Continued HER2 Suppression With Lapatinib Plus Trastuzumab Versus Trastuzumab Alone

• Overall survival [ Time Frame: Time from randomization until death ]
• Clinical benefit response rate (CR, PR or SD ≥24 weeks) [ Time Frame: End of Study ] [ Designated as safety issue: No ]
• Determine the qualitative and quantitative adverse event profile of the 2 treatment arms [ Time Frame: End of Study ] [ Designated as safety issue: No ]

• Incidence of brain metastasis at first progression
• Clinical benefit response rate (CR, PR or SD ≥24 weeks) [ Designated as safety issue: No ]
• Determine the qualitative and quantitative adverse event profile of the 2 treatment arms [ Designated as safety issue: No ]

This is a randomized, open-label, multi-center Phase III study evaluating the efficacy and safety of lapatinib in combination with trastuzumab versus trastuzumab alone as continued HER2 suppression therapy in women with HER2-positive metastatic breast cancer (MBC). Eligible subjects will have completed 12 to 24 weeks of first- or second-line treatment with trastuzumab plus chemotherapy, experienced either complete disappearance of all metastatic lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions, and been indicated to continue to receive trastuzumab alone as maintenance therapy. Eligible subjects entering the LPT112515 study on first-line treatment will have no known history of central nervous system (CNS) metastases; subjects entering the study on second-line treatment will have no known history of CNS metastases or have stable (asymptomatic and off steroids ≥3 months) CNS metastases. The primary objective of this study is to compare progression-free survival (PFS) in subjects with HER2-positive MBC randomized to receive treatment with lapatinib plus trastuzumab versus those randomized to receive trastuzumab alone. The secondary objectives include overall survival, clinical benefit response rate (CR, PR or SD ≥24 weeks) and the qualitative and quantitative adverse event profile of the 2 treatment arms. It is estimated that 280 subjects (140 per group) will be required to observe 193 PFS events.

• Drug: Lapatinib
  Oral Lapatinib 1000 mg once daily. Lapatinib is a small molecule, reversible inhibitor targeting HER2 tyrosine kinase receptor.
• Biological: Trastuzumab
  IV Trastuzumab 6 mg/kg every three weeks. Trastuzumab is a humanized, monoclonal antibody directed against the extracellular domain of the HER2 tyrosine kinase receptor.

• Experimental: Arm 1: Lapatinib plus Trastuzumab
  Interventions:

  • Drug: Lapatinib
  • Biological: Trastuzumab
• Active Comparator: Arm 2: Trastuzumab
  Intervention: Biological: Trastuzumab

Inclusion Criteria:

• Signed the informed consent form (ICF)
• Female, ≥18 years of age
• Histologically verified breast cancer with distant metastases (metastatic breast cancer)
• Documentation of HER2 overexpression or gene amplification in the invasive component of either the primary tumor or metastatic disease site 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 HER2 gene copies to chromosome 17 signal ratio of ≥2.0]
• Completed 12 to 24 weeks of first- or second-line treatment with trastuzumab in combination with chemotherapy
• Either complete disappearance of all lesions, or persistence of metastatic disease (stable disease) without unequivocal progression or the occurrence of new lesions
• Documentation of lesion response during the course of therapy received prior to randomization (i.e., improvement or no worsening of tumor burden; the absence of new lesions)
• Measurable disease is not required for study participation
• No known or suspected (associated neurological signs and symptoms) brain metastases (including leptomeningeal involvement)
• Stable brain metastasis (defined as asymptomatic and off steroids ≥3 months) are permitted in subjects entering LPT112515 on second-line treatment (completed 12-24 weeks of second-line treatment with trastuzumab plus chemotherapy)
• Baseline of Left Ventricular Ejection Fraction (LVEF) ≥50% measured by echocardiography (ECHO) or multi-gated acquisition scan (MUGA)
• Completion of screening assessments (Refer to protocol for further details)
• Have adequate marrow and organ function as defined in Table 2. Table 2 Laboratory Values 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 *Calculated by the Cockcroft-Gault Equation (Refer to protocol for details) Abbreviations: ANC, absolute neutrophil count; ULN, upper limit of normal; AST, aspartate aminotransferase; ALT, alanine aminotransferase

Exclusion Criteria:

• History of other malignancy. 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
• Eastern Cooperative Oncology Group (ECOG) Performance Status >2
• Concurrent anti-cancer treatment, except anti-hormonal therapy for subjects with hormone receptor positive breast cancer
• Concurrent treatment with an investigational agent
• Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib
• Concurrent treatment with protocol-defined prohibited medications (refer to protocol for details)
• Serious cardiac illness or medical condition including but not confined to:
• Uncontrolled arrhythmias
• Uncontrolled or symptomatic angina
• History of congestive heart failure (CHF)
• Myocardial infarction <6 months from study entry
• Acute or current active (requiring anti-viral therapy) hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• Concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent)
• Women of childbearing potential, including women whose last menstrual period was <12 months ago (unless surgically sterile) who are unable or unwilling to use adequate contraceptive measures during the study treatment period. Adequate contraception includes intra-uterine device, barrier methods with spermicide, or oral contraceptives (unless clinically contraindicated for the subject population or per local practice, refer to protocol for further details)
• Pregnant or lactating females
• Any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator or GSK medical monitor , contra-indicates participation