Combination of Bevacizumab, Pertuzumab, and Sandostatin for Adv. Neuroendocrine Cancers

• To determine overall response rate of patients with low grade neuroendocrine cancer when treated with the combination of bevacizumab, pertuzumab and sandostatin LAR®.
• To determine the disease control rate (objective response + stable disease), time to treatment progression, progression-free survival, and overall survival in patients with advanced low grade neuroendocrine cancer when treated with bevacizumab, pertuzumab and Sandostatin LAR® treatment.
• To define the toxicity and safety of the combination of bevacizumab, pertuzumab and Sandostatin LAR® when used in patients with advanced low grade neuroendocrine cancer.

Inclusion criteria

• Patients with biopsy-proven advanced, unresectable or metastatic, well-differentiated (or low-grade) neuroendocrine carcinoma, including typical carcinoid, pancreatic islet cell and other well-differentiated neuroendocrine carcinomas.
• Patients with documented evidence of disease progression.
• Patients currently receiving or previously treated with single agent Sandostatin LAR® are eligible.
• Patients must have >=1 unidimensional measurable lesion definable by

MRI or CT scan. Disease must be measurable per RECIST version 1.1 criteria.

• Left Ventricular Ejection Fraction (LVEF) >=50% as determined by either ECHO or MUGA <=6 weeks prior to study entry.
• An ECOG Performance Status of 0-2.
• Laboratory values as follows:

• ANC >=1500/μL
• Hgb >=9 g/dL
• Platelets >=100,000/μL
• AST/SGOT <=2.5 x ULN or <=5.0 x ULN in patients with liver metastases
• ALT/SGPT <=2.5 x ULN or <=5.0 x ULN in patients with liver metastases
• Bilirubin <=1.5 x ULN
• Creatinine <=2.0 mg/dL or calculated creatinine clearance >=50 mL/min
• Patients >=18 years of age.
• Patients must have a life expectancy >12 weeks.
• Patient must be accessible for treatment and follow-up.
• Women of childbearing potential must have a negative serum or urine pregnancy test performed <=7 days prior to start of treatment. Women of childbearing potential must use effective birth control measures during treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately.
• Patients must be able to understand the nature of the study and give

written informed consent, and comply with study requirements

Exclusion criteria

• Patients with poorly differentiated neuroendocrine carcinoma, highgrade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid, atypical carcinoid, anaplastic carcinoid, and small cell carcinoma are not eligible.
• Previous treatment with VEGF or EGFR inhibitors.
• Cytotoxic chemotherapy, immunotherapy or radiotherapy <=4 weeks prior to study entry.
• History or known presence of central nervous system (CNS) metastases.
• Patients who have had a major surgical procedure (not including mediastinoscopy), open biopsy, or significant traumatic injury <=4 weeks prior to beginning treatment.
• Female patients who are pregnant or lactating.
• History of hypersensitivity to active or inactive excipients of any component of treatment (bevacizumab, sandostatin, and/or pertuzumab).
• Patients with proteinuria at screening as demonstrated by urine dipstick for proteinuria >=2+ (patients discovered to have >=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection, and must demonstrate <=1 g of protein/24 hours to be eligible).
• Patients with a serious non-healing wound, active ulcer, or untreated bone fracture.
• Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
• Patients with history of hematemesis or hemoptysis (defined as having bright red blood of ½ teaspoon or more per episode) <=1 month prior to study enrollment.
• History of myocardial infarction or unstable angina <=6 months prior to beginning treatment.
• Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and /or diastolic blood pressure >100 mmHg while on antihypertensive medications). Initiation of antihypertensive agents is permitted provided adequate control is documented at least 1 week prior to Day of study treatment.
• New York Heart Association (NYHA) grade II or greater congestive

heart failure (CHF).

• Serious cardiac arrhythmia requiring medication.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) <=6 months prior to Day 1 of treatment.
• History of stroke or transient ischemic attack <=6 months prior to beginning treatment.
• Any prior history of hypertensive crisis or hypertensive encephalopathy.
• History of abdominal fistula or gastrointestinal perforation <=6 months prior to Day 1 of beginning treatment.
• Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
• Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection.
• Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
• Use of any non-approved or investigational agent <=28 days prior to administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
• Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a DFS >=5 years.
• Infection requiring IV antibiotics.