| | Requirement |
| 1 | Histologically or cytologically confirmed adenocarcinoma of the breast with locally
recurrent or metastatic disease, and candidate for chemotherapy. Patients with
measurable and non-measurable disease are eligible.
Locally recurrent disease must not be amenable to resection with curative intent.
Note: Patients with de-novo Stage IV disease are eligible |
| 2 | HER2-positive (defined as 3+ IHC or FISH amplification ratio greater than or equal to 2.0) MBC
confirmed by a Sponsor-designated central laboratory. It is strongly recommended
that a formalin-fixed paraffin-embedded (FFPE) tissue block from the primary tumor
be submitted for central laboratory confirmation of HER2 eligibility; however, if that
is not possible, 25 unstained and freshly cut slides will be submitted. (Tissue will
subsequently be used for assessment of biomarkers.) |
| 3 | Age greater than or equal to 18 years |
| 4 | Left Ventricular Ejection Fraction (LVEF) greater than or equal to 50% at baseline (within 42 days of
randomization) as determined by either ECHO or MUGA. If the patient is randomized, the same method of LVEF assessment, ECHO
or MUGA, must be used throughout the study, and to the extent possible, be obtained
at the same institution). |
| 5 | Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 |
| 6 | For women of childbearing potential, agreement to use an effective form of
contraception (patient and/or partner, e.g., surgical sterilization, a reliable barrier
method [condoms, diaphragm], intrauterine devices, or abstinence) and to
continue its use for the duration of study treatment and for 6 months after the last
dose of study treatment |
| 7 | Patient must have signed and dated IRB approved informed consent and HIPAA authorization forms. |
| 1 | History of anticancer therapy for MBC (with the exception of one prior hormonal
regimen for MBC). This includes any EGFR or anti-HER2 agents or vaccines, cytotoxic chemotherapy,
or more than one prior hormonal regimen for MBC |
| 2 | 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 |
| 3 | 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 < 12 months |
| 4 | History of persistent Grade greater than or equal to 2 hematologic toxicity resulting from previous adjuvant
therapy |
| 5 | Current peripheral neuropathy of NCI-CTCAE, Version 3.0, Grade greater than or equal to 3 at
randomization |
| 6 | History of other malignancy within the last 5 years, except for carcinoma in situ of
the cervix or basal cell carcinoma |
| 7 | Current clinical or radiographic evidence of central nervous system (CNS) metastases.
CT or MRI scan of the brain is mandatory (within 28 days of randomization) in
cases of clinical suspicion of brain metastases. |
| 8 | History of exposure to the following cumulative doses of anthracyclines:
• doxorubicin or liposomal doxorubicin > 360 mg per meter squared
• epirubicin > 720 mg per meter squared
• mitoxantrone > 120 mg per meter squared and idarubicin > 90 mg per meter squared
• Other (e.g., liposomal doxorubicin or other anthracycline > the equivalent of
360 mg per meter squared of doxorubicin)
• If more than 1 anthracycline has been used, then the cumulative dose must not
exceed the equivalent of 360 mg per meter squared of doxorubicin. |
| 9 | Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic
> 100 mmHg) or unstable angina |
| 10 | History of CHF of any New York Heart Association (NYHA) criteria, or serious
cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal
supraventricular tachycardia) |
| 11 | History of myocardial infarction within 6 months of randomization |
| 12 | History of LVEF decline to below 50% during or after prior trastuzumab
neo-adjuvant or adjuvant therapy |
| 13 | Current dyspnea at rest due to complications of advanced malignancy, or other
diseases that require continuous oxygen therapy |
| 14 | Inadequate organ function, evidenced by the following laboratory results within
28 days prior to randomization:
• Absolute neutrophil count < 1,500
• Platelet count < 100,000
• Hemoglobin < 9
• Total bilirubin > upper limit of normal (ULN) (unless the patient has documented
Gilbert’s syndrome)
• AST (SGOT) and ALT (SGPT) > 2.5 × ULN
• AST (SGOT) or ALT (SGPT) > 1.5 × ULN with concurrent serum alkaline
phosphatase > 2.5 × ULN (unless bone metastases are present)
• Serum creatinine > 2.0 or 177
• International normalized ratio (INR) and activated partial thromboplastin time
(aPTT) > 1.5 × ULN (unless on therapeutic coagulation) |
| 15 | Current severe, uncontrolled systemic disease (e.g., clinically significant
cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or
bone fractures) |
| 16 | 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 |
| 17 | Pregnant or lactating women |
| 18 | History of receiving any investigational treatment within 28 days of randomization |
| 19 | Current known infection with HIV, HBV, or HCV |
| 20 | Receipt of IV antibiotics for infection within 14 days of randomization |
| 21 | Current chronic daily treatment with corticosteroids (dose of > 10 mg/ day
methylprednisolone equivalent) (excluding inhaled steroids) |
| 22 | Known hypersensitivity to any of the study drugs |
| 23 | Assessed by the investigator to be unable or unwilling to comply with the
requirements of the protocol |
