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A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer (MARIANNE)

This study has been completed.
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01120184
First received: April 28, 2010
Last updated: January 3, 2017
Last verified: January 2017
  Purpose
This randomized, 3-arm, multicentre, phase III study will evaluate the efficacy and safety of trastuzumab emtansine (T-DM1) with pertuzumab or trastuzumab emtansine (T-DM1) with pertuzumab-placebo (blinded for pertuzumab), versus the combination of trastuzumab (Herceptin) plus taxane (docetaxel or paclitaxel) in patients with HER2-positive progressive or recurrent locally advanced or previously untreated metastatic breast cancer. Patients will be randomized to 1 of 3 treatment arms (Arms A, B or C). Arm A will be open-label, whereas Arms B and C will be blinded.

Condition Intervention Phase
Breast Cancer
Drug: docetaxel
Drug: paclitaxel
Drug: pertuzumab
Drug: pertuzumab-placebo
Drug: trastuzumab [Herceptin]
Drug: trastuzumab emtansine
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Study of Trastuzumab-DM1 Plus Pertuzumab Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With Death or Disease Progression According to Independent Review Facility (IRF) Assessment [ Time Frame: 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) ]
    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 participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • Progression-Free Survival (PFS) According to IRF Assessment [ Time Frame: 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) ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants Who Died Prior to Clinical Cutoff [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination) ]
    The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • Overall Survival (OS) at Clinical Cutoff [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination) ]
    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.

  • Percentage of Participants With Death or Disease Progression According to Investigator Assessment [ Time Frame: 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) ]
    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 participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • PFS According to Investigator Assessment [ Time Frame: 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) ]
    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.

  • Percentage of Participants Experiencing Treatment Failure [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]
    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 participant withdrawal. The percentage of participants with treatment failure was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • Time to Treatment Failure (TTF) [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]
    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 participant 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.

  • One-Year Survival Rate [ Time Frame: From randomization until 1 year ]
    The percentage of participants 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.

  • Percentage of Participants With Grade ≥3 Adverse Events [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose ]
    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.

  • Percentage of Participants Who Died at 2 Years [ Time Frame: From randomization until 2 years ]
  • Overall Survival Truncated at 2 Years [ Time Frame: From randomization until 2 years ]
    Overall Survival truncated at 2 years was defined as the time from the date of randomization to the date of death from any cause. Participants who were alive at 2 years had been censored at 2 years. Median duration of overall survival truncated at 2 years was estimated using Kaplan-Meier analyses, and corresponding CIs were computed using the Brookmeyer-Crowley method.

  • Percentage of Participants With Grade 5 Adverse Events [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (continuously until 28 days after last dose ]
    Adverse events were graded according to NCI CTCAE version 4.0. Grade 5 adverse events are those events which led to death.

  • Percentage of Participants With Grade 3-4 Laboratory Parameters [ Time Frame: 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 ]
    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.

  • Percentage of Participants With Decline of ≥2 Points From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Baseline, Day 1 of every Cycle up to Clinical Data Cut (up to 48 months) ]
    The ECOG performance status is a scale used to quantify cancer participants' 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.

  • Hospitalization Days [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]
    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 participants.

  • Percentage of Participants With Hospitalization [ Time Frame: Up to 48 months from randomization until clinical cutoff of 16-Sept-2014 ]
    Hospitalization was defined as a non-administration-related hospitalization due to serious adverse event, while on study treatment.

  • Percentage of Participants With Objective Response According to IRF Assessment [ Time Frame: 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) ]
    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 participants with a best overall response of CR or PR (ie, the objective response rate [ORR]) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.

  • Percentage of Participants With Objective Response According to Investigator Assessment [ Time Frame: 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) ]
    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 participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.

  • Duration of Response According to IRF Assessment [ Time Frame: 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) ]
    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.

  • Percentage of Participants With a Best Overall Response of CR, PR, or Stable Disease (SD) According to IRF Assessment [ Time Frame: 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) ]
    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 participants with a best overall response of CR, PR, or SD was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.

