A Study of Trastuzumab Emtansine (Kadcyla) Plus Pertuzumab (Perjeta) Following Anthracyclines in Comparison With Trastuzumab (Herceptin) Plus Pertuzumab and a Taxane Following Anthracyclines as Adjuvant Therapy in Participants With Operable HER2-Positive Primary Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Trastuzumab Emtansine; Trastuzumab; Pertuzumab; Paclitaxel; Epirubicin; Doxorubicin; Docetaxel; Cyclophosphamide; 5-Fluorouracil
Intervention description: Trastuzumab emtansine IV infusion (duration 90 minutes) will be administered at 3.6 mg/kg q3w for up to 18 cycles (1 cycle = 21 days).; Trastuzumab IV infusion (duration 90 minutes) will be administered at 8 mg/kg loading dose followed by 6 mg/kg IV q3w for up to 18 cycles (1 cycle = 21 days).; Pertuzumab infusion (duration 60 minutes) will be administered at 840 mg loading dose followed by 420 mg IV q3w for up to 18 cycles (1 cycle = 21 days).; IV infusion of paclitaxel 80 mg/m^2 once weekly may be administered concurrently with trastuzumab in combination with pertuzumab for 12 weeks.; 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using epirubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.; 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using doxorubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.; IV infusion either docetaxel every 3 weeks (q3w) (at 100 milligram per square meter [mg/m^2] for 3 cycles (1 cycle = 21 days); at 75 mg/m2 for 4 cycles; or start at 75 mg/m^2 in the first cycle and escalate to 100 mg/m^2 if no dose limiting toxicity occurs, for a total of 3 cycles at minimum) may be administered concurrently with trastuzumab in combination with pertuzumab.; 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using cyclophosphamide (FEC) may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.; 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using 5-fluorouracil, may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.
Intervention MeSH terms: Maytansine; Docetaxel; Ado-Trastuzumab Emtansine; Cyclophosphamide; Doxorubicin; Fluorouracil; Trastuzumab; Epirubicin; Pertuzumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1846.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This two-arm, randomized, open-label, multicenter study will evaluate the efficacy and safety
      of trastuzumab emtansine in combination with pertuzumab versus trastuzumab in combination
      with pertuzumab and a taxane as adjuvant therapy in participants with human epidermal growth
      (HER) factor 2 (HER2)-positive primary invasive breast cancer. Following surgery and
      anthracycline-based chemotherapy, participants will receive either trastuzumab emtansine at a
      dose of 3.6 milligrams per kilogram (mg/kg) and pertuzumab at a dose of 420 milligrams (mg)
      intravenously (IV) every 3 weeks (q3w) or trastuzumab at a dose of 6 mg/kg and pertuzumab at
      a dose of 420 mg IV q3w in combination with a taxane.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
             (</=) 1

          -  Non-metastatic histologically confirmed primary invasive breast carcinoma that was
             operable

          -  HER2-positive breast cancer

          -  Known hormone receptor status of the primary tumor

          -  Adequately excised: participants must have undergone either breast-conserving surgery
             or mastectomy/nipple- or skin-sparing mastectomy

          -  Pathological tumor-node-metastasis staging (Union for International Cancer
             Control-American Joint Committee on Cancer [UICC/AJCC] 7th edition): eligible
             participants must have either:

        Node-positive disease (pN more than or equal to [>/=] 1), any tumor size except T0, and any
        hormonal receptor status; or Node-negative disease (pN0) with pathologic tumor size >2.0
        centimeters by standard local assessment and negative for estrogen receptor (ER) and
        progesterone receptor (PR) determined by a central pathology laboratory

          -  Participants with synchronous bilateral invasive disease are eligible only if both
             lesions are HER2-positive

          -  No more than 9 weeks (63 days) may elapse between definitive breast surgery (or the
             last surgery if additional resection required for breast cancer) and randomization

          -  Baseline left ventricular ejection fraction (LVEF) >/=55% measured by echocardiogram
             (ECHO; preferred) or multiple-gated acquisition (MUGA) scans

          -  Documentation on hepatitis B virus (HBV) and hepatitis C virus (HCV) serology is
             required

          -  Female participants of childbearing potential must be willing to use one highly
             effective form of non-hormonal contraception or two effective forms of non-hormonal
             contraception. For male participants with partners of childbearing potential, one
             highly effective form of contraception or two effective forms of contraception must be
             used. Contraception must continue for the duration of study treatment and for 6 months
             after the last dose of study treatment

        Exclusion Criteria:

          -  History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma

          -  History of non-breast malignancies within the 5 years prior to randomization, except
             for carcinoma in situ (CIS) of the cervix, CIS of the colon, melanoma in situ, and
             basal cell and squamous cell carcinomas of the skin

          -  Any clinical T4 tumor as defined by tumor-node-metastasis classification in UICC/AJCC
             7th edition, including inflammatory breast cancer

          -  For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment
             (for example, neoadjuvant or adjuvant), including but not limited to, chemotherapy,
             anti-HER2 therapy (for example, trastuzumab, trastuzumab emtansine, pertuzumab,
             lapatinib, neratinib, or other tyrosine kinase inhibitors), hormonal therapy, OR
             anti-cancer radiation therapy (RT) (intra-operative radiotherapy as a boost at the
             time of primary surgery is acceptable)

          -  Previous therapy with anthracyclines, taxanes, or HER2-targeted therapy for any
             malignancy

          -  History of DCIS and/or lobular CIS (LCIS) that was treated with any form of systemic
             chemotherapy, hormonal therapy, or RT to the ipsilateral breast where invasive cancer
             subsequently developed. Participants who had their DCIS/LCIS treated with surgery only
             and/or contralateral DCIS treated with radiation are allowed to enter the study

          -  Participants with contraindication to RT while adjuvant RT is clinically indicated

          -  Concurrent anti-cancer treatment in another investigational trial

          -  Cardiopulmonary dysfunction as defined by protocol: angina pectoris requiring
             anti-anginal medication, serious cardiac arrhythmia not controlled by adequate
             medication, severe conduction abnormality, or clinically significant valvular disease,
             significant symptoms (Grade >/=2) relating to left ventricular dysfunction, cardiac
             arrhythmia, or cardiac ischemia, myocardial infarction within 12 months prior to
             randomization, uncontrolled hypertension, evidence of transmural infarction on
             electrocardiogram (ECG), requirement for oxygen therapy

          -  Other concurrent serious diseases that may interfere with planned treatment, including
             severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes,
             or known infection with HIV

          -  Any known active liver disease. For participants who are known carriers of HBV/HCV,
             active hepatitis B/C infection must be ruled out per local guidelines

          -  Inadequate hematologic, renal or liver function

          -  Pregnant or lactating women

          -  Hypersensitivity to any of the study medications or any of the ingredients or
             excipients of these medications, including hypersensitivity to benzyl alcohol

          -  Chronic immunosuppressive therapies, including systemic corticosteroids