A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Pertuzumab; Placebo; Trastuzumab; Docetaxel
Intervention description: Pertuzumab was administered as an intravenous (IV) loading dose of 840 milligrams (mg) q3w on Day 1 of Cycle 1 (1 Cycle length = 21 days), and 420 mg q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination.; Placebo (matching pertuzumab) was administered intravenously.; Trastuzumab was administered as an IV loading dose of 8 milligrams per kilogram (mg/kg) q3w on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 6 mg/kg q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination.; Docetaxel was administered as an IV dose of 75 milligrams per square meter of body surface area (mg/m^2) q3w on Day 2 of Cycle 1 (1 Cycle length = 21 days), and 75 mg/m^2 (up to 100 mg/m^2 as per treating physician discretion) q3w on Day 1 of subsequent cycles until investigator-assessed radiographic or clinical progressive disease, unmanageable toxicity, or study termination. On or prior to Cycle 6, docetaxel was only to be discontinued for progressive disease or unmanageable toxicity. After Cycle 6, continuation of docetaxel treatment was at the discretion of the participant and treating physician.
Intervention MeSH terms: Docetaxel; Trastuzumab; Pertuzumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 808.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Herceptin; Breast cancer; MBC; Taxotere; HER2; HER2 positive breast cancer; HER2 + breast cancer; HER2-positive; HER2-positive metastatic breast cancer

Summary:

      This study was a Phase III, randomized, double-blind, placebo-controlled, multicenter
      international clinical trial conducted to investigate the use of pertuzumab in combination
      with trastuzumab and docetaxel as first-line treatment for participants with human epidermal
      growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Participants could
      have received one prior hormonal treatment for MBC. Participants may have received systemic
      breast cancer treatment in the neo-adjuvant or adjuvant setting, provided that the
      participant had experienced a disease-free interval (DFI) of greater than or equal to (≥)12
      months from completion of adjuvant systemic treatment (excluding hormonal therapy) to
      metastatic diagnosis. Participants may have received trastuzumab and/or a taxane during the
      neo-adjuvant or adjuvant treatment.

      Participants were randomized in 1:1 ratio to receive either pertuzumab or placebo, along with
      trastuzumab and docetaxel once every 3 weeks (q3w), during the treatment phase of the study
      until investigator-assessed radiographic or clinical progressive disease, unmanageable
      toxicity, or study termination. Participants in the Placebo arm were not allowed to receive
      open-label pertuzumab after discontinuation from study treatment. However, if any analysis of
      overall survival had met the predefined criteria for statistical significance, participants
      in the Placebo arm still on treatment were offered the option to receive open-label
      pertuzumab in addition to other study medications.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed adenocarcinoma of the breast with locally
             recurrent or metastatic disease, and candidate for chemotherapy. Participants with
             measurable and non-measurable disease are eligible (locally recurrent disease must not
             be amenable to resection with curative intent; participants with de novo Stage IV
             disease are eligible)

          -  Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer
             (MBC)

          -  Left ventricular ejection fraction (LVEF) ≥50 percent (%) at baseline (within 42 days
             of randomization)

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

          -  For women of childbearing potential and men with partners of childbearing potential,
             agreement to use a highly effective form of contraception and to continue its use for
             the duration of study treatment and for at least 7 months after the last dose of study
             treatment

        Exclusion Criteria:

          -  History of anti-cancer therapy for MBC (with the exception of one prior hormonal
             regimen for MBC, which must be stopped prior to randomization)

          -  History of approved or investigative tyrosine kinase/HER inhibitors for breast cancer
             in any treatment setting, except trastuzumab used in the neoadjuvant or adjuvant
             setting

          -  History of systemic breast cancer treatment in the neo-adjuvant or adjuvant setting
             with a disease-free interval from completion of the systemic treatment (excluding
             hormonal therapy) to metastatic diagnosis of less than (<)12 months

          -  History of persistent Grade ≥2 hematologic toxicity resulting from previous adjuvant
             therapy

          -  Current peripheral neuropathy of National Cancer Institute-Common Terminology Criteria
             for Adverse Events (NCI-CTCAE) Version 3.0, Grade ≥3 at randomization

          -  History of other malignancy within the last 5 years, except for carcinoma in situ of
             the cervix, basal cell carcinoma or squamous cell carcinoma of the skin that has been
             previously treated with curative intent

          -  Current clinical or radiographic evidence of central nervous system (CNS) metastases

          -  Computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain is
             mandatory in cases of clinical suspicion of brain metastases

          -  History of exposure to cumulative doses of anthracyclines

          -  Current uncontrolled hypertension or unstable angina

          -  History of congestive heart failure (CHF) of any New York Heart Association (NYHA)
             criteria, or serious cardiac arrhythmia requiring treatment (exception: atrial
             fibrillation or paroxysmal supraventricular tachycardia)

          -  History of myocardial infarction within 6 months of randomization

          -  History of LVEF decline to below 50% during or after prior trastuzumab neo-adjuvant or
             adjuvant therapy

          -  Current dyspnea at rest due to complications of advanced malignancy, or other diseases
             that require continuous oxygen therapy

          -  Inadequate organ function, as defined in the protocol, within 28 days prior to
             randomization

          -  Current severe, uncontrolled systemic disease

          -  Major surgical procedure or significant traumatic injury within 28 days prior to study
             treatment start or anticipation of the need for major surgery during the course of
             study treatment

          -  Pregnant or lactating women

          -  History of receiving any investigational treatment within 28 days of randomization

          -  Current known infection with human immunodeficiency virus (HIV), hepatitis B virus
             (HBV), or hepatitis C virus (HCV)

          -  Receipt of IV antibiotics for infection within 14 days of randomization

          -  Current chronic daily treatment with corticosteroids (excluding inhaled steroids)

          -  Known hypersensitivity to any of the study drugs

          -  Assessed by the investigator to be unable or unwilling to comply with the requirements
             of the protocol