A Phase II, Single-Arm, Multi-Center Study Evaluating the Combination of Vinorelbine and Lapatinib in Women With ErbB2 Overexpressing Metastatic Breast Cancer

Inclusion Criteria:

A subject will be eligible for inclusion in this study only if all of the following
criteria apply:

1. Signed informed consent prior to registration.

2. Considered by the Investigator to have a life expectancy of ≥12 weeks.

3. Subjects must have histologically confirmed invasive breast cancer with Stage IV
disease at primary diagnosis or at relapse after curative-intent surgery.

• Where the disease is restricted to a solitary lesion, the neoplastic nature of the
lesion should be confirmed by cytology or histology.

4. Documented amplification of ErbB2 3+ by immunohistochemistry or a positive score
(>2.2) by fluorescence in situ hybridization (FISH) using a local laboratory result
(which will be considered sufficient in this study with no further verification by a
central laboratory). NOTE: If both IHC and FISH results available, FISH results must
be used for eligibility.

5. Subjects must not have received more than 1 prior chemotherapeutic regimen in the
metastatic setting.

6. All prior chemotherapy, immunotherapy, biologic therapy, or surgery (except for minor
surgical procedures) must be discontinued at least 4 weeks prior to first dose of
investigational product. Hormonal therapy must be discontinued at least 1 week prior
to first dose.

7. Prior diagnosis of cancer is allowed as long as the subject is free of disease and
has been off treatment for prior malignancies for 5 years. Subjects with completely
resected basal or squamous cell skin cancer or successfully treated cervical
carcinoma in situ will be allowed if it has been 1 year or longer since definitive
surgery.

8. Subjects must have measurable disease, according to Response Evaluation Criteria in
Solid Tumors (RECIST) guidelines.

9. Females aged ≥18 years with any menopausal status:

- Non-child-bearing potential (i.e., women with functioning ovaries who have a
current documented tubal ligation or hysterectomy, or women who are
postmenopausal)

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

- Complete abstinence from intercourse from 2 weeks prior to administration of the
first dose of study medication until 28 days after the final dose of study
medication; or

- Consistent and correct use of one of the following acceptable methods of birth
control: male partner who is sterile prior to the female subject's entry into
the study and is the sole sexual partner for that female subject; any
intrauterine device with a documented failure rate of less than 1% per year;
oral contraceptives (either combined or progestogen only) where not
contraindicated for this subject population or per local practice.; or barrier
methods, including diaphragm or condom with a spermicide.

10. ECOG performance status (PS) of 0 to 2 [Oken, 1982] (Appendix 1).

11. Subjects must have normal organ and marrow function as defined in Table 1. Table 1
Baseline Laboratory Values for Adequate Organ Function System Laboratory Value
Hematologic Absolute neutrophil count ≥1.5 × 10^9/L Hemoglobin ≥9 g/dL Platelets ≥100
× 10^9/L Hepatic Serum bilirubin ≤1.25 × upper limit of normal (ULN) Aspartate
aminotransferase and alanine aminotransferase

- 3 × ULN without liver metastases

- 5 × ULN if documented liver metastases Renal Serum creatinine ≤1.5 mg/dL

- OR - Calculated creatinine clearance ≥40 mL/min

12. Subjects must have a cardiac ejection fraction of at least 50% (as measured by
echocardiogram [ECHO] or multigated acquisition scan [MUGA]) and within the
institutional range of normal. Subjects who require cardiac medications (e.g.
positive inotropic agents or afterload reducers) for abnormal ejection fraction are
ineligible. MUGA scans will be accepted in cases where an ECHO cannot be performed or
is inconclusive. The same modality to assess cardiac ejection fraction must be used
consistently throughout the study.

13. 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 must have
completed radiation treatment and recovered from all acute radiation
treatment-related toxicities (e.g., bone marrow suppression) prior to commencement of
combination treatment.

14. Subjects with stable central nervous system (CNS) metastases. Subjects with stable
CNS metastases are defined as follows: subject is asymptomatic with CNS metastases
that have been stable for at least 3 months as confirmed by computed tomography
(CT)/magnetic resonance imaging (MRI). Subjects with evidence of
leptomeningeal/parenchymal involvement are eligible only if they are not taking
steroids or enzyme-inducing anticonvulsants within 4 weeks of commencement of the
study. Treatment with prophylactic anticonvulsants is permitted, unless listed as a
prohibited medication.

15. Subject must be free of gastrointestinal diseases that impede swallowing and
retaining of oral medications.

16. Able to swallow and retain oral medication (intact pill).

17. 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.

18. Subjects whose disease is estrogen receptor + and/or progesterone receptor + or
unknown status will only be included in the study if they meet the following
criteria:

- They have symptomatic visceral disease that requires chemotherapy.

- The disease is considered by the Investigator to be progressing rapidly or is
life threatening.

- Subjects who have received endocrine therapy and who are no longer benefiting
from this therapy.

Exclusion Criteria:

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

1. Subjects taking treatment with medications provided in the list of restricted
medications and substances in the drug information section for lapatinib are not
eligible for the study. This includes human immunodeficiency virus-positive subjects
receiving combination anti-retroviral therapy because of possible pharmacokinetic
interactions with lapatinib.

2. Prior therapy with lapatinib.

3. Prior therapy with vinorelbine for treatment of breast cancer.

4. More than 1 line of therapy for treatment of MBC.

5. Concurrent anticancer or concomitant radiotherapy treatment.

6. 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.

7. 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)

8. 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.

9. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to any of the agents used in this study or their excipients.

10. 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.

11. Concurrent disease or condition that would make the woman inappropriate for study
participation, or any serious medical disorder that would interfere with the woman's
safety.

12. Pregnant or lactating females at any time during the study (due to the potential
teratogenic or abortifacient effects of lapatinib and breastfeeding).

13. 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 or small bowel.

Women with ulcerative colitis are also excluded.

14. Peripheral neuropathy of Grade 2 or greater.

15. Unresolved or unstable, serious toxicity from prior administration of another
investigational drug and/or of prior cancer treatment.

16. Dementia, altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent.