A Phase Ib/II Study of BEZ235 and Trastuzumab in Patients With HER2-positive Breast Cancer Who Failed Prior to Trastuzumab

Inclusion Criteria:

- Patient is a female ≥ 18 years of age

- Patient has a histologically and/or cytologically confirmed diagnosis of
HER2-positive invasive breast cancer with inoperable locally advanced or metastatic
disease

- Patients with controlled or asymptomatic CNS metastases are eligible

- Patient has adequate bone marrow and organ functions, and has recovery from all
clinically significant toxicities related to prior anti-neoplastic therapies

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelets ≥ 100 x 109/L

- Hemoglobin (Hgb) ≥ 9.0 g/dL

- INR ≤ 2

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (or ≤
5.0 x ULN if liver metastases are present)

- Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total
bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)

- Serum creatinine ≤ 1.5 x ULN

- Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L]

- HbA1c ≤ 8%

- Patient has received prior trastuzumab (alone or in combination) but NO more than 3
prior cytotoxic chemotherapy lines

- Prior endocrine and radiotherapy allowed

- Patient has ECOG performance status of 0-2 (Phase Ib) or 0-1 (Phase II)

Additional inclusion criteria for phase II:

- Available tumor tissue (archival or fresh) for biomarker analysis; known PI3K
activation status

- At least one measurable lesion as per RECIST 1.1

- Patient has received prior treatment with a taxane

- Patient has "trastuzumab-resistance disease" defined as:

- Recurrence while on trastuzumab (or T-DM1) or within 12 months since the last
infusion in the adjuvant setting

- Progression while on or within 4 weeks since the last infusion of trastuzumab (or
T-DM1) in the locally advanced or metastatic setting

Exclusion Criteria:

- Previous treatment with PI3K and/or mTOR inhibitors

- Symptomatic/uncontrolled Central Nervous System (CNS) metastases

- Concurrent malignancy or malignancy in the last 3 years prior to enrollment

- Wide field radiotherapy ≤ 28 days or limited field radiation for palliation ≤ 14 days
prior to starting study drug

- Active cardiac disease (e.g. LVEF less than institutional lower limit of normal, QTcF
> 480 msec, unstable angina pectoris, ventricular, supraventricular or nodal
arrhythmias)

- Inadequately controlled hypertension

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of BEZ235

- Treatment at start of study treatment with drugs with a known risk to induce Torsades
de Pointes, moderate and strong inhibitors or inducers of isoenzyme CYP3A4, warfarin
and coumadin analogues, LHRH agonists

- Intolerance or contraindications to trastuzumab treatment

- Pregnant or nursing (lactating) woman

Additional exclusion criteria for phase II:

- Prior treatment with capecitabine and lapatinib

- Intolerance or contraindications to capecitabine and lapatinib

- Previous treatment with HER-2 targeted agents other than trastuzumab or T-DM1

- Peripheral neuropathy ≥ Grade 2