Ziv-Aflibercept for Advanced Progressive Carcinoid Tumors

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