Clinical trial NCT01471847 (phase 1, status: completed)
Conditions: locally advance breast cancer (labc), metastatic breast cancer (mbc)
ICD codes: C79.81, D24.1, D24.2, D24.9, D49.3, C44.501, D48.60
Drugs: bez235 + trastuzumab phase l/phase ll), lapatinib + capecitabine (phase ii)
SMILES: CN1C(=O)N(C2=C1C=NC1=CC=C(C=C21)C1=CN=C2C=CC=CC2=C1)C1=CC=C(C=C1)C(C)(C)C#N, CCCCCOC(=O)NC1=NC(=O)N(C=C1F)[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Eligibility criteria:

        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