MK-2206, Paclitaxel and Trastuzumab in Treating Patients With HER2-overexpressing Solid Tumor Malignancies

Inclusion Criteria

• Histologically or cytologically-confirmed metastatic or locally advanced, unresectable HER2+ cancer. HER2+ will be defined as 3+ expression by immunohistochemistry (IHC) OR >2-fold gene amplification by Fluorescence In Situ Hybridization (FISH).
• Male or female and ≥18 years of age on the day of signing informed consent.
• Performance status of 0-2 on the ECOG Performance Scale and life expectancy > 3 months.
• Have evaluable disease. Measureable disease is not required
• Adequate organ function as indicated by the following laboratory values:
• Absolute neutrophil count (ANC) = ≥1, 500 /μL
• Platelets = ≥100,000 /μL
• Hemoglobin = ≥9 g/dL
• Serum creatinine = ≤1.5 x upper limit of normal (ULN) OR calculated creatinine clearance = ≥60 mL/min for patients with creatinine levels >1.5 x institutional ULN
• Serum total bilirubin = ≤1.5 x ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 x ULN
• AST (SGOT) and ALT (SGPT) = ≤2.5 x ULN
• Prothrombin time (PT)/INR = ≤1.2 x ULN
• Partial thromboplastin time (PTT) = ≤1.2 x ULN
• Fasting serum glucose = ≤126 mg/dl
• Hemoglobin A1c (HgbA1c) = ≤7%
• Potassium = in normal range
• Female patient of childbearing potential must test negative for pregnancy and agree to the use of effective methods of contraception while on study.
• Voluntarily agree to participate by giving written informed consent.
• Able to swallow capsules and has no surgical or anatomical condition that will prevent the patient from swallowing and absorbing oral medications on an ongoing basis.
• Prior taxane, trastuzumab, lapatinib, and other HER2 directed therapy in the adjuvant or metastatic setting is allowed.
• Any number of prior lines of chemotherapy in the metastatic setting is allowed.
• Concomitant use of bisphosphonates is allowed.
• Patients with stable and clinically insignificant central nervous system (CNS) disease are allowed. Patients must be off steroids with no new CNS symptoms or findings on radiographic imaging for 1 month.

Exclusion Criteria

• Patient who has had chemotherapy, radiotherapy, or hormonal therapy within 3 weeks (6 weeks for nitrosoureas, mitomycin C or bevacizumab), or who has not recovered from the adverse events due to previous agents administered more than 4 weeks prior to Study Day 1. Patient must not have received trastuzumab or lapatinib within 2 weeks of study Day 1. If the patient has residual toxicity from prior treatment, toxicity must be ≤ Grade 1.
• Less than 4 weeks post major surgical procedure (defined as one that required general anesthesia)(all surgical wounds must be fully healed).
• Currently participating or has participated in a study with an investigational compound or device within 30 days of Study Day 1.
• Known active CNS metastases and/or carcinomatous meningitis. However, patients with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 1 month prior to entry as defined as: (1) no evidence of new or enlarging CNS metastasis (2) off steroids that are used to minimize surrounding brain edema. Patients with clinically insignificant brain metastases that do not require treatment are eligible.
• Has a primary central nervous system tumor.
• Known hypersensitivity to the components of study drug or its analogs.
• History or current evidence of clinically significant heart disease including:
• Left ventricular ejection fraction (LVEF) 450 msec (Bazett's Formula), congenitally long QT syndrome, and/or current anti-arrhythmic therapy, has received any marketed or experimental compound in the last 4 weeks prior to entering the study with possible or known effects of QT prolongation, or cumulative high-dose anthracycline therapy.
• Evidence of clinically significant bradycardia (heart rate <50), or a history of clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree AV block (Mobitz Type 2),