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
Condition: Multiple Endocrine Neoplasia Type 1; Pancreatic Neuroendocrine Carcinoma
MeSH terms: Neuroendocrine Tumors; Carcinoma, Neuroendocrine; Endocrine Gland Neoplasms; Multiple Endocrine Neoplasia; Multiple Endocrine Neoplasia Type 1; Carcinoma, Islet Cell
Intervention: Computed Tomography Perfusion Imaging; Laboratory Biomarker Analysis; Ziv-Aflibercept
Intervention description: Undergo computed tomography perfusion imaging; Correlative studies; Given IV
Intervention MeSH terms: Aflibercept; Endothelial Growth Factors
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies ziv-aflibercept in treating and perfusion computed tomography
      perfusion imaging in predicting response in patients with pancreatic neuroendocrine tumors
      that have spread to other parts of the body or cannot be removed by surgery. Ziv-aflibercept
      may stop the growth of tumor cells by blocking blood flow to the tumor. Diagnostic
      procedures, such as computed tomography perfusion, imaging may help measure a patient's
      response to ziv-aflibercept treatment.
    

Eligibility criteria:

        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