Phase I-II Study to Determine the Maximum Tolerated Dose (MTD) of AUY922 in Advanced Solid Malignancies, and Efficacy in HER2+ or ER+ Locally Advanced or Metastatic Breast Cancer Patients

Exclusion Criteria

• •1. Patients with CNS metastasis which are:
• •* Symptomatic or
• •* Require treatment for symptom control and/or
• •* Growing
• •Note: patients without clinical signs or symptoms of CNS involvement are not required to have a CT/MRI of the brain
• •2. Prior treatment with any HSP90 or HDAC inhibitor compound.
• •3. Patient who received systemic anti-cancer treatment prior to the first dose of AUY922 within the following time frames:
• •* Chemotherapy within 4 weeks
• •* Radiotherapy within 4 weeks
• •* Palliative radiotherapy: within 2 weeks
• •* Trastuzumab treatment within 4 weeks
• •* Nitrosoureas, mitomycin and monoclonal antibodies (except trastuzumab): within 6 weeks
• •* Any continuous-dosing (i.e. daily dosing, every-other-day dosing, Monday- Wednesday-Friday dosing, weekly etc) of systemic anticancer treatment for which the recovery period is not known, or investigational drugs (i.e. targeted agents) within a duration of ≤ 5 half lives of the agent and their active metabolites (if any)
• •4. Patients who have not recovered from side effects of previous systemic anticancer therapy to less than grade 2 CTCAE prior to the first dose.
• •5. Pregnant or lactating women.
• •* History (or family history) of long QT syndrome.
• •* Mean QTc ≥ 450 msec on screening ECG
• •* History of clinically manifest ischemic heart disease including myocardial infarction, stable or unstable angina, coronary arteriography or cardiac stress testing/imaging with findings consistent with coronary occlusion or infarction, ≤ 6 months prior to study start.
• •* History of heart failure or left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA or ECHO
• •7. Known diagnosis of HIV infection (HIV testing is not mandatory).
• •8. Acute or chronic liver disease, acute or chronic renal disease or other concurrent severe and/or uncontrolled medical conditions (e.g. uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
• •Mean QTc ≥ 450 msec on screening ECG and clinically significant ECG abnormalities including one or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevations or depressions \> 1mm, or 2nd (Mobitz II) or 3rd degree AV block; clinically significant ECG abnormalities including one or more of the following: left bundle branch block (LBBB), right bundle branch block (RBBB) with left anterior hemiblock (LAHB). ST segment elevations or depressions \> 1mm, or 2nd (Mobitz II) or 3rd degree AV block.
• •History (or family history) of long QT syndrome, heart failure or left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA or ECHO, history of clinically manifest ischemic heart disease including myocardial infarction, stable or unstable angina, coronary arteriography or cardiac stress testing/imaging with findings consistent with coronary occlusion or infarction, ≤ 6 months prior to study start; history or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes.