This research study is a Phase II clinical trial, which tests the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug, Ziv-aflibercept, is being studied. It also means that the FDA has not yet approved Ziv-aflibercept for use in patients with your type of cancer.

Every person has molecules in their bloodstream called vascular endothelial growth factors (VEGFs). These molecules help grow and sustain new blood vessels needed by the human body. Cancer tumors hijack this mechanism because they need new blod vessels and oxygen to grow. Ziv-aflibercept is an antibody. Antibodies are proteins that are produced naturally in our bodies and help to recognize foreign substances in our body. Ziv-aflibercept is a "targeted therapy" called a "VEGF Trap", that "traps" (binds) these VEGFs and prevents the cancer from using them to grow.

Though Ziv-aflibercept has not yet been FDA approved for the treatment of carcinoid tumors, it has recently been approved for patients with treatment-resistant colorectal cancer.

In this research study, we will use Ziv-aflibercept in combination with standard octreotide therapy to see if it slows the growth or spread of your carcinoid tumor. Standard octreotide (sandostatin) therapy is currently approved for treating symptoms of carcinoid tumors, such as those caused by carcinoid syndrome. Carcinoid syndrome is caused by hormones and other substances released by carcinoid tumors into the bloodstream. One of these secreted substances is serotonin, one of the body's natural chemical messengers. When excess serotonin secreted by the carcinoid tumors reaches the body's tissues, it is thought to cause diarrhea and redness (flushing) of the face, chest or back. Excess serotonin may also cause changes in the structure of the heart valves, which can impair the heart's function. Octreotide works by binding to receptors found on carcinoid tumors and prevents the release of hormones from the tumor.

If you are willing to participate in this study you will be asked to undergo some screening tests and procedures to confirm that you are eligible. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that you do not take part in the research study. If you have had some of these tests or procedures recently, they may or may not have to be repeated. These tests and procedures include: a medical history, physical examination, CT or MRI, blood tests, serum chromogranin A, urine tests, 24-hour urine collection, pregnancy test and an electrocardiogram. If these tests show that you are eligible to participate in the research study, you will begin the study treatment. If you do not meet the eligibility criteria, you will not be able to participate in this research study.

If you meet the requirements for this study and you agree to continue your participation, you will receive Ziv-aflibercept every two weeks. Each dose of Ziv-aflibercept consists of an approximately 60 minutes infusion (through a needle into a vein). You will also receive an injection of Octreotide LAR (long acting release) monthly as part of your treatment for carcinoid tumor. This injection will be given to you by a nurse in your buttock. You may already be on Octreotide LAR. In that case, you will continue taking it at the same dose and schedule.

You will need to come to the clinic every two weeks while participating in this study. Each cycle is 28 days.

The following tests and procedures will be performed on Days 1 and 15 of each cycle: questions about your health, physical exam (Day 1 of each cycle only), vital signs, blood tests, pregnancy test (Day 1 of each cycle only).

Urine tests will be performed every other cycle.

The following tests and procedures will be done at the end of every third cycle: CT scan or MRI, Serum Chromogranin A, 24-hour urine collection.

After the final dose of the study drug the following tests and procedures will be performed: questions about your general health, physical exam, vital signs, blood tests, pregnancy test, EKG, Serum Chromogranin A, 24-hour urine collection.

Inclusion Criteria:

• Histologically confirmed well differentiated or moderately differentiated neuroendocrine tumor from either a primary or metastatic site
• Must have disease that is not amenable to curative resection
• Must have evidence of disease progression within 12 months prior to study entry
• Must have measurable disease (RECIST 1.1)
• Prior chemoembolization of local ablative therapies are allowed, provided there is measurable disease outside of the area treated, or documented evidence of progression at the site of prior treatment
• No limit to number of prior treatments. Prior bevacizumab allowed unless discontinued due to unacceptable toxicity. Prior TKI targeting VEGF receptors allowed
• Treatment with a somatostatin analog required for all subjects
• Subjects with history of hypertension must be adequately controlled
• Therapeutic anticoagulation is allowed. Must be on a stable dose of anticoagulant medication
• Must agree to use adequate contraception prior to study entry, for the duration of study participation and for 3 months after last administration of study drug

Exclusion Criteria:

• Prior treatment including chemoembolization within 4 weeks of study entry
• Major surgery within 4 weeks of study entry or minor surgery within 2 weeks of study entry
• Pregnant or breastfeeding
• Poorly differentiated carcinoma, high grade neuroendocrine tumor or small cell carcinoma
• Prior treatment with Ziv-aflibercept
• Pancreatic neuroendocrine tumor (islet cell carcinoma)will be excluded from this study. All non functional and functional islet cell carcinomas such as insulinoma, glucagonoma, gastrinoma, VIPoma will be excluded.
• Not adequately recovered from toxicity of previous therapy
• Known untreated brain or other central nervous system metastases
• Known allergy to any of the study agents or to compounds of similar chemical or biologic composition
• History of congestive heart failure
• Symptomatic peripheral arterial disease
• Unhealed wounds, ulcers or bone fractures
• HIV positive or active Hepatitis infection
• History of abdominal fistula, GI perforation, intra abdominal abscess, uncontrolled GI bleeding, diverticulitis within 6 months of study entry
• History of arterial thrombotic events such as myocardial infarction, unstable angina pectoris or any ischemic or hemorrhagic cerebrovascular accident within the past 6 months
• No history of pulmonary embolism, DVT or vascular access related thrombosis if not also receiving adequate anticoagulation at a stable dose.
• No history of prior or synchronous malignancy except if treated with curative intent at least 3 years prior to study entry, or adequately treated non-melanoma skin cancer, cervical carcinoma in situ, or prostate intraepithelial neoplasia without evidence of prostate cancer
• Uncontrolled non-malignant illness that may increase the risks associated with study participation or may interfere with the conduct of the study or interpretation of study results
• Uncontrolled psychiatric illness or social situations that would limit compliance with study requirements

Patients were followed for AEs from first dose of study treatment, throughout the study, and through 30 days of the last study treatment, an average of 16 months. Participants removed from study for unacceptable adverse events were followed until resolution or stabilization of the adverse event.

Adverse Event (AE): An adverse event (AE) is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. Abnormal laboratory values or diagnostic test results constitute adverse events only if they are determined to be of clinical significance or require treatment or further diagnostic tests. Adverse events are reported for all patients, based on starting dose