  • Percentage of Participants 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 [ Time Frame: 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) ]
    The FACT-Taxane is a self-reported instrument which measures the health-related quality of life (HRQOL) of participants 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 participants with treatment-related symptoms was calculated using following formula: [number of participants meeting the above threshold divided by the number analyzed] multiplied by 100. Corresponding CIs were computed using the Blyth-Still-Casella exact method.

  • Percentage of Participants Reporting Nausea According to the Relevant Single Items of The FACT Colorectal Cancel (FACT-C) Module [ Time Frame: At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2 ]
    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 participants with nausea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100.

  • Percentage of Participants Reporting Diarrhea According to the Relevant Single Items of The FACT-C Module [ Time Frame: At Baseline, Day 8 of Cycle 1, and Days 1 and 8 of Cycle 2 ]
    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 participants with diarrhea was calculated using following formula: [number of participants with any level of either symptom divided by the number analyzed] multiplied by 100.

  • Percentage of Participants 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 [ Time Frame: Up to 39 months from randomization until progression or clinical cutoff of 16Sept2014 (Pre amendment C: every 9 weeks for 1st 81 weeks, every 12 weeks thereafter; post amendment C: 1st day of every cycle for first 8 cycles, every other cycle thereafter) ]
    The FACT-B is a self-reported instrument which measures HRQOL of participants 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 participants with deterioration was calculated as [number of participants meeting the above threshold divided by the number analyzed] multiplied by 100.

  • Time to Deterioration in HRQoL as Assessed by FACT-B TOI-PFB Score [ Time Frame: Up to 39 months from randomization until progression or clinical cutoff of 16Sept2014 (Pre amendment C: every 9 weeks for 1st 81 weeks, every 12 weeks thereafter; post amendment C: 1st day of every cycle for first 8 cycles, every other cycle thereafter) ]
    The FACT-B is a self-reported instrument which measures HRQOL of participants 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.

  • Change From Baseline in Rotterdam Symptom Checklist (RSCL) Activity Level Scale Score [ Time Frame: Baseline, Cycle 7 (Week 18) ]
    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.

  • Change From Baseline in Work Productivity According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score [ Time Frame: Baseline, Cycle 7 (Week 18) ]
    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 participants 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 participants 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)

  • Change From Baseline in Activity Impairment According to Work Productivity and Activity Impairment (WPAI) Questionnaire Score [ Time Frame: Baseline, Cycle 7 (Week 18) ]
    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 participants 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 participants 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).

  • Percentage of Participants 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 [ Time Frame: 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) ]
    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 participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.

  • Percentage of Participants With a Best Overall Response of CR or PR According to IRF Assessment Among Those With Low HER2 mRNA Levels [ Time Frame: 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) ]
    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 participants with a best overall response of CR or PR (ie, the ORR) was calculated as [number of participants meeting the respective criteria divided by the number analyzed] multiplied by 100.

  • Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With High HER2 mRNA Levels [ Time Frame: 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) ]
    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 participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • PFS According to IRF Assessment Among Those With High HER2 mRNA Levels [ Time Frame: 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) ]
    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.

  • Percentage of Participants With Death or Disease Progression According to IRF Assessment Among Those With Low HER2 mRNA Levels [ Time Frame: 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) ]
    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 participants with death or disease progression was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • PFS According to IRF Assessment Among Those With Low HER2 mRNA Levels [ Time Frame: 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) ]
    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.

  • Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With High HER2 mRNA Levels [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination) ]
    The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • OS at Clinical Cutoff Among Those With High HER2 mRNA Levels [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination) ]
    OS was defined as the time from randomization to death from any cause. Median duration of OS was estimated using Kaplan-Meier analysis.

  • Percentage of Participants Who Died Prior to Clinical Cutoff Among Those With Low HER2 mRNA Levels [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination) ]
    The percentage of participants who died prior to clinical cutoff was calculated as [number of participants with event divided by the number analyzed] multiplied by 100.

  • OS at Clinical Cutoff Among Those With Low HER2 mRNA Levels [ Time Frame: Up to 50 months from randomization until clinical cutoff of 16-Sept-2014 (every 3 months until death, loss to follow-up, withdrawal, or study termination) ]
    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.


Enrollment: 1095
Study Start Date: July 2010
Study Completion Date: October 2016
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Trastuzumab + Taxane (docetaxel or paclitaxel) Drug: docetaxel
75 mg/m2 or 100 mg/m2 intravenously every 3 weeks for a minimum of 6 cycles.
Drug: paclitaxel
80 mg/m2 intravenously weekly for a minimum of 18 weeks
Drug: trastuzumab [Herceptin]
trastuzumab [Herceptin] doses when administered with docetaxel: 8 mg/kg intravenously on cycle 1 followed by 6 mg/kg every 3 weeks in subsequent cycles or trastuzumab (Herceptin) doses when administered with paclitaxel: 4 mg/kg intravenously on day 1 of cycle 1 followed by 2 mg/kg weekly starting on day 8 of cycle 1.
Experimental: Trastuzumab emtansine + pertuzumab Drug: pertuzumab
840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
Drug: trastuzumab emtansine
3.6 mg/kg intravenously every 3 weeks
Experimental: Trastuzumab emtansine + pertuzumab placebo Drug: pertuzumab-placebo
840 mg intravenously on day 1 of cycle 1 followed by 420 mg intravenously every 3 weeks in subsequent cycles
Drug: trastuzumab emtansine
3.6 mg/kg intravenously every 3 weeks

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients >/=18 years of age
  • HER2-positive breast cancer
  • Histologically or cytologically confirmed adenocarcinoma of the breast with locally recurrent or metastatic disease, and be a candidate for chemotherapy. Patients with locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent.
  • Patients must have measurable and/or non-measurable disease which must be evaluable per RECIST 1.1
  • ECOG Performance Status 0 or 1
  • Adequate organ function as determined by laboratory results

Exclusion Criteria:

  • History of prior (or any) chemotherapy for metastatic breast cancer or recurrent locally advanced disease
  • An interval of <6 months from the last dose of vinca-alkaloid or taxane cytotoxic chemotherapy until the time of metastatic diagnosis
  • Hormone therapy <7 days prior to randomization
  • Trastuzumab therapy and/or lapatinib (neo- or adjuvant setting) <21 days prior to randomization
  • Prior trastuzumab emtansine or pertuzumab therapy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01120184

