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

The purpose of this Phase II trial will be to define the activity of a VEGF inhibitor

bevacizumab, HER1/HER2 inhibitor pertuzumab, and sandostatin for patients with

advanced neuroendocrine cancers. In particular, the efficacy of bevacizumab and

pertuzumab treatment is of great interest. The primary endpoint of this trial will be

response rate. Toxicity and progression-free survival will be obtained and evaluated.

* 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.

Eligibility Criteria:
Inclusion Criteria:

1. 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.
2. Patients with documented evidence of disease progression.
3. Patients currently receiving or previously treated with single agent Sandostatin LAR® are eligible.
4. Patients must have \>=1 unidimensional measurable lesion definable by

   MRI or CT scan. Disease must be measurable per RECIST version 1.1 criteria.
5. Left Ventricular Ejection Fraction (LVEF) \>=50% as determined by either ECHO or MUGA \<=6 weeks prior to study entry.
6. An ECOG Performance Status of 0-2.
7. 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
8. Patients \>=18 years of age.
9. Patients must have a life expectancy \>12 weeks.
10. Patient must be accessible for treatment and follow-up.
11. 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.
12. Patients must be able to understand the nature of the study and give

written informed consent, and comply with study requirements

Exclusion Criteria:

1. Patients with poorly differentiated neuroendocrine carcinoma, highgrade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid, atypical carcinoid, anaplastic carcinoid, and small cell carcinoma are not eligible.
2. Previous treatment with VEGF or EGFR inhibitors.
3. Cytotoxic chemotherapy, immunotherapy or radiotherapy \<=4 weeks prior to study entry.
4. History or known presence of central nervous system (CNS) metastases.
5. Patients who have had a major surgical procedure (not including mediastinoscopy), open biopsy, or significant traumatic injury \<=4 weeks prior to beginning treatment.
6. Female patients who are pregnant or lactating.
7. History of hypersensitivity to active or inactive excipients of any component of treatment (bevacizumab, sandostatin, and/or pertuzumab).
8. 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).
9. Patients with a serious non-healing wound, active ulcer, or untreated bone fracture.
10. Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).
11. 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.
12. History of myocardial infarction or unstable angina \<=6 months prior to beginning treatment.
13. 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.
14. New York Heart Association (NYHA) grade II or greater congestive

    heart failure (CHF).
15. Serious cardiac arrhythmia requiring medication.
16. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) \<=6 months prior to Day 1 of treatment.
17. History of stroke or transient ischemic attack \<=6 months prior to beginning treatment.
18. Any prior history of hypertensive crisis or hypertensive encephalopathy.
19. History of abdominal fistula or gastrointestinal perforation \<=6 months prior to Day 1 of beginning treatment.
20. 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.
21. Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection.
22. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.
23. 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.
24. 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.
25. Infection requiring IV antibiotics.