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Study in Participants With Early-Stage or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer to Evaluate Treatment With Trastuzumab Plus (+) Pertuzumab + Docetaxel Compared With Trastuzumab + Placebo + Docetaxel

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02586025
Recruitment Status : Active, not recruiting
First Posted : October 26, 2015
Results First Posted : January 3, 2019
Last Update Posted : March 12, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This is an Asia-Pacific regional, randomized, double-blind, multicenter trial designed to evaluate treatment with trastuzumab + pertuzumab + docetaxel compared with trastuzumab + placebo + docetaxel in chemotherapy-naïve participants with early-stage or locally advanced HER2-positive breast cancer. The anticipated treatment duration is approximately 17 months.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: FEC Chemotherapy Procedure: Surgery Drug: Docetaxel Drug: Pertuzumab Drug: Placebo Drug: Trastuzumab Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 329 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Study to Evaluate Pertuzumab in Combination With Docetaxel and Trastuzumab as Neoadjuvant Therapy, and Pertuzumab in Combination With Trastuzumab as Adjuvant Therapy After Surgery and Chemotherapy in Patients With Early-Stage or Locally Advanced HER2-Positive Breast Cancer
Actual Study Start Date : March 14, 2016
Actual Primary Completion Date : October 23, 2017
Estimated Study Completion Date : April 30, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Trastuzumab, Pertuzumab, Docetaxel
Prior to surgery: trastuzumab, pertuzumab, and docetaxel for 4 cycles (1 cycle = 21 days). After surgery/chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC): trastuzumab and pertuzumab up to 1 year total.
Drug: FEC Chemotherapy
Fluorouracil 500-600 milligrams per square meter (mg/m2), epirubicin 90-120 mg/m2, and cyclophosphamide 500-600 mg/m2 by intravenous (IV) infusion every 3 weeks for three cycles (Cycles 5-7). FEC chemotherapeutic agents will be administered following surgery on Day 1 of each specified cycle.

Procedure: Surgery
All participants who are eligible for surgery will undergo surgery and have their pathologic response evaluated.

Drug: Docetaxel
Docetaxel IV infusion in 3-week cycles. Neoadjuvant treatment: 75 mg/m2 for Cycles 1-4.

Drug: Pertuzumab
Pertuzumab IV infusion in 3-week cycles. Prior to surgery (neoadjuvant treatment): 840 milligrams (mg) loading dose for Cycle 1, followed by 420 mg for Cycles 2-4. After surgery and 3 cycles of FEC chemotherapy (adjuvant treatment): 840 mg loading dose for Cycle 8, followed by 420 mg for Cycles 9-20)
Other Name: RO4368451

Drug: Trastuzumab
Trastuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 8 milligrams per kilogram (mg/kg) loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2-4. Adjuvant treatment: 8 mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9-20.
Other Name: RO0452317

Experimental: Trastuzumab, Placebo, Docetaxel
Prior to surgery: trastuzumab, placebo, and docetaxel for 4 cycles (1 cycle = 21 days). After surgery/FEC chemotherapy: trastuzumab and placebo up to 1 year total.
Drug: FEC Chemotherapy
Fluorouracil 500-600 milligrams per square meter (mg/m2), epirubicin 90-120 mg/m2, and cyclophosphamide 500-600 mg/m2 by intravenous (IV) infusion every 3 weeks for three cycles (Cycles 5-7). FEC chemotherapeutic agents will be administered following surgery on Day 1 of each specified cycle.

Procedure: Surgery
All participants who are eligible for surgery will undergo surgery and have their pathologic response evaluated.

Drug: Docetaxel
Docetaxel IV infusion in 3-week cycles. Neoadjuvant treatment: 75 mg/m2 for Cycles 1-4.

Drug: Placebo
Placebo by IV infusion in 3-week cycles as neoadjuvant treatment (Cycles 1-4)and as adjuvant treatment (Cycles 8-20)

Drug: Trastuzumab
Trastuzumab IV infusion in 3-week cycles. Neoadjuvant treatment: 8 milligrams per kilogram (mg/kg) loading dose for Cycle 1, followed by 6 mg/kg for Cycles 2-4. Adjuvant treatment: 8 mg/kg loading dose for Cycle 8, followed by 6 mg/kg for Cycles 9-20.
Other Name: RO0452317




Primary Outcome Measures :
  1. Percentage of Participants With Total Pathologic Complete Response (tpCR) as Assessed by the Independent Review Committee (IRC) [ Time Frame: At surgery (Cycle 4 Days 22-35) ]
    This tpCR was assessed by the independent review committee (IRC). tpCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (that is, ypT0/is, ypN0, in accordance with the current American Joint Committee on Cancer [AJCC] staging system). The analysis was based on the Intent-to-Treat (ITT) population with participants grouped by the treatment assigned at the time of randomization. Participants whose tpCR assessment was missing or invalid were counted as not achieving tpCR. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery.


