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• Documentation of Disease:
• Histologic Documentation: Well- or moderately-differentiated neuroendocrine tumors of pancreatic and non-pancreatic
(i.e. carcinoid) origin by local pathology
• The pathology report must state ONE of the following: 1) well- or moderately-differentiated neuroendocrine tumor,
2) low- or intermediate-grade neuroendocrine tumor, or 3) carcinoid tumor or atypical carcinoid tumor; documentation
of histology from a primary or metastatic site is allowed
• Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma without
specification of differentiation status, adenocarcinoid tumor, or goblet cell carcinoid tumor are not eligible. Patients
with well-differentiated grade 3 neuroendocrine tumor are eligible
• Stage: Locally advanced/unresectable or metastatic disease
• Tumor Site: Histological documentation of neuroendocrine tumor of pancreatic, gastrointestinal (GI), lung, thymus, other, or unknown primary site• GI, lung, thymus, other, and unknown primary NETs will enroll in the carcinoid tumor cohort of the study
• Functional (i.e., associated with symptoms or clinical syndrome related to hormone secretion by tumor) or
nonfunctional tumors are allowed
• Radiologic Evaluation: Target lesions must have shown evidence of disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria in the 12 months prior to registration• the radiologic images, imaging reports, and clinic notes indicating growth of existing lesions, development of new lesions, or treatment changes must be submitted
• Measurable Disease
• Patients must have measurable disease per RECIST 1.1 by computer tomography (CT) scan or magnetic
resonance imaging (MRI)
• Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as >= 1 cm
with CT or MRI (or >= 1.5 cm for lymph nodes)• non-measurable disease includes disease smaller than these
dimensions or lesions considered truly non-measurable including: leptomeningeal disease, ascites, pleural or
pericardial effusion, lymphangitic involvement of skin or lung
• Prior Treatment
• Patient must have experienced disease progression after receiving or intolerance leading to treatment
discontinuation of at least one Food and Drug Administration (FDA)-approved line of therapy (except somatostatin
analogs); prior lines of therapy must include one of the following: everolimus, sunitinib, or lutetium Lu 177 dotatate
in patients with pancreatic NET, everolimus in patients with lung NET; everolimus or lutetium Lu 177 dotatate in
patients with gastrointestinal NET
• Prior treatment (except somatostatin analogs) with biologic therapy, immunotherapy, chemotherapy,
investigational agent for malignancy, and/or radiation must be completed at least 28 days prior to registration
• Prior treatment with somatostatin analogs is allowed, and continuation of treatment with somatostatin analogs
while on cabozantinib/placebo is allowed provided that the patient has been on a stable dose for at least two months
• Prior systemic treatment with radionuclide therapy must be completed at least 6 weeks prior to registration
• Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective
internal radiation therapy) or ablative therapies is allowed if measurable disease remains outside of the treated area
or if there is documented disease progression in a treated site• prior liver-directed or other ablative treatment must
be completed at least 28 days prior to registration
• Patients should have resolution of any toxic effects of prior therapy (except alopecia and fatigue) to National
Cancer Institute (NCI) CTCAE, version 5.0, grade 1 or less
• Patients must have completed any major surgery at least 12 weeks prior to registration and any minor surgery
(including uncomplicated tooth extractions) at least 28 days prior to registration• complete wound healing from
major surgery must have occurred at least 28 days prior to registration, and complete wound healing from minor
surgery must have occurred at least 10 days prior to registration
• Women of childbearing potential must have a negative pregnancy test done = < 14 days prior to registration
• A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy• or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
• Absolute neutrophil count (ANC) >= 1,500/mm ^3
• Hemoglobin >= 9 g/dL
• Platelet count >= 100,000/mm ^3
• Prothrombin time (PT)/ international normalized ratio (INR), partial thromboplastin time (PTT) < 1.3 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) = < 3 x ULN
• Total bilirubin = < 1.5 x ULN
• Except in the case of Gilbert disease, in which case total bilirubin must be = < 3 x ULN
• Creatinine = < 1.5 mg/dL OR creatinine clearance >= 45 mL/min
• Albumin >= 2.8 g/dL
• Potassium within normal limits (WNL)
• Supplementation is acceptable to achieve a value WNL• in patients with low albumin levels, a corrected calcium
value WNL is acceptable• in patients with abnormal thyroid stimulating hormone (TSH), if free T4 is normal and
patient is clinically euthyroid, patient is eligible
• Phosphorus WNL
• Supplementation is acceptable to achieve a value WNL• in patients with low albumin levels, a corrected calcium
value WNL is acceptable• in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid,
patient is eligible
• Calcium WNL
• Supplementation is acceptable to achieve a value WNL• in patients with low albumin levels, a corrected calcium
value WNL is acceptable• in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid,
patient is eligible
• Magnesium WNL
• Supplementation is acceptable to achieve a value WNL• in patients with low albumin levels, a corrected
calcium value WNL is acceptable• in patients with abnormal TSH, if free T4 is normal and patient is clinically
euthyroid, patient is eligible
• Urine protein to creatinine (UPC) ratio = < 1
• QT interval corrected for heart rate using Fridericia's formula (QTcF) = < 500 msec
• TSH WNL
• Supplementation is acceptable to achieve a value WNL• in patients with low albumin levels, a corrected calcium
value WNL is acceptable• in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid,
patient is eligible
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