Study of AMG 386 in Combination With Paclitaxel and Carboplatin in Subjects With Ovarian Cancer

Inclusion Criteria:

• Female subjects more than 18 years of age with newly diagnosed high-risk FIGO Stage I (grade 3, or aneuploid grade 1 or 2) or Stages II-IV epithelial ovarian, primary peritoneal and fallopian tube cancer with an indication for first-line treatment with paclitaxel and carboplatin x 6 cycles. Subjects with pseudomyxoma, mesothelioma, adenocarcinoma of unknown primary tumor, sarcoma, or neuroendocrine histology are excluded.
• Subjects with high-risk stage I, stage II, or stage IIIA-B must have had prior primary debulking surgery that occurred no less than 4 weeks, and no more than 12 weeks, prior to enrollment. Subjects must have recovered fully from surgery in the opinion of the investigator
• Subjects with Stage IIIC or IV disease who have not had primary debulking surgery must have planned interval debulking surgery following 3 cycles of AMG 386, paclitaxel and carboplatin
• Female 18 years of age or older at the time the written informed consent is obtained
• Subjects of child-bearing potential who have not undergone a bilateral salpingo-oophorectomy and are sexually active must consent to use an accepted and effective non-hormonal method of contraception (i.e, double barrier method (eg, condom plus diaphragm) from signing the informed consent through 6 months after last dose of study drug
• GOG Performance Status of 0 or 1
• Life expectancy ≥ 3 months (per investigator opinion)
• Subject plans to begin protocol-directed therapy within 7 days from enrollment
• Adequate organ and hematological function as evidenced by the following laboratory studies prior to enrollment:

Hematological function, as follows:

• Hemoglobin ≥ 9 g/dL
• Absolute neutrophil count (ANC) ≥ 1.5 x 10x9/L
• Platelet count ≥ 100 x 10x9/L and ≤ 850 x 10x9/L
• PTT or aPTT ≤ 1.5 x ULN per institutional laboratory range and INR ≤ 1.5

Renal function, as follows:

• Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤ 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample
• Creatinine clearance > 40 mL/min per 24-hr urine collection or calculated according to the Cockcroft-Gault formula

Hepatic function, as follows:

• AST and ALT ≤ 2.5 x ULN per institutional laboratory range (or ≤ 5 x ULN if liver metastases are present)
• Total bilirubin ≤ 1.5x institutions' ULN Nutritional
• Albumin ≥ 2.8 g/dL

Exclusion Criteria:

• Prior use of anticancer therapy or experimental therapy for epithelial ovarian, primary peritoneal or fallopian tube cancers
• Previous abdominal and/or pelvic external beam radiotherapy
• Subjects believed to be a higher than average risk of bowel perforation. This includes current symptoms of partial or complete bowel obstruction, recent (within 6 months) history of fistula or bowel perforation, subjects requiring total parenteral nutrition and continuous hydration
• History of arterial or venous thromboembolism within 12 months prior to enrollment
• History of clinically significant bleeding within 6 months prior to enrollment
• History of central nervous system metastasis
• Known active or ongoing infection (except uncomplicated urinary tract infection) within 14 days prior to enrollment
• Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor
• Current or within 30 days prior to enrollment treatment with immune modulators such as systemic cyclosporine or tacrolimus
• Prior myeloablative high-dose chemotherapy with allogeneic or autologous stem cell (or bone marrow) transplant
• Clinically significant cardiac disease within 12 months prior to enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication or placement of percutaneous transluminal coronary angioplasty/stent
• Uncontrolled hypertension as defined as diastolic blood pressure > 90 mmHg OR systolic blood pressure > 140 mmHg. The use of anti-hypertensive medications to control hypertension is permitted
• Subjects with a history of prior malignancy, except:

Malignancy treated with curative intent and with no known active disease present for ≥ 3 years prior to enrollment and felt to be at low risk for recurrence by treating physician, Adequately treated non-melanomatous skin cancer or lentigo maligna without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease

• Major surgery within 28 days prior to enrollment or still recovering from prior surgery
• Minor surgical procedures, including placement of tunneled central venous access device, within 3 days prior to enrollment
• History of allergic reactions to bacterially-produced proteins
• Hypersensitivity to paclitaxel or drugs using the vehicle cremophor
• Pregnant (ie, positive beta-human chorionic gonadotropin test) or is breast feeding or planning to become pregnant within 6 months after the end of treatment
• Subject has known positive test(s) for human immunodeficiency virus (HIV) infection, hepatitis C virus, acute or chronic active hepatitis B infection
• Any condition which in the investigator's opinion makes the subject unsuitable for study participation
• Any uncontrolled concurrent illness or history of any medical condition that may interfere with the interpretation of the study results
• Non-healing wound, ulcer (including gastrointestinal) or fracture
• Subject has previously been enrolled onto this study
• Subject will not be available for follow-up assessment
• Subject has known sensitivity to any of the products to be administered during dosing
• 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