Secondary Outcome Measures :
  1. Percentage of Participants With tpCR as Assessed by the Local Pathologist [ Time Frame: At surgery (Cycle 4 Days 22-35) ]
    This tpCR was assessed by the local pathologist. tpCR is defined as the absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes after completion of neoadjuvant therapy and surgery (that is, ypT0/is, ypN0, in accordance with the current American Joint Committee on Cancer [AJCC] staging system). The analysis was based on the Intent-to-Treat (ITT) population with participants grouped by the treatment assigned at the time of randomization. Participants whose tpCR assessment was missing or invalid were counted as not achieving tpCR. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery.

  2. Percentage of Participants With Breast Pathologic Complete Response (bpCR), Defined as ypT0/is According to the American Joint Committee on Cancer Staging System as Assessed by the IRC [ Time Frame: At surgery (Cycle 4 Days 22-35) ]
    This bpCR was assessed by the IRC. bpCR is defined as the absence of any residual invasive cancer on the hematoxylin and eosin evaluation of the resected breast specimen after completion of neoadjuvant therapy and surgery (that is, ypT0/is, in accordance with current AJCC staging system). The analysis was based on the Intent-to-Treat (ITT) population with participants grouped by the treatment assigned at the time of randomization. Participants whose bpCR assessment was missing or invalid were counted as not achieving bpCR. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery.

  3. Percentage of Participants With bpCR as Assessed by the Local Pathologist [ Time Frame: At surgery (Cycle 4 Days 22-35) ]
    This bpCR was assessed by the local pathologist. bpCR is defined as the absence of any residual invasive cancer on the hematoxylin and eosin evaluation of the resected breast specimen after completion of neoadjuvant therapy and surgery (that is, ypT0/is in accordance with current AJCC staging system). The analysis was based on the Intent-to-Treat (ITT) population with participants grouped by the treatment assigned at the time of randomization. Participants whose bpCR assessment was missing or invalid were counted as not achieving bpCR. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery.

  4. Percentage of Participants With Complete Response, Partial Response, Stable Disease, or Progressive Disease During Cycles 1-4, According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: At surgery (Cycle 4 Days 22-35) ]
    Clinical responses that include the percentage of participants with a Complete Response, Partial Response, Stable Disease, or Progressive Disease were determined by the investigator during Cycles 1‒4 (prior to surgery) on the basis of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Only participants with measurable disease at baseline were included in the analysis. The analysis was based on the Intent-to-Treat (ITT) population with participants grouped by the treatment assigned at the time of randomization. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery.

  5. Percentage of Participants With an Objective Response (Complete or Partial Response) During Cycles 1-4, According to RECIST Version 1.1 [ Time Frame: At surgery (Cycle 4 Days 22-35) ]
    An objective response was defined as the percentage of participants who achieved a complete response or partial response as the best tumor response during the neoadjuvant period (that is, during Cycles 1‒4 prior to surgery), as determined by the investigator on the basis of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. No confirmation was required for objective response. Only participants with measurable disease at baseline were included in the analysis. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery.

  6. Kaplan-Meier Estimate of the Percentage of Participants With 3 Years of Event-Free Survival [ Time Frame: From Baseline to EFS event or date last known to be alive and event-free (up to 5 years) ]
    The Kaplan-Meier approach will be used to estimate the percentage of participants with 3 years of event-free survival (EFS). EFS is defined as the time from randomization to the first documentation of one of the following events: Disease progression (before surgery) as determined by the investigator with use of RECIST v1.1 Any evidence of contralateral disease in situ was not identified as progressive disease; Disease recurrence (local, regional, distant, or contralateral) after surgery; Death from any cause. After treatment completion/discontinuation, follow-up data will be collected every 3 months for 1 year and then every 6 months thereafter, until disease progression or recurrence or until 5 years after randomization of the last participant, whichever occurs first. Participants who do not have an EFS event at the time of the analysis are planned to be censored as of the date they are last known to be alive and event-free.

