Phase 2 AMG 386 in Comb. Paclitaxel for Subjects With Advanced Recurrent Epithelial Ovarian or Primary Peritoneal Cancer

Primary Objective:

To estimate the treatment effect as measured by progression free survival (PFS) of subjects with recurrent ovarian cancer receiving AMG 386 (either 3 mg/kg or 10 mg/kg IV QW) in combination with paclitaxel (80 mg/m2 IV QW; 3 on/1 off)compared to subjects receiving paclitaxel (80 mg/m2 IV QW; 3 on/1 off) plus placebo

Secondary Objective(s):

• To evaluate the safety and tolerability of the combination regimen of AMG 386/paclitaxel
• To estimate other measures of treatment effect (by parameters other than PFS) of subjects receiving AMG 386 in combination with paclitaxel compared to subjects receiving paclitaxel plus placebo
• To evaluate the AMG 386 pharmacokinetics parameters (Cmax and Cmin ) when administered with paclitaxel in subjects with recurrent ovarian cancer
• To estimate the incidence of occurrence of anti-AMG 386 antibody formation
• To estimate the change and duration of change on blood levels of CA-125
• To evaluate the clinical benefit among subjects receiving AMG 386 10 mg/kg monotherapy after disease progression on paclitaxel
• To estimate the impact of AMG 386 on patient reported ovarian cancer specific symptoms and HRQoL using the FACT-O, the FACT-O ovarian cancer subscale (OCS), and the FACT-O 3-item (O1, O2, O3) cancer symptom specific subscale (OCS 3-item subscale)

Exploratory Objective(s):

• To explore the associations between progression free survival, objective response, CA-125, and continuous measures of tumor burden (the percentage change from baseline in the sum of the longest diameters of target lesions)
• To explore the pharmacodynamic (PD) response as assessed by changes in blood levels of angiogenic cytokines, tumor apoptosis, CA-125 and other markers
• To investigate the effects of genetic variation in drug metabolism, cancer genes and drug target genes on ovarian cancer and subject response to investigational product (separate informed consent)
• To explore the impact of AMG 386 on patient reported overall health status as measured by the EuroQoL (EQ-5D)

Hypothesis:

This study will provide an estimate and corresponding 2-sided 80% confidence interval with an approximate maximum half-width of 0.22 of the efficacy, as measured by the PFS hazard ratio of AMG 386 in combination with paclitaxel versus paclitaxel alone for 2 pooled dose groups of AMG 386 (10 mg/kg QW and 3 mg/kg QW) in combination with paclitaxel versus the paclitaxel plus placebo group.

In. Criteria -Subjects must have histologically or cytologically documented epithelial ovarian (FIGO Stage II-IV), fallopian tube or primary peritoneal cancer.

(Subjects with pseudomyxoma or mesothelioma are excluded)

• Radiographically documented progression per RECIST criteria with modifications or progression of CA-125 as defined by the Rustin during or subsequent to the last chemotherapy regimen.
• May include measurable or non-measurable disease
• All scans and x-rays used to document measurable or non-measurable disease must be done within 3 weeks (21 days) of enrollment.
• No more than 3 previous regimens of anti-cancer therapy. Subjects must have received at least one platinum containing regimen
• 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 use an accepted and effective non-hormonal method of contraception (ie, double barrier method (eg, condom plus diaphragm)) from signing the informed consent through 6 months after last dose of study drug.

Laboratory

• Adequate organ and hematological function as evidenced by the following laboratory studies within 2 weeks (14 days) of randomization:
• Hematological function, as follows:

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L and ≤ 850 x 109/L Hemoglobin ≥ 9 g/dL PTT or aPTT≤ 1.5 x ULN per institutional laboratory rand and INR ≤ 1.5 x 109/L per instiutiona laboratory range

Renal function, as follows:

Creatinine ≤ 2.0 mg/dL Calculated creatinine clearance > 40 cc/min according to the Cockcroft-Gault formula

-Hepatic function, as follows: Total bilirubin ≤ 2.0 x ULN SGOT (AST) and SGPT (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present) Nutritional

• Albumin ≥ 2.8 mg/dL General
• GOG Performance Status of 0 or 1
• Subject plans to begin protocol directed therapy within 7 days of randomization Ex Criteria
• Subjects believed to be a higher than average risk for bowel perforation. This includes 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
• Known ongoing small bowel dysfunction (ie, persistent nausea, vomiting)
• Radiotherapy ≤ 14 days prior to randomization. Subjects must have recovered from all radiotherapy-related toxicities
• If all sites of disease have been irradiated, documented progression must have occurred in at least one site of disease subsequent to the radiation therapy.
• Previous abdominal radiotherapy
• Has not yet completed a 21 day washout period for any previous anti-cancer systemic therapies (60 days for bevacizumab or any molecule of long half-life).
• Enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or is receiving other investigational agent(s)
• Current or prior history of central nervous system metastasis
• Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 peripheral neuropathy ≥grade 2
• History of arterial or venous thrombosis within 12 months prior to randomization
• Concurrent or prior (within 1 week before study day 1) anticoagulation therapy, excluding aspirin and anti platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (ie, ≤ 1 mg daily) for prophylaxis against thrombosis is acceptable while on study
• History of bleeding diathesis or clinically significant bleeding within 14 days of randomization
• Major surgical procedure within 4 weeks (28 days) prior to Study Day 1
• Minor surgical procedure, or placement of central venous access device, within 7 days of Study Day 1
• Paracentesis and/or thoracentesis are permitted prior to and while on study at the discretion of the investigator as clinically indicated. Investigators should document the frequency of paracenteses and/or thoracentesis that occurred prior to the enrollment of the subject in this study on the appropriate eCRFs. Investigators should also document each paracentesis and/or thoracentesis that occurs while a subject is on study on the appropriate eCRFs.
• Subjects with a history of prior malignancy, except:
• Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before 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
• Prior myeloablative high dose chemotherapy with allogeneic or autologous stem cell (or bone marrow) transplant
• Clinically significant cardiac disease within 12 months of study enrollment, including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent
• Non-healing wound, ulcer or fracture
• Ongoing or active infection
• Unacceptable hypersensitivity to paclitaxel or drugs containing cremophor
• Known positive test for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B surface antigen
• Currently or previously treated with angiopoietin inhibitors, or inhibitors of TIE-1 or TIE-2 including, but not limited to, AMG 386, XL880, XL820
• Prior therapy against vascular endothelial growth factor or the vascular endothelial growth factor receptors including, but not limited to, bevacizumab, sunitinib, sorafenib, motesanib (AMG 706) or cediranib (AZD-2171), is permitted so long as the agent does not have any known activity against angiopoietin 1 or 2, or the receptors TIE-1 or TIE-2
• Current or within 30 days of randomization treatment with immune modulators such as cyclosporine and tacrolimus