Cabozantinib works by blocking the growth of new blood vessels that feed a tumor. In addition to blocking the formation of new blood cells in tumors, cabozantinib also blocks pathways that may be responsible for allowing cancers cells to become resistant to other "anti-angiogenic" drugs. Cabozantinib has been studied or is being study in research studies as a possible treatment for various types of cancer, including prostate cancer, brain cancer, thyroid cancer, lung cancer, and kidney cancer.

In this research study, the investigators wish to learn if cabozantinib is effective in treating patients with pancreatic neuroendocrine and carcinoid tumors.

Subjects will take cabozantinib orally, once per day, in cycles of 28 days.

During each cycle subjects will have the following procedures:

• Physical examination, including measurement of weight and vital signs
• Questions regarding any side effects
• Blood sample (about 1 tablespoon) for routine laboratory tests of blood cell counts, blood chemistries, organ function and blood clotting
• Blood sample (about 4 tablespoons) for research test to measure biomarkers to assess the response to study drug
• Urine sample for routine urine tests to monitor health

On Day 15 (beginning of week 3) during the first 3 cycles:

• Physical examination, including measurement of weight and vital signs
• Questions regarding any side effects
• Blood sample (about 1 tablespoon) for routine laboratory tests of blood cell counts, blood chemistries, organ function and blood clotting
• Blood sample (about 4 tablespoons) for research test to measure biomarkers to assess the response to study drug Subjects will receive a CT scan or MRI every two cycles (every two months) to evaluate disease.

Inclusion Criteria:

• Locally unresectable or metastatic, histologically-confirmed, carcinoid or pancreatic neuroendocrine tumor. Tumors must be considered well- or moderately-differentiated. Patients with poorly differentiated neuroendocrine carcinoma or cell carcinoma are excluded from the study.

• A tumor sample is required for enrollment (except for patients diagnosed > 7 years ago).

• Must have measurable disease by RECIST criteria

• Must have evidence of progressive disease within 12 months of study entry

• Prior or concurrent therapy with somatostatin analogs is permitted. If on somatostatin/octreotide, must be on a stable dose for at least two months.

• Age ≥ 18 years

• No major surgery or radiation in the prior 4 weeks prior to enrollment

• No prior therapy with cabozantinib

• ECOG Performance status ≤ 1

• Participants must have adequate organ and marrow function as defined below:

  • Absolute neutrophil count > 1,500/mcL
  • Platelets > 100,000/mcL
  • Total bilirubin </= 1.5X normal institutional limits
  • AST (SGOT) and ALT (SGPT) </=2.5x normal institutional limits, or < 5x if liver metastases are present
  • Creatinine </= 1.5x normal institutional limits or creatinine clearance > 50mL/min
  • Urine Protein:Creatinine ratio of <1
  • Lipase < 1.5X upper limit of normal
  • Serum Albumin ≥ 2.8 g/dl

• Sexually active subjects must agree to use medically accepted methods of birth control during the course of the study and for 3 months following discontinuation of study treatments (excluding women who are not of child bearing potential and men who have been sterilized).

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

Exclusion Criteria

• Subjects receiving any other standard or investigational anticancer agents, with the exception of somatostatin/octreotide therapy. If patients has received prior cytotoxic chemotherapy, must be at least three weeks since last treatment before first dose of study treatment.

• Major surgery or radiation treatment <4 weeks prior to enrollment. In addition, cannot have received radiation to the thorax or gastrointestinal tract within three months of the first dose of study treatment.

• Cannot have received radionuclide treatment within 6 weeks of first dose of study treatment.

• High grade or poorly differentiated neuroendocrine tumors

• Ongoing immunosuppression with systemic steroids or other immune modulator

• Presence of CNS metastatic disease

• Uncontrolled hypertension defined by SBP > 140 or DBP > 90 despite titration of anti hypertensive medications

• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia other than chronic atrial fibrillation, or psychiatric illness/social situations that would limit compliance with study requirements. Congestive heart failure or symptomatic coronary artery disease within 3 months prior to enrollment

• Cerebrovascular accident within prior 6 months

• The subject has a history of clinically significant hematemesis or a recent history of hemoptysis of > 2.5 mL of red blood or other signs indicative of pulmonary hemorrhage or evidence of endobronchial lesion(s).

• The subject has a pulmonary lesion abutting or encasing a major blood vessel.

• Previous history of pulmonary embolism or deep venous thrombosis

• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or Coumadin-related agents, heparin, thrombin or FXa inhibitors, and antiplatelet agents (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic Low Molecular Weight Heparin (LMWH) are permitted.

• At the time of screening, active peptic ulcer disease or active inflammatory bowel disease (including ulcerative colitis or Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis, or appendicitis.

• History of abdominal fistula, gastrointestinal perforation, bowel obstruction, gastric outlet obstruction, or intra-abdominal abscess within six months of study enrollment.

• History of GI surgery within the past 28 days. If >28 days since GI surgery, must have confirmation of complete healing before initiating treatment with study drug.

• Other disorders associated with a high risk of fistula formation, including PEG tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea or esophagus.

• Other clinically significant disorders such as:

  • Active infection requiring systemic treatment
  • Serious non-healing wound/ulcer/bone fracture
  • History of organ transplant
  • Concurrent uncompensated hypothyroidism or thyroid dysfunction
  • History of major surgery within 4 weeks or minor surgical procedures within one week before randomization

• The subject has a corrected QT interval calculated by the Fridericia formula > 500ms within 28 days before randomization.

• Severely impaired lung function

• Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past 3 years or any currently active malignancy

• Pregnant women are excluded from this study due to the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with the treatment protocol, breastfeeding should be discontinued if the mother is treated on protocol.

Participants were followed for AEs and SAEs starting from the first dose of study treatment, throughout the study, and through 30 days from the last study treatment. Median treatment duration was 8 cycles for the Carcinoid cohort and 12.5 cycles for the PNET cohort. Patients were followed for AEs during the time on treatment plus 30 days (median of 9.6 months). Participants were followed for All-Cause Mortality for longer (median 89.1 months).

Adverse Event (AE): An adverse event (AE) is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. Abnormal laboratory values or diagnostic test results constitute adverse events only if they are determined to be of clinical significance or require treatment or further diagnostic tests