  7. Kaplan-Meier Estimate of the Percentage of Participants With 3 Years of Disease-Free Survival [ Time Frame: From surgery to DFS event or date last known to be alive and event-free (up to 5 years) ]
    The Kaplan-Meier approach will be used to estimate the percentage of participants with 3 years of disease-free survival (DFS). DFS was defined as the time from first date of no disease (i.e., date of surgery) to first documentation of one of the following events: Disease recurrence (local, regional, distant, or contralateral) after surgery. Any evidence of contralateral disease in situ was not identified as disease recurrence; Death from any cause. After treatment completion/discontinuation, follow-up data will be collected every 3 months for 1 year and then every 6 months thereafter, until disease progression or recurrence or until 5 years after randomization of the last participant, whichever occurs first. Participants were considered to be disease-free if they underwent surgery and no recurrence of disease was reported thereafter. Data from participants who do not have an event at analysis are planned to be censored as of the date they are last known to be alive and event-free.

  8. Kaplan-Meier Estimate of the Percentage of Participants With 3 Years of Overall Survival [ Time Frame: From Baseline to OS event or date last known to be alive (up to 5 years) ]
    The Kaplan-Meier approach will be used to estimate the percentage of participants with 3 years of overall survival (OS). OS was defined as the time from randomization to death from any cause. After treatment completion/discontinuation, follow-up data will be collected every 3 months for 1 year and then every 6 months thereafter, until disease progression or recurrence or until 5 years after randomization of the last participant, whichever occurs first. Data from participants who are alive at the time of the analysis are planned to be censored as of the last date they were known to be alive.

  9. Percentage of Participants With At Least One Adverse Event During the Neoadjuvant Treatment Period [ Time Frame: Baseline up to end of Cycle 4 (1 cycle = 21 days) ]
    The percentage of participants who experienced at least one adverse event during the neoadjuvant period is reported here. The neoadjuvant treatment period began after randomization upon receiving the first dose of any of the neoadjuvant study medications and ended before receiving the first dose of adjuvant study treatment. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery.

  10. Percentage of Participants With At Least One Adverse Event During the Adjuvant Treatment Period [ Time Frame: From Cycle 5 up to Cycle 20 (1 cycle = 21 days) ]
    The percentage of participants who experienced at least one adverse event during the adjuvant period is reported here. The adjuvant treatment period began after primary surgery, upon receiving the first dose of any of the adjuvant study medications. It ended 42 days after the last dose of adjuvant study treatment upon treatment completion or discontinuation. The duration of one treatment cycle is 21 days; the administration of therapy in Cycle 5 should not occur until 2 weeks after surgery. At the clinical cut-off date for the primary analysis (23-Oct-2017), the majority of participants had not completed the adjuvant treatment. Limited data were collected during the adjuvant period; full data will be reported at study completion.

  11. Percentage of Participants With At Least One Adverse Event During the Treatment-Free Follow-Up Period [ Time Frame: From end of overall study treatment until disease progression or recurrence (up to 5 years) ]
    The percentage of participants who experienced at least one adverse event during the treatment-free follow-up period is reported here. The treatment-free follow-up period started the day after the end of the overall study treatment period and continued until disease progression or recurrence or until 5 years after randomization of the last patient, whichever occurred first. At the clinical cut-off date for the primary analysis (23-Oct-2017), limited data were collected during the treatment-free follow-up period; full data will be reported at study completion.

  12. Percentage of Participants Who Experienced a Primary Cardiac Event [ Time Frame: From Baseline until end of study (up to 5 years) ]
    A primary cardiac event is defined as heart failure (New York Heart Association [NYHA] Class III or NYHA Class IV) and a drop in left ventricular ejection fraction (LVEF) of at least 10 ejection fraction points from baseline and to below 50%.

  13. Percentage of Participants Who Experienced a Secondary Cardiac Event [ Time Frame: From Baseline until end of study (up to 5 years) ]
    A secondary cardiac event is defined as an asymptomatic or mildly symptomatic (NYHA Class II) drop in left ventricular ejection fraction (LVEF) by multiple-gated acquisition (MUGA) scan or echocardiogram confirmed by a second LVEF assessment within approximately 3 weeks showing also a documented drop. A significant LVEF drop is defined as an absolute decrease of at least 10 points below the baseline measurement and to below 50%.

  14. Maximum Change From Baseline in Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Baseline; Day 1 of Cycles 2, 4, 5, 8, 11, and 20 (1 cycle = 21 days) ]
    Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method should be used throughout the study for each participant and preferably performed and evaluated by the same assessor. Here, we report the maximum change from baseline in LVEF at any point during the study.

