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