• The safety and tolerability endpoints will consist of evaluating adverse events and changes in laboratory values and finding a dose regimen where no more than one out of three subjects experiences a Dose Limiting Toxicity (DLT) [ Time Frame: 12 Months ] [ Designated as safety issue: Yes ]
  

• A secondary endpoint of this study is efficacy. The objective tumour response rate will be evaluated by radiological scans. Disease progression and response evaluations will be determined according to the definitions established in RECIST. [ Time Frame: 12 Months ] [ Designated as safety issue: No ]
  

This is an open-label Phase I study of fixed dose oral lapatinib administered in combination with an escalating dose of epirubicin in patients with metastatic breast cancer. This Phase I study employs a dose escalation scheme in order to determine the optimally-tolerated regimen (OTR) of lapatinib and epirubicin administered in combination. Secondary endpoints include assessment of the tumour response rate, pharmacokinetic analysis and evaluation of tumour biomarkers. Approximately fifteen to thirty (15-30) subjects are planned to be enrolled in this Phase I study. Following the completion of this Phase I study and the determination of the OTR of lapatinib and epirubicin a Phase II study will be initiated.

Inclusion Criteria

1. Aged (>18) with confirmed diagnosis of metastatic breast cancer

2. Female subjects must either be of:

   • Non-child-bearing potential (i.e., a woman with functioning ovaries who has a current documented tubal ligation or hysterectomy or a woman who is menopausal); or

   • Child-bearing potential (i.e. a woman with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. This category includes women with oligomenorrhoea (even severe), women who are perimenopausal and young women who have begun to menstruate), who have a negative serum pregnancy test at screening, and agree to one of the following:

     • Complete abstinence from intercourse from the time of the screening pregnancy test until 28 days after the final dose of test article; or

     • Consistent and correct use of one of the following acceptable methods of birth control:

       • Male partner who is sterile prior to the female patient's entry into the study and is the sole sexual partner for that female patient; or
       • Oral contraceptives (either combined or progestogen only), or
       • Injectable progestogen-only contraceptives or
       • Implants of levonorgestrel, or
       • Any intrauterine device (IUD) with a documented failure rate of less than 1% per year; or
       • Barrier methods (e.g. condoms, diaphragms, caps) only if used in combination with one of the above acceptable methods.
3. Patients may have received prior non-anthracycline based regimes in either the neo-adjuvant, adjuvant and/or metastatic setting and in addition patients presenting with de novo metastasis are eligible for the study;
4. May have received prior radiotherapy as treatment for primary tumour; however, is not required for study entry;
5. Patients may receive bisphosphonates where they are clinically indicated.
6. Subjects who received Herceptin/ErbB inhibitors in the adjuvant setting are eligible if they had progression of their disease more than 6 months after completion of treatment.
7. Subjects who received Herceptin in the metastatic setting are eligible if they have not received Herceptin in the previous three months.
8. Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
9. Patients with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence. Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical carcinoma in situ, melanoma in situ, and basal cell or squamous cell carcinoma of the skin;
10. Are able to swallow and retain oral medication;
11. Are able to complete all screening assessments as outlined in the protocol;

12. Adequate haematology, renal and hepatic function

    • Absolute neutrophil count greater than or equal to 1,500/microlitres
    • Platelets greater than or equal to 100,000/microlitre
    • Haemoglobin greater than or equal to 9 g/dL (5mmol/L)
    • Calculated creatinine clearance greater than or equal to 60 ml/min as determined by the the Cockroft and Gault equation on page 37
    • Aspartate (AST) or alanine transaminase (ALT) less than 3 times the upper limit of the normal range (ULN).
    • Total bilirubin greater than the local ULN, unless the patient has a documented history of congenital hypobilirubinemia.
    • Left ventricular ejection fraction (LVEF) within the institutional normal range as measured by ECHO (if ECHO cannot be performed or if the Investigator feels it is not conclusive to evaluate LVEF, then a MUGA scan should be performed).
13. Have signed the informed consent form (ICF);
14. Life expectancy of more than 3 months in the best judgement of the investigator

Exclusion Criteria:

Women will not be eligible for inclusion in this study if any of the following criteria apply:

1. Had prior therapy with an ErbB1 and/or ErbB2 inhibitor; within the past three months.
2. Any subjects with prior chemotherapy in the adjuvant or neoadjuvant setting with anthracycline or anthracenedione-containing regimens.
3. Receive concurrent non study anti-cancer therapy (chemotherapy, immunotherapy, and biologic therapy) while taking study medication;
4. Have unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment;
5. Have malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Women with ulcerative colitis are also excluded;
6. Have a concurrent disease or condition that would make the patient inappropriate for study participation, or any serious medical disorder that would interfere with the patient safety;
7. Have an active or uncontrolled infection;
8. Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
9. Have a known history of uncontrolled or symptomatic angina, arrhythmias, CHF or other cardiac disorders;
10. Are pregnant or breastfeeding;
11. Receive concurrent treatment with an investigational agent or participate in another clinical trial;
12. Receive concurrent treatment with prohibited medications (refer to Section Error! Reference source not found. for details on prohibited medications);
13. Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication;
14. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lapatinib or excipients;
15. Patients with a history of prolonged QT interval.