Lapatinib in Combination With Vinorelbine

Approximately 105 subjects will be enrolled in the study and randomized 2:1 to one of the following regimens Arm A (n=70): Lapatinib 1250 mg orally once daily continuously plus Vinorelbine 20mg/m2 intravenously (IV) on day 1 and 8, every third week, or Arm B (n=35): Lapatinib 1250 mg orally once daily (QD) continuously plus Capecitabine 2000 mg/m2/day orally in 2 doses 12 hours apart on days 1-14 every third week. Randomization will be stratified according to the following variables: 1) Prior receipt of therapy for metastatic breast cancer (Yes or No), and 2) Site of metastatic disease (Visceral/Soft tissue or Bone-only). Subjects will receive randomized study treatment until disease progression or discontinuation of study treatment due to unacceptable toxicity, withdrawal of consent, lost to follow up, or death. All subjects who discontinue study treatment without documented progression will continue to be followed for progression according to protocol-schedule until new anti-cancer therapy is initiated and/or progression or death is documented. Survival data will be collected for all subjects to ensure a minimum of 18 months survival data. This study will include a safety run-in phase for approximately the first 30 subjects (20 randomized to lapatinib and vinorelbine; 10 to lapatinib and capecitabine).

Inclusion criteria

• Signed informed consent prior to registration.
• Considered by the investigator to have a life expectancy of ≥12 weeks.
• Subjects must be female and have histologically - confirmed invasive breast cancer with Stage IV disease at primary diagnosis or at relapse after curative - intent surgery.
• Documented overexpression of ErbB2
• Subjects should have progressive disease following prior therapy which may include anthracyclines, taxanes, and trastuzumab.
• Females aged ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1.
• Subjects must have adequate organ and marrow function
• Subjects must have a cardiac ejection fraction of at least 50% and within the institutional range of normal.
• Radiotherapy prior to initiation of study medication is allowed to a limited area ( e . g . , palliative therapy ) , if it is not the sole site of disease.
• Subjects with stable central nervous system (CNS) metastases are permitted.
• Subject must be free of gastrointestinal diseases or any other conditions that impede swallowing, retaining, and absorption of oral medications.
• Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of study medication. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted.

Exclusion criteria

• Subjects taking prohibited medications are not eligible for the study.
• Therapy with lapatinib, vinorelbine, or capecitabine prior to randomization into this study.
• Prior therapy with more than one chemotherapeutic regimen for metastatic breast cancer.
• Concurrent anticancer or concomitant radiotherapy treatment.
• History of uncontrolled or symptomatic angina; history of arrhythmias requiring medications ; clinically significant myocardial infarction < 6 months from study entry; uncontrolled or symptomatic congestive heart failure; ejection fraction below the institutional normal limit; or any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
• Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
• Use of an investigational drug within 30 days or 5 half - lives, whichever is longer, preceding the first dose of investigational treatment, or, concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients that in the opinion of the investigator or GSK Medical Monitor contraindicates their participation.
• Known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD).
• Known history of uncontrolled inter - current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness / social situations that would limit compliance with study requirements.
• Concurrent disease or condition that would make the subject inappropriate for study participation , or any serious medical disorder that would interfere with the subject's safety.
• Pregnant or lactating females at any time during the study (due to the potential teratogenic or abortifacient effects of lapatinib and breastfeeding).
• Subjects with diseases affecting gastrointestinal function resulting in an inability to take oral medication , including ; malabsorption syndrome, disease significantly affecting gastrointestinal function , or resection of the stomach , small bowel , or colon. Subjects with inflammatory bowel disease or ulcerative colitis are also excluded.
• Peripheral neuropathy of Grade 2 or greater.
• Unresolved or unstable, serious toxicity from prior administration of another investigational drug and / or of prior cancer treatment.
• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.