  15. Change From Baseline in Left Ventricular Ejection Fraction (LVEF) Over Time [ Time Frame: Baseline; Day 1 of Cycles 2, 4, 5, 8, 11, and 20 (1 cycle = 21 days) ]
    Left ventricular ejection fraction (LVEF) is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. A normal LVEF ranges from 55% to 70%, as measured by echocardiogram (preferred) or multiple-gated acquisition (MUGA) scan. The same method should be used throughout the study for each participant and preferably performed and evaluated by the same assessor. Here, we report the change from baseline in LVEF over time.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Histologically confirmed invasive breast carcinoma with a primary tumor size of more than (>) 2 centimeters (cm) by standard local assessment technique
  • Breast cancer stage at presentation: early-stage (T2-3, N0-1, M0) or locally advanced (T2-3, N2 or N3, M0; T4, any N, M0)
  • HER2-positive breast cancer confirmed by a Sponsor-designated central laboratory and defined as 3+ score by immunohistochemistry in > 10 percent (%) of immunoreactive cells or HER2 gene amplification (ratio of HER2 gene signals to centromere 17 signals equal to or more than [>=] 2.0) by in situ hybridization
  • Known hormone receptor status (estrogen receptor and/or progesterone receptor)
  • Eastern Cooperative Oncology Group Performance Status equal to or less than (<=) 1
  • Baseline left ventricular ejection fracture >= 55% measured by echocardiography (preferred) or multiple gated acquisition scan
  • Negative serum pregnancy test

Exclusion Criteria:

  • Stage IV metastatic breast cancer
  • Inflammatory breast cancer
  • Previous anti-cancer therapy or radiotherapy for any malignancy
  • History of other malignancy within 5 years prior to screening, except for appropriately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
  • Concurrent anti-cancer treatment in another investigational trial, including hormone therapy, bisphosphonate therapy, or immunotherapy
  • Major surgical procedure unrelated to breast cancer within 4 weeks prior to randomization or from which the participant has not fully recovered
  • Serious cardiac illness or medical condition
  • Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness
  • Any abnormalities in liver, kidney or hematologic function laboratory tests immediately prior to randomization
  • Sensitivity to any of the study medications, any of the ingredients or excipients of these medications, or benzyl alcohol
  • Pregnant or lactating

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02586025


Locations
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China
The Affiliated Hospital of Military Medical Sciences(The 307th Hospital of Chinese PLA)
Beijing, China, 100071
Jilin Cancer Hospital
Changchun, China, 130012
the First Hospital of Jilin University
Changchun, China, 130021
Fujian Medical University Union Hospital
Fujian, China, 350001
Sun Yet-sen University Cancer Center
Guangzhou, China, 510060
Guangdong General Hospital
Guangzhou, China, 510080
Zhejiang Cancer Hospital
Hangzhou, China, 310022
Harbin Medical University Cancer Hospital
Harbin, China, 150081
Shandong Cancer Hospital
Jinan, China, 250117
The 1st Affiliated Hospital of Nanchang Unversity
Nanchang, China, 330006
Jiangsu Province Hospital
Nanjing, China, 210036
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Shanghai, China, 200025
Fudan University Shanghai Cancer Center
Shanghai, China, 200032
Henan Cancer Hospital
Zhengzhou, China, 450008
Korea, Republic of
Kyungpook National University Medical Center
Daegu, Korea, Republic of, 41404
Ajou University Medical Center
Gyeonggi-do, Korea, Republic of, 16499
Korea University Guro Hospital
Seoul, Korea, Republic of, 08308
Taiwan
Taipei Medical University -Shuang Ho Hospital
New Taipei City, Taiwan, 23561
China Medical University Hospital; Surgery
Taichung, Taiwan, 404
Mackay Memorial Hospital; Dept of Surgery
Taipei, Taiwan, 104
Taipei Medical University Hospital
Taipei, Taiwan, 110
Wanfang Hospital
Taipei, Taiwan, 116
Thailand
Bhumibol Adulyadej Hospital; Medicine
Bangkok, Thailand, 10220
Srinagarind Hospital, Khon Kaen University; Surgery
Khon Kaen, Thailand, 40002
Songklanagarind Hospital; Department of Surgery
Songkla, Thailand, 90110
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Study Protocol  [PDF] December 6, 2016
Statistical Analysis Plan  [PDF] July 5, 2017


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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02586025     History of Changes
Other Study ID Numbers: YO28762
First Posted: October 26, 2015    Key Record Dates
Results First Posted: January 3, 2019
Last Update Posted: March 12, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Pertuzumab
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Docetaxel
Trastuzumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological