A Study to Evaluate the Pharmacokinetics, Efficacy, and Safety of Subcutaneous Administration of the Fixed-Dose Combination of Pertuzumab and Trastuzumab in Combination With Chemotherapy in Participants With HER2-Positive Early Breast Cancer
Condition: Early Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Cyclophosphamide; Doxorubicin; Docetaxel; Paclitaxel; Pertuzumab IV; FDC of Pertuzumab and Trastuzumab SC; Trastuzumab IV; Trastuzumab SC; Surgery; Post-operative Radiotherapy; Hormone Therapy
Intervention description: Cyclophosphamide 600 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of ddAC Q2W or AC Q3W) for Cycles 1-4.; Doxorubicin 60 mg/m2 will be administered IV on Day 1 of each cycle of treatment (as part of either ddAC Q2W or AC Q3W) for Cycles 1-4.; As part of one of the two investigator's choices of chemotherapy (AC followed by docetaxel), docetaxel 75 mg/m2 will be administered IV on Day 1 of Cycle 5 and then 100 mg/m2 IV at the discretion of the investigator for Cycles 6-8 (Q3W), if no dose-limiting toxicity occurs.; As part of one of the two investigator's choices of chemotherapy (ddAC followed by paclitaxel), paclitaxel 80 mg/m2 will be administered IV QW for 12 weeks.; Pertuzumab will be administered as a fixed non-weight-based dose of 840-mg IV loading dose and then 420-mg IV maintenance dose Q3W.; The FDC of pertuzumab and trastuzumab will be administered SC at a fixed non-weight-based dose. A loading dose of 1200 mg SC pertuzumab and 600 mg SC trastuzumab is then followed by a maintenance dose of 600 mg SC pertuzumab and 600 mg SC trastuzumab Q3W.; Trastuzumab will be administered as an 8-mg/kg IV loading dose and then 6 mg/kg IV maintenance dose Q3W.; After surgery (from Cycle 9 onwards), participants in Arm A will be allowed to switch from trastuzumab IV to trastuzumab SC, at the discretion of the investigator, in the countries where trastuzumab SC is routinely used. For participants who switch, a fixed dose of 600 mg trastuzumab SC (irrespective of the patient's weight) will be administered in the adjuvant phase.; Participants in both cohorts are scheduled to undergo surgery after 8 cycles of neoadjuvant therapy. Participants may undergo breast-conserving surgery or mastectomy according to routine clinical practice.; If indicated, radiotherapy is given after chemotherapy and surgery, during adjuvant HER2-targeted therapy and hormone therapy (for hormone-receptor positive disease).; For hormone receptor positive breast cancer, tamoxifen or aromatase inhibitors will be allowed as adjuvant hormone therapy for postmenopausal participants and with ovarian suppression or ablation for premenopausal participants in countries where it has been registered for this indication. Its use must be consistent with the registered label. Hormone therapy is given after chemotherapy and surgery during adjuvant HER2-targeted therapy.
Intervention MeSH terms: Paclitaxel; Docetaxel; Cyclophosphamide; Doxorubicin; Trastuzumab; Pertuzumab; Hormones
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 500.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a global Phase III, two-arm, open-label, multicenter, randomized study to investigate
      the pharmacokinetics, efficacy, and safety of the fixed-dose combination (FDC) of pertuzumab
      and trastuzumab for subcutaneous (SC) administration in combination with chemotherapy in
      patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer in
      the neoadjuvant/adjuvant setting.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Ability to comply with the study protocol, in the investigator's judgment

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1

          -  Female and male patients with Stage II - IIIC (T2-T4 plus any N, or any T plus N1-N3,
             M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically
             confirmed invasive breast cancer

          -  Primary tumor >2 cm in diameter, or node-positive disease (clinically or on imaging,
             and node positivity confirmed with cytology and/or histopathology)

          -  HER2-positive breast cancer confirmed by a central laboratory prior to study
             enrollment. HER2-positive status will be determined based on pretreatment breast
             biopsy material.

          -  Hormone receptor status of the primary tumor, centrally confirmed

          -  Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant
             therapy

          -  Availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue block for
             central confirmation of HER2 and hormone receptor status and additional biomarker
             research

          -  Baseline left ventricular ejection fraction (LVEF) ≥55% measured by echocardiogram
             (ECHO) or multiple-gated acquisition scan (MUGA)

          -  For women of childbearing potential (WOCBP) who are sexually active: agreement to
             remain abstinent or use one highly effective non-hormonal contraceptive method with a
             failure rate of <1% per year, or two effective non-hormonal contraceptive methods
             during the treatment period and for 7 months after the last dose of HER2-targeted
             therapy, and agreement to refrain from donating eggs during this same period

          -  For men: men must remain abstinent or use a condom with a spermicidal product during
             the treatment period and for 7 months after the last dose of HER2-targeted therapy to
             avoid exposing the embryo. Men must refrain from donating sperm during this same
             period.

          -  A negative serum pregnancy test must be available prior to randomization for WOCBP,
             unless they have undergone surgical sterilization

          -  No major surgical procedure unrelated to breast cancer within 28 days prior to
             randomization or anticipation of the need for major surgery during the course of study
             treatment

        Exclusion Criteria:

          -  Stage IV (metastatic) breast cancer

          -  Patients with a history of invasive breast cancer

          -  Patients with a history of concurrent or previously treated non-breast malignancies
             except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ
             carcinomas, including cervix, colon, and skin

          -  Patients who have received any previous systemic therapy for treatment or prevention
             of breast cancer, or radiation therapy for treatment of cancer

          -  Patients who have a past history of ductal carcinoma in situ or lobular carcinoma in
             situ if they have received any systemic therapy for its treatment or radiation therapy
             to the ipsilateral breast

          -  Patients with high-risk for breast cancer who have received chemo-preventative drugs
             in the past are not allowed to enter the study

          -  Patients with multicentric breast cancer, unless all tumors are HER2-positive

          -  Patients with bilateral breast cancer

          -  Patients who have undergone an excisional biopsy of primary tumor and/or axillary
             lymph nodes

          -  Axillary lymph node dissection prior to initiation of neoadjuvant therapy

          -  Sentinel lymph node biopsy prior to neoadjuvant therapy

          -  Treatment with any investigational drug within 28 days prior to randomization

          -  Serious cardiac illness or medical conditions

          -  Inadequate bone marrow function, renal function or impaired liver function

          -  Current severe, uncontrolled systemic disease that may interfere with planned
             treatment

          -  Pregnant or breastfeeding, or intending to become pregnant during the study or within
             7 months after the last dose of HER2-targeted therapy

          -  Any serious medical condition or abnormality in clinical laboratory tests that, in the
             investigator's judgment, precludes the patient's safe participation in and completion
             of the study

          -  Known active liver disease, for example, active viral hepatitis infection, autoimmune
             hepatic disorders, or sclerosing cholangitis

          -  Concurrent, serious, uncontrolled infections, or known infection with HIV

          -  Known hypersensitivity to study drugs, excipients, and/or murine proteins

          -  Current chronic daily treatment with corticosteroids

          -  History of other malignancy within 5 years prior to screening, except for
             appropriately treated carcinoma in situ of the cervix, colon, skin, and/or
             non-melanoma skin carcinoma

          -  History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such
             as structural heart disease, coronary heart disease, clinically significant
             electrolyte abnormalities, or family history of sudden unexplained death or long QT
             syndrome