Trastuzumab in Combination With AMG 479 in HER-2 Overexpressing MBC Progressing on Trastuzumab

Inclusion Criteria

• •1. History of biopsy-proven HER-2-overexpressing breast cancer and radiographic evidence of metastatic disease. The HER-2 status can be determined either by immunohistochemistry (score, 3+) or by fluorescence in situ hybridization.
• •2. Patients must have received anthracycline-, taxane- and capecitabine-based chemotherapy for breast cancer. In addition, patients must have developed progressive disease to trastuzumab- or lapatinib-based therapy within the last 3 months. Patients who develop metastatic breast cancer within 3 months after receiving trastuzumab or lapatinib in the adjuvant and/or neoadjuvant setting are eligible. Three prior lines of HER2-directed therapy (containing either trastuzumab or lapatinib) for metastatic breast cancer are allowed.
• •3. Woman \>/=18 years old.
• •4. Performance status 0-2 (by Eastern Cooperative Oncology Group {ECOG} scale).
• •6. Continuation from # 5: Serum creatinine \</= 1.5 x the ULN or calculated creatinine clearance (by Cockcroft-Gault formula) \>/=40 mL/min; Aspartate aminotransferase (AST) \</= 2.5 x ULN; Alanine aminotransferase (ALT) \</= 2.5 x ULN; Alkaline phosphatase \</= 2.5 x ULN (\</= 5 x ULN with bone/liver metastases ); Bilirubin \</= 1.5 x ULN.
• •7. Glycosylated hemoglobin (HgbA1c)\</= 8%
• •8. Fasting blood glucose \</= 160 mg/dL (Fasting will require subjects to refrain from all food and beverage \[except water\] for at least 8 hours). Documentation will confirm patient compliance with nothing by mouth (NPO) status prior to lab exam.
• •9. Patients must not be pregnant. A pregnancy test will be obtained if the patient is a woman of child-bearing potential, defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses at any time in the preceding 24 consecutive months).
• •10. Patients must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment.
• •11. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>/= 20 mm with conventional techniques, including palpation, plain x-ray, or magnetic resonance imaging (MRI), or or \>/= 10 mm with spiral computed tomography (CT) scan. Bone metastases and pleural effusions are not considered measurable disease.
• •12. Patients may not be receiving any other investigational agents within 30 days of registration.
• •13. Left ventricular ejection fraction determined by echocardiogram or multiple-gated acquisition scan (MUGA) (cardiac scan) must be 50% or higher.
• •2. Prior malignancy (other than in situ cervical cancer, or basal cell or squamous cell carcinoma of the skin), unless treated with curative intent and without evidence of disease for 3 years or longer.
• •3. Administration of other prior anticancer therapies within 4 weeks of enrollment, except Trastuzumab and Lapatinib.
• •4. Toxicities related to prior anticancer treatment (except alopecia) that have not resolved to \</= grade 1 according to common terminology criteria for adverse events (CTCAE V4.0) before registration or prior to start of therapy.
• •5. Prior treatment with investigational treatment targeted to IGF axis including, but not limited to, CP-751,871, IM-A12, RO4858696.
• •6. Previous exposure to AMG 479.
• •7. Currently receiving systemic antibiotic therapy for the treatment of an active infection.
• •8. History of bleeding diathesis.
• •9. Known positive test for human immunodeficiency virus, or chronic hepatitis B or C infection.
• •10. Any co-morbid medical condition that may put the subject at significant risk for toxicity.
• •11. Major surgical procedure within 28 days of registration (prior to the start of therapy).
• •12. Minor surgical procedures within 7 days of registration although placement of central access device, fine needle aspiration, thoracentesis or paracentesis \> 1 day before registration is acceptable.
• •13. Known inability to tolerate intravenous (IV) drug administration.
• •14. Has not yet completed at least 30 days before registration since ending other investigational device or drug study(s)
• •15. Subject has known sensitivity to any of the products to be administered during dosing.
• •16. Subject will not be available for follow-up assessments.
• •17. Subject has any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures.
• •18. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• •19. History of venous thromboembolism.
• •20. Patient with reproductive potential who will not agree to use one highly effective method of contraceptive such as implants, injectables, intrauterine devices (IUDs) such as copper T or Levonorgestrel-releasing intrauterine system (LNG-IUS), sexual abstinence, vasectomised partner, or condom or occlusive cap (diaphragm or cervical/vault cap) supplemented with the use of a spermicide during treatment.
• •21. Poorly controlled diabetes mellitus
• •22. Patient with hearing impairment of \> grade 3.