Ziv-aflibercept and Octreotide Pamoate in Treating Patients with Metastatic Neuroendocrine Tumors That Cannot Be Removed by Surgery

Inclusion Criteria

• Participants must have histologically confirmed well differentiated or moderately differentiated neuroendocrine tumor from either a primary or metastatic site; carcinoid tumors of any primary site are eligible
• Participants must have disease that is not amenable to curative resection
• Participants must have evidence of disease progression within 12 months prior to study entry
• Participants 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
• There is no limit to number of prior treatments; prior bevacizumab is allowed unless it was discontinued due to unacceptable toxicity; prior therapy with tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor (VEGF) receptors is allowed
• Treatment with a somatostatin analog (e.g., octreotide acetate) is required for all participants; octreotide naive patients may initiate this during the screening period or at start of study
• Prior treatment including chemoembolization or other ablative therapy, any cytotoxic, biologic or other investigational agents must have been completed at least 4 weeks prior to study entry
• Prior palliative radiation must have been completed at least 2 weeks prior to study entry
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Participants with a history of hypertension must be adequately controlled with antihypertensive medication and blood pressure (BP) must be less than 140/90 mmHg prior to initiation of ziv-aflibercept
• Therapeutic anticoagulation is allowed; the participant must be on a stable dose of anticoagulant medication (warfarin, or low molecular weight heparin [LMWH]) prior to study entry
• Any major surgery must be completed at least 4 weeks prior to study entry; minor surgical procedures (except insertion of vascular access device) must have been completed at least 2 weeks prior to study entry
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months after last administration of ziv-aflibercept; women of child bearing potential must have a negative pregnancy test (urine or blood) within 14 days of registration
• Absolute neutrophil count >= 1,500/mcL
• Hemoglobin > 9 g/dL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 x upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x upper limit of normal or =< 5 x upper limit of normal if liver metastases are present
• Alkaline phosphatase =< 5 x upper limit of normal
• Creatinine =< 1.5 x upper limit of normal
• Urine protein/creatinine ratio of less than 1
• Participant is able to understand and comply with study requirements and is willing to sign a written informed consent document

Exclusion Criteria

• Poorly differentiated carcinoma, high grade neuroendocrine tumor or small cell carcinomas are excluded from this study
• Prior treatment with ziv-aflibercept is not allowed
• Pancreatic neuroendocrine tumors (islet cell carcinoma) will be excluded from this study; all non functional and functional islet cell carcinomas such as insulinoma, glucagonoma, gastrinoma, vasoactive intestinal peptide (VIP)oma will be excluded
• No other investigational, biologic or chemotherapy agents, localized ablation or chemoembolization for 4 weeks prior to study entry
• Participant has not adequately recovered from toxicity of previous therapy
• Participants with known untreated brain or other central nervous system metastases are excluded
• Pregnant or nursing mothers are excluded
• Known allergy to any of the study agents or to compounds of similar chemical or biologic composition are excluded (including other somatostatin analogs)
• Participants with a history of congestive heart failure (New York Heart Association [NYHA] class II, III or IV) are excluded
• No symptomatic peripheral arterial disease
• No unhealed wounds, ulcers or bone fractures
• No known human immunodeficiency virus (HIV) positive, or active hepatitis infection
• No history of abdominal fistula, gastrointestinal (GI) perforation, intra abdominal abscess, uncontrolled GI bleeding, diverticulitis within 6 months of study entry
• No history of arterial thrombotic events such as myocardial infarction (MI), unstable angina pectoris or any ischemic or hemorrhagic cerebrovascular accident (CVA) within past 6 months
• Participants with history of pulmonary embolism, deep vein thrombosis (DVT), or vascular access related thrombosis will be allowed on study provided they are receiving adequate anticoagulation at a stable dose at the time of study entry
• No history of prior or synchronous malignancy, except * Prior malignancy was treated with curative intent and there is no known active disease present for greater than or equal to 3 years prior to study entry * Participants with adequately treated non-melanoma skin cancers, cervical carcinoma in situ, or prostatic intraepithelial neoplasia without evidence of prostate cancer are eligible
• Any uncontrolled non-malignant illness that in the opinion of the treating investigator may increase the risks associated with study participation or may interfere with the conduct of the study or interpretation of study results would exclude the participant
• Uncontrolled psychiatric illness or social situations that would limit compliance with study requirements would exclude the participant