  Hide Study Locations
Locations
United States, Arizona
Tucson, Arizona, United States, 85704
United States, Arkansas
Little Rock, Arkansas, United States, 72204
Little Rock, Arkansas, United States, 72205
United States, California
La Jolla, California, United States, 92093
LaJolla, California, United States, 92037
Montebello, California, United States, 90640
Monterey Park, California, United States, 91754
San Diego, California, United States, 92108
San Diego, California, United States, 92123
Santa Ana, California, United States, 92705
Vallejo, California, United States, 94589
United States, Colorado
Aurora, Colorado, United States, 80045
United States, Connecticut
New Haven, Connecticut, United States, 06510
United States, Delaware
Newark, Delaware, United States, 19713
United States, District of Columbia
Washington, District of Columbia, United States, 20010
United States, Florida
Aventura, Florida, United States, 33180
Coral Springs, Florida, United States, 33065-5701
Fort Myers, Florida, United States, 33916
Jacksonville, Florida, United States, 32224
Loxahatchee, Florida, United States, 33470
Miami, Florida, United States, 33136
United States, Georgia
Athens, Georgia, United States, 30607
Gainesville, Georgia, United States, 30501
United States, Hawaii
Honolulu, Hawaii, United States, 96813
United States, Idaho
Boise, Idaho, United States, 83712
United States, Illinois
Chicago, Illinois, United States, 60637
Decatur, Illinois, United States, 62526
Harvey, Illinois, United States, 60426
Maywood, Illinois, United States, 60153
Peoria, Illinois, United States, 61615
Urbana, Illinois, United States, 61801
United States, Indiana
Indianapolis, Indiana, United States, 46202
Lafayette, Indiana, United States, 47905
United States, Iowa
Cedar Rapids, Iowa, United States, 52403
Sioux City, Iowa, United States, 51101
United States, Kentucky
Louisville, Kentucky, United States, 40202
United States, Maine
Scarborough, Maine, United States, 04074
York, Maine, United States, 03909
United States, Maryland
Annapolis, Maryland, United States, 21401
Baltimore, Maryland, United States, 21202
Bethesda, Maryland, United States, 20817
United States, Massachusetts
Boston, Massachusetts, United States, 02118
United States, Michigan
Detroit, Michigan, United States, 48201
Grand Rapids, Michigan, United States, 49503
United States, Minnesota
Duluth, Minnesota, United States, 55805
Minneapolis, Minnesota, United States, 55454
Rochester, Minnesota, United States, 55905
Saint Louis Park, Minnesota, United States, 55416
United States, Missouri
Jefferson City, Missouri, United States, 65109
Springfield, Missouri, United States, 65804
St Louis, Missouri, United States, 63141
United States, Nebraska
Omaha, Nebraska, United States, 68114
United States, New Hampshire
Lebanon, New Hampshire, United States, 03756
United States, New Jersey
Hackensack, New Jersey, United States, 07601
New Brunswick, New Jersey, United States, 08901
United States, New Mexico
Albuquerque, New Mexico, United States, 87110
Albuquerque, New Mexico, United States, 87131-0001
Farmington, New Mexico, United States, 87401
United States, New York
Abany, New York, United States, 12208
Fresh Meadows, New York, United States, 11366
Jamaica, New York, United States, 11432
Lake Success, New York, United States, 11042
New York, New York, United States, 10029
New York, New York, United States, 10065
United States, North Carolina
Charlotte, North Carolina, United States, 28203
Hickory, North Carolina, United States, 28602
Washington, North Carolina, United States, 27889
United States, North Dakota
Fargo, North Dakota, United States, 58122-9988
United States, Ohio
Cincinnati, Ohio, United States, 45242
United States, Oregon
Portland, Oregon, United States, 97225
United States, Pennsylvania
Hershey, Pennsylvania, United States, 17033
United States, Rhode Island
East Providence, Rhode Island, United States, 02915
United States, South Carolina
Charleston, South Carolina, United States, 29414
Charleston, South Carolina, United States, 29524
Columbia, South Carolina, United States, 29210
United States, South Dakota
Sioux Falls, South Dakota, United States, 57105
United States, Tennessee
Chattanooga, Tennessee, United States, 37404
Memphis, Tennessee, United States, 38104
Memphis, Tennessee, United States, 38120
Nashville, Tennessee, United States, 37203
Nashville, Tennessee, United States, 37232
United States, Texas
Amarillo, Texas, United States, 79106
Dallas, Texas, United States, 75390-9063
Houston, Texas, United States, 77030
San Antonio, Texas, United States, 78217
United States, Utah
Ogden, Utah, United States, 84403
United States, Washington
Everett, Washington, United States, 98201
Seattle, Washington, United States, 98195
Tacoma, Washington, United States, 98405
Walla Walla, Washington, United States, 99362
United States, Wisconsin
Madison, Wisconsin, United States, 53705
Argentina
Caba, Argentina, C1050AAK
Florencio Varela, Argentina, B1878DVB
San Miguel de Tucuman, Argentina, T4000IAK
Australia, New South Wales
Newcastle, New South Wales, Australia, 2298
Sydney, New South Wales, Australia, 2060
Australia, Queensland
Auchenflower, Queensland, Australia, 4066
Australia, South Australia
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Melbourne, Victoria, Australia, 3002
Austria
Salzburg, Austria, 5020
Wien, Austria, 1090
Bahamas
Nassau, Bahamas, N9311
Belgium
Bruxelles, Belgium, 1200
Namur, Belgium, 5000
Wilrijk, Belgium, 2610
Bosnia and Herzegovina
Banja Luka, Bosnia and Herzegovina, 78000
Sarajevo, Bosnia and Herzegovina, 71000
Brazil
Rio de Janeiro, RJ, Brazil, 20560-120
Natal, RN, Brazil, 59040150
Porto Alegre, RS, Brazil, 90430-090
Porto Alegre, RS, Brazil, 90610-000
Porto Alegre, RS, Brazil, 91350-200
Itajai, SC, Brazil, 88301-220
Sao Paulo, SP, Brazil, 01246-000
Sao Paulo, SP, Brazil, 01317-000
Canada, Alberta
Edmonton, Alberta, Canada, T6G 1Z2
Canada, Ontario
Toronto, Ontario, Canada, M2K 1E1
Canada, Quebec
Sherbrooke, Quebec, Canada, J1H 5N4
Canada
Quebec, Canada, G1S 4L8
Colombia
Bogota, Colombia, 11001
Bucaramanga, Colombia
Cali, Colombia
Pasto, Colombia
Czech Republic
Brno, Czech Republic, 656 53
Olomouc, Czech Republic, 775 20
Praha 2, Czech Republic, 128 08
Praha, Czech Republic, 180 00
Denmark
Hillerod, Denmark, 3400
Vejle, Denmark, 7100
France
Besancon, France, 25030
Clermont Ferrand, France, 63011
Lille, France, 59020
Marseille, France, 13273
Montpellier, France, 34298
Nancy, France, 54100
Paris, France, 75231
Paris, France, 75475
Paris, France, 75970
Poitiers, France, 86021
Saint Cloud, France, 92210
St Priest En Jarez, France, 42271
Germany
Essen, Germany, 45136
Halle, Germany, 06120
Hamburg, Germany, 20249
Hannover, Germany, 30177
Heidelberg, Germany, 69120
Magdeburg, Germany, 39108
Mainz, Germany, 55131
Minden, Germany, 32429
Muenchen, Germany, 80637
Trier, Germany, 54290
Greece
Athens, Greece, 11528
Heraklion, Greece, 711 10
Larissa, Greece, 41 110
Guatemala
Guatemala City, Guatemala, 01015
Guatemala, Guatemala, 01009
Hungary
Budapest, Hungary, 1031
Budapest, Hungary, 1083
Budapest, Hungary, 1125
Pecs, Hungary, 7624
Italy
Catanzaro, Calabria, Italy, 88100
Meldola, Emilia-Romagna, Italy, 47014
Modena, Emilia-Romagna, Italy, 41100
Reggio Emilia, Emilia-Romagna, Italy, 42100
Rimini, Emilia-Romagna, Italy, 47900
Udine, Friuli-Venezia Giulia, Italy, 33100
Milano, Lombardia, Italy, 20141
Pavia, Lombardia, Italy, 27100
Rozzano, Lombardia, Italy, 20089
Catania, Sicilia, Italy, 95100
Messina, Sicilia, Italy, 98123
Prato, Toscana, Italy, 59100
Perugia, Umbria, Italy, 06156
Verona, Veneto, Italy, 37126
Japan
Aichi, Japan, 446-0073
Aichi, Japan, 464-8681
Ehime, Japan, 791-0280
Fukuoka, Japan, 802-0077
Fukuoka, Japan, 811-1395
Gifu, Japan, 501-1194
Gunma, Japan, 371-8511
Hiroshima, Japan, 734-8551
Hokkaido, Japan, 003-0804
Hyogo, Japan, 663-8501
Hyogo, Japan, 673-8558
Ishikawa, Japan, 920-8641
Iwate, Japan, 020-8505
Kagoshima, Japan, 892-0833
Kanagawa, Japan, 216-8511
Kanagawa, Japan, 259-1193
Kumamoto, Japan, 860-8556
Kumamoto, Japan, 862-8505
Kyoto, Japan, 606-8507
Miyagi, Japan, 980-8574
Niigata, Japan, 951-8566
Okayama, Japan, 700-8558
Okayama, Japan, 701-0114
Osaka, Japan, 540-0006
Osaka, Japan, 565-0871
Saitama, Japan, 350-1298
Saitama, Japan, 362-0806
Shizuoka, Japan, 411-8777
Shizuoka, Japan, 420-8527
Tochigi, Japan, 329-0498
Tokyo, Japan, 104-0045
Tokyo, Japan, 105-8470
Tokyo, Japan, 135-8550
Tokyo, Japan, 142-8666
Tokyo, Japan, 160-0023
Tokyo, Japan, 181-8611
Korea, Republic of
Gyeonggi-do, Korea, Republic of, 463-707
Seoul, Korea, Republic of, 110-744
Seoul, Korea, Republic of, 135-710
Seoul, Korea, Republic of, 138-736
Seoul, Korea, Republic of, 152-703
Macedonia, The Former Yugoslav Republic of
Skopje, Macedonia, The Former Yugoslav Republic of, 1000
Malaysia
Kuala Lumpur, Malaysia, 59100
Petaling Jaya, Selangor, Malaysia, 46050
Selangor, Malaysia, 46150
Mexico
Acapulco, Mexico, 39670
Aguascalientes, Mexico, 20230
Guadalajara, Mexico, 44670
Monterrey, Mexico, 64020
Oaxaca, Mexico, 68000
Obregon, Mexico, 85000
Toluca, Mexico, 50180
New Zealand
Auckland, New Zealand, 1009
Hamilton, New Zealand
Panama
Panama City, Panama, 32400
Peru
Arequipa, Peru, 04001
Lima, Peru, 11
Piura, Peru, 20011
Philippines
Cebu City, Philippines, 6000
San Juan, Philippines, 1500
Poland
Bydgoszcz, Poland, 85-796
Gdansk, Poland, 80-211
Krakow, Poland, 31-115
Lublin, Poland, 20-090
Warszawa, Poland, 02-781
Portugal
Porto, Portugal, 4200-072
Romania
Bucharest, Romania
Cluj Napoca, Romania, 400015
Cluj-Napoca, Romania, 400006
Russian Federation
Ivanovo, Russian Federation, 153040
Kazan, Russian Federation, 420029
Moscow, Russian Federation, 115478
Moscow, Russian Federation, 143423
Pyatigorsk, Russian Federation, 357502
Ryazan, Russian Federation, 390011
Samara, Russian Federation, 443031
Stavropol, Russian Federation, 355045
Tula, Russian Federation, 300053
Vladimir, Russian Federation, 600009
Spain
Elche, Alicante, Spain, 03203
Santiago de Compostela, La Coruña, Spain, 15706
Barcelona, Spain, 08003
Barcelona, Spain, 08035
Jaen, Spain, 23007
La Coruña, Spain, 15006
Madrid, Spain, 28007
Madrid, Spain, 28041
Madrid, Spain, 28046
Malaga, Spain, 29010
Valencia, Spain, 46010
Sweden
Linkoeping, Sweden, 58185
Malmo, Sweden, 205 02
Switzerland
Baden, Switzerland, 5404
Basel, Switzerland, 4031
Chur, Switzerland, 7000
Taiwan
Changhua, Taiwan, 500
Kaohsiung, Taiwan, 807
Taipei, Taiwan, 100
Taipei, Taiwan, 114
Thailand
Bangkok, Thailand, 10400
Bangkok, Thailand, 10700
Chiang Mai, Thailand, 50200
Songkhla, Thailand, 90110
Turkey
Adana, Turkey, 01250
Adana, Turkey, 01330
Ankara, Turkey, 06500
Izmir, Turkey, 35100
United Kingdom
Bristol, United Kingdom, BS2 8ED
Cambridge, United Kingdom, CB2 0QQ
Glasgow, United Kingdom, G12 0YN
Leicester, United Kingdom, LE1 5WW
London, United Kingdom, NW3 2QG
London, United Kingdom, SE1 9RT
London, United Kingdom, SW3 6JJ
Manchester, United Kingdom, M20 4BX
Nottingham, United Kingdom, NG5 1PB
Peterborough, United Kingdom, PE 3 9GZ
Portsmouth, United Kingdom, PO6 3LY
Sheffield, United Kingdom, S10 2SJ
Southampton, United Kingdom, SO16 6YD
Stoke-on-Trent, United Kingdom, ST4 6QG
Sutton, United Kingdom, SM2 5PT
Truro, United Kingdom, TR1 3LJ
Sponsors and Collaborators
Hoffmann-La Roche
Genentech, Inc.
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01120184     History of Changes
Other Study ID Numbers: BO22589
Study First Received: April 28, 2010
Results First Received: May 2, 2016
Last Updated: January 3, 2017

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Ado-trastuzumab emtansine
Pertuzumab
Taxane
Paclitaxel
Albumin-Bound Paclitaxel
Trastuzumab
Maytansine
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic

ClinicalTrials.gov processed this record on May 24, 2017