Ziv-Aflibercept in Treating and Computed Tomography Perfusion Imaging in Predicting Response in Patients With Pancreatic Neuroendocrine Tumors That Are Metastatic or Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. Estimate the objective response rate (RR) of ziv-aflibercept among patients with advanced
pancreatic neuroendocrine tumors (NET)s according to Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1.

II. Test the following hypotheses: that baseline perfusion computed tomography (CT)
parameters can predict which patients with advanced pancreatic neuroendocrine tumors (pNETs)
will respond to treatment with ziv-aflibercept.

SECONDARY OBJECTIVES:

I. Estimate progression free survival (PFS) duration among patients treated with
ziv-aflibercept.

II. Evaluate the relationship between response rate and baseline blood volume (BV) and
between response rate and baseline permeability surface (PS).

TERTIARY OBJECTIVES:

I. Determine whether post-treatment changes in BV expressed as relative change from baseline
correlate with response to ziv-aflibercept.

II. Determine whether post-treatment tumor blood flow (BF) (absolute measurement) correlates
with response to ziv-aflibercept.

III. Determine whether post-treatment changes in BF and, BV, expressed as relative change
from baseline, correlate with relative change in sum of tumor diameters (RECIST 1.1
measurements).

IV. Determine the effect of ziv-aflibercept therapy on post-treatment blood flow (BF), BV,
mean transit time (MTT), and PS at 4 weeks after treatment.

V. Evaluate the changes in tumor perfusion parameters at time of progression.

OUTLINE:

Patients receive ziv-aflibercept intravenously (IV) over 60-120 minutes on day 1. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients
undergo computed tomography perfusion imaging at baseline, day 21 of course 1, and at time of
progression.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed low or intermediate grade
pancreatic NET; patients with neuroendocrine tumors associated with multiple endocrine
neoplasia type 1 (MEN1) syndrome will be eligible

- Patients must have unresectable or metastatic disease

- Patients must have at least one measurable site of disease according to RECIST 1.1
that has not been previously irradiated

- Patients must have at least one lesion suitable for perfusion CT; the lesion should be
greater than or equal to 3 cm in size in the cranial caudal direction

- Patient must have no contraindication for CT with iodinated contrast

- Patients who are on a somatostatin analogue for control of hormonal syndromes must be
on a stable dose (no change in mg dose of long acting octreotide or lanreotide,
changes in dosing interval of +/- 1 week is allowed) for 2 months prior to date of
study entry

- Women of child-bearing potential must have a negative serum pregnancy test within 7
days prior to date of study entry; women who have had menses within the past 2 years,
who have not had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy
are considered to be of child-bearing potential; patients with elevated human
chorionic gonadotropin (hCG) at baseline that is judged to be related to the tumor are
eligible if hCG levels do not show the expected doubling when repeated 5-7 days later,
or pregnancy has been ruled out by vaginal ultrasound

- Any number of prior lines of systemic anti-neoplastic therapy are allowed; treatment
with =< 1 prior VEGF inhibitor will be allowed

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 x institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Urine protein:creatinine ratio =< 1.0 OR 24-hour urine protein =< 500 mg (24-hour
total urine protein only need be obtained if urine protein:creatinine ratio < 1.0)

- Patients must have prothrombin time (PT)/international normalized ratio (INR)/partial
thromboplastin time (PTT) within 1.2 x the upper limit of normal

- Patients must have resting blood pressure (BP) no greater than 140 mmHg (systolic) or
90 mmHg (diastolic) for eligibility; initiation or adjustment of BP medication is
permitted prior to study entry

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Less than 28 days elapsed from prior radiotherapy, from prior surgery and prior
chemotherapy to the time of randomization; less than 42 days elapsed from prior major
surgery to the time of randomization

- Adverse events (with exception of alopecia, peripheral sensory neuropathy and those
listed in specific exclusion criteria) from any prior anti cancer therapy of grade > 1
(National Cancer Institute Common Terminology Criteria [NCI CTCAE] version [v.]4.0)

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) > 2

- History of brain metastases, uncontrolled spinal cord compression, or carcinomatous
meningitis or new evidence of brain or leptomeningeal disease

- Other prior malignancy; adequately treated basal cell or squamous cell skin cancer,
carcinoma in situ of the cervix or any other cancer from which the patient has been
disease free for > 5 years are allowed

- Participation in another clinical trial and any concurrent treatment with any
investigational drug within 30 days prior to study entry

- Any of the following within 6 months prior to study entry: myocardial infarction,
severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York
Heart Association (NYHA) class III or IV congestive heart failure, stroke or transient
ischemic attack

- Any of the following within 3 months prior to study entry: grade 3-4 gastrointestinal
bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive esophagitis or
gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary
embolism or other uncontrolled thromboembolic event

- Occurrence of deep vein thrombosis within 4 weeks, prior to study entry

- Acquired immuno deficiency syndrome (AIDS-related illnesses) or known human
immunodeficiency virus (HIV) disease requiring antiretroviral treatment

- Any severe acute or chronic medical condition, which could impair the ability of the
patient to participate to the study or to interfere with interpretation of study
results

- Pregnant or breast feeding women; positive pregnancy test (serum or urine beta-human
chorionic gonadotropin [HCG]) for women of reproductive potential

- Patient with reproductive potential (female and male) who do not agree to use an
accepted effective method of contraception (hormonal or barrier methods, abstinence)
during the study treatment period and for at least 3 months following completion of
study treatment; for female patient enrolled, the following methods of contraception
are acceptable: oral contraceptives accompanied by the use of a second method of
contraception, or intra uterine device (IUD) or women who are surgically sterile, or
women who are post -menopausal or other reasons have no chance of becoming pregnant

- Absence of signed and dated Institutional Review Board-approved patient informed
consent from prior to enrollment in the study

- EXCLUSION CRITERIA RELATED TO ZIV-AFLIBERCEPT

- Urine protein-creatinine ratio (UPCR) > 1 urinalysis or total urine protein > 500
mg/24 hours (h)

- Serum creatinine > 1.5 x upper limit of normal (ULN); if creatinine 1.0-1.5 x ULN,
creatinine clearance, calculated according to Cockcroft-Gault formula, < 60 ml/min
will exclude the patient

- History of uncontrolled hypertension, defined as systolic blood pressure > 150 mmHg
while simultaneous diastolic blood pressure > 100 mmHg, or systolic blood pressure >
180 mmHg when diastolic blood pressure < 90 mmHg, on at least 2 repeated
determinations on separate days within 3 months prior to study enrollment

- Patients on anticoagulant therapy with unstable dose of warfarin and/or having an
out-of- therapeutic range INR (> 3) within the 4 weeks prior to study entry

- Evidence of clinically significant bleeding diathesis or underlying coagulopathy (e.g.
INR > 1.5 without vitamin K antagonist therapy), non-healing wound