A Phase II, Randomized, Open-label Study of Lapatinib Plus Chemotherapy Versus Trastuzumab Plus Chemotherapy in HER2-positive and p95HER2-positive Metastatic Breast Cancer

Inclusion Criteria:

• Female ≥ 18 years of age

• Histologically or cytologically confirmed invasive breast cancer with distant metastasis(ses) (designated as Stage IV or metastatic breast cancer)

  • Diagnosis with Stage IV or metastatic disease at either primary diagnosis or recurrence

• Not received prior systemic or local treatment (e.g., chemotherapy, endocrine or radiotherapy) for Stage IV/metastatic breast cancer

  • Prior adjuvant and/or neo-adjuvant therapy is permitted
• Documentation of HER2 overexpression or gene amplification, in the invasive component of either a metastatic disease site or primary tumor, defined as: 3+ by IHC and/or HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ≥2.0]
• Documentation by the central laboratory of positive p95HER2 expression in the invasive component of either a metastatic disease site (preferred) or primary tumor
• No history of CNS metastases (including leptomeningeal involvement) or stable CNS metastases (defined as asymptomatic and off steroids for ≥ 3 months)
• Baseline Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA)
• Recovered or stabilized from all adverse events associated with prior anti-cancer therapies, including radiotherapy, at the time of screening
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Have adequate marrow and organ function as defined as:

SYSTEM LABORATORY VALUES Hematologic ANC ≥1.5 x 109/L Hemoglobin ≥9 g/dL (after transfusion if needed) Platelets ≥100 x 109/L Hepatic Albumin ≥ 2.5 g/dL Serum bilirubin ≤1.5 x ULN unless due to Gilbert's syndrome AST and ALT ≤3 x ULN Renal Calculated creatinine clearance ≥ 40 mL/min Serum Creatinine ≤1.5 mg/dL or 132.6µmol/L (Abbreviations: ANC, absolute neutrophil count; ULN, upper limit of normal; AST, aspartate aminotransferase; ALT, alanine aminotransferase)

• Women of childbearing potential, including women whose last menstrual period was <12 months ago (unless surgically sterile) must have a negative serum pregnancy test and agree to use effective contraception, as defined in protocol
• Signed Informed Consent Form

Exclusion Criteria:

• History of other malignancy. Exception: Subjects who have been disease-free for 5 years or subjects with a history of completely resected non-melanoma skin cancer (basal or squamous) are eligible
• Concurrent anti-cancer treatment or concurrent treatment with an investigational drug
• Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study treatment
• Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib (time from last dose of trastuzumab or lapatinib to randomization must be ≥3 months)

• Serious cardiac illness or medical condition including but not confined to:

  • Uncontrolled arrhythmias
  • Uncontrolled or symptomatic angina
  • History of congestive heart failure (CHF)
  • Documented myocardial infarction <6 months from study entry
• Current active hepatic or biliary disease (with exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• Concurrent disease or condition, or any pre-existing medical disorder that in the opinion of the investigator may interfere with the subject's safety, obtaining informed consent or compliance to the study procedures
• Pregnant or lactating female
• Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels (consult with GSK Medical Monitor if uncertain about eligibility)
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study drugs or their excipients that, in the opinion of the investigator contra-indicates participation