Safety Study of AMG 386 to Treat HER2-positive Locally Recurrent or Metastatic Breast Cancer

Inclusion Criteria:

- histologically or cytologically confirmed adenocarcinoma of the breast with locally
recurrent or metastatic disease not amenable to any local treatment with curative
intent.

- HER2-positive by FISH, CISH, or IHC 3+

- ECOG performance status 0 or 1

- Left ventricular ejection fraction greater than or equal to institutional lower limit
of normal

- Adequate laboratory studies (hematological, chemistries and urinalysis)

- Life expectancy greater than or equal to 3 months

- Cohort A only:

- Trastuzumab naïve or trastuzumab in the neo-adjuvant setting

- No clinically significant drop in cardiac function prior exposure to trastuzumab

- No prior chemotherapy for metastatic or locally recurrent breast cancer

- No prior lapatinib therapy

- At least 3 weeks from enrollment since prior chemotherapeutic agents, including
taxanes, in the neoadjuvant or adjuvant setting

- At least 3 months from enrollment since prior trastuzumab in the neoadjuvant or
adjuvant setting

- Cohort B only:

- Must have failed trastuzumab in the first-line metastatic setting. Trastuzumab must be
discontinued for at least 3 weeks prior to enrollment

- Must have received prior chemotherapy as adjuvant therapy or for metastatic disease

- Prior chemotherapy treatment must be discontinued for at least 3 weeks prior to
enrollment

- No prior capecitabine

- No prior lapatinib

Exclusion Criteria:

- Inflammatory breast cancer

- Central nervous system metastasis

- Clinically significant cardiovascular disease

- Radiation therapy ≤ 14 days prior to enrollment.

- Concurrent anticoagulation therapy, excluding aspirin, anti-platelet agents, low
molecular weight heparin or low dose warfarin per protocol.

- Uncontrolled hypertension defined as diastolic blood pressure > 90 mmHg OR systolic
blood pressure > 140 mmHg.

- Subjects with a history of prior malignancy, except:

- For Cohort B only:

- Current or prior history of long QT syndrome

- Baseline ECG report of QTc interval of > 480 milliseconds

- Severe chronic liver disease (Child Pugh C)