standard errors computed using Greenwood`s method.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for 6-month and 1-year Survival
Groups [1] All groups
Method [2] z-test
P Value [3] 0.1805
Difference in Survival Percentage [4] 11.7
95% Confidence Interval ( -5.41 to 28.75 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  1-year survival
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  The p-value for the difference in survival rates was derived from the z-test using the standard errors computed using Greenwood`s method.
[4] Other relevant estimation information:
  No text entered.



6.  Secondary:   Time to Pain Symptom Progression   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Time to Pain Symptom Progression
Measure Description Time to pain symptom progression was defined as the time from randomization to the first documentation of an increase in narcotic use and/or a 10 point increase from Baseline in the pain score as measured by the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire for patients with bone metastases (EORTC QLQ-BM22). The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study. Only participants with a Baseline pain score and at least 1 post-baseline pain score were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
Number of Participants Analyzed  
[units: participants]
  297     117  
Time to Pain Symptom Progression  
[units: Months]
Median ( 95% Confidence Interval )
  2.9  
  ( 2.2 to 3.7 )  
  3.6  
  ( 2.7 to 4.5 )  


Statistical Analysis 1 for Time to Pain Symptom Progression
Groups [1] All groups
Method [2] Log Rank
P Value [3] 0.4952
Hazard Ratio (HR) [4] 1.115
95% Confidence Interval ( 0.819 to 1.517 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The analysis was stratified for 1) World region (United States, Western Europe, or Other); 2) Number of prior regimens, excluding single-agent hormones, for treatment of metastatic or unresectable locally advanced/recurrent disease (≤ 3 or > 3); and 3) Presence of visceral disease (any visceral disease vs no visceral disease).
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No text entered.
[4] Other relevant estimation information:
  No text entered.



7.  Secondary:   Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle   [ Time Frame: Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years) ]

Measure Type Secondary
Measure Title Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle
Measure Description The EORTC QLQ-BM22 assesses the symptoms of bone metastases using 22 items: 5 items for sites of pain, 3 pain characteristics, 8 functional interference aspects, and 6 psychosocial aspects. The pain score was derived from the 3 pain characteristic items. Each item was rated on a 4-point scale, where 1=Not at all to 4=Very much. The pain score was the sum of the 3 pain characteristic scores and was normalized to a scale of 0 to 100. A higher score indicates greater pain. A negative change score indicates improvement.
Time Frame Baseline to the clinical cut-off date of 11 Feb 2013 (up to 2 years)  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Randomized population: All participants who were randomized to the study. Only participants with a Baseline pain score and at least 1 post-baseline pain score were included in the analysis. Participants were included in the treatment group to which they were randomized.

Reporting Groups
  Description
Trastuzumab Emtansine Trastuzumab emtansine 3.6 mg/kg intravenously every 3 weeks until disease progression (as assessed by the investigator) or unmanageable toxicity.
Treatment of Physician’s Choice Treatment of physician’s choice until disease progression (as assessed by the investigator) or unmanageable toxicity. The treatments included single-agent chemotherapy, single-agent or dual-agent hormonal therapy for hormone receptor positive-disease, and HER2-directed therapy.

Measured Values
    Trastuzumab Emtansine     Treatment of Physician’s Choice  
Number of Participants Analyzed  
[units: participants]
  297     117  
Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle  
[units: Units on a scale]
Mean ± Standard Deviation
   
Cycle 2 (n=282,98)     -3.4  ± 21.1     -9.4  ± 22.1  
Cycle 3 (n=257,86)     -4.6  ± 21.1     -6.1  ± 21.4  
Cycle 4 (n=236,74)     -4.8  ± 19.6     -3.8  ± 24.1  
Cycle 5 (n=224,54)     -6.6  ± 22.8     -2.7  ± 18.9  
Cycle 6 (n=195,42)     -4.8  ± 23.5     2.4  ± 17.1  
Cycle 7 (n=163,30)     -4.2  ± 23.8     -1.5  ± 15.6  
Cycle 8 (n=130,20)     -7.0  ± 21.0     2.2  ± 18.6  
Cycle 9 (n=97,15)     -5.8  ± 22.2     6.7  ± 20.1  
Cycle 10 (n=80,7)     -8.9  ± 21.2     1.6  ± 11.9  
Cycle 11 (n=56,8)     -10.5  ± 23.1     0.0  ± 8.4  
Cycle 12 (n=48,7)     -11.3  ± 25.8     1.6  ± 7.7  
Cycle 13 (n=40,5)     -10.0  ± 23.3     2.2  ± 12.2  
Cycle 14 (n=33,5)     -10.1  ± 21.8     0.0  ± 7.9  
Cycle 15 (n=27,3)     -13.2  ± 22.0     0.0  ± 0.0  
Cycle 16 (n=19,3)     -12.3  ± 19.6     -3.7  ± 6.4  
Cycle 17 (n=15,2)     -7.4  ± 22.9     -5.6  ± 7.9  
Cycle 18 (n=11,0)     -9.1  ± 12.0     NA  ± NA [1]
Cycle 19 (n=8,0)     1.4  ± 9.3     NA  ± NA [1]
Cycle 20 (n=4,0)     -5.6  ± 23.1     NA  ± NA [1]
Cycle 21 (n=3,0)     -3.7  ± 6.4     NA  ± NA [1]
Termination Visit (n=84,37)     -1.6  ± 21.8     -9.0  ± 23.3  
[1] There were no participants with available data.

No statistical analysis provided for Change From Baseline in the EORTC QLQ-BM22 Pain Score on Day 1 of Each Cycle




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
  Hide More Information

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


Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
phone: 800 821-8590


No publications provided


Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01419197     History of Changes
Other Study ID Numbers: TDM4997g, BO25734, 2011-000509-29
Study First Received: August 16, 2011
Results First Received: February 7, 2014
Last Updated: April 3, 2014
Health Authority: United States: Food and Drug Administration