Cabozantinib and Nivolumab for Carcinoid Tumors

Inclusion Criteria: * Patients with locally unresectable or metastatic well-differentiated neuroendocrine tumor of non-pancreatic (ie, carcinoid) origin * Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease. * Patients must have evidence of radiographic disease progression within the past 12 months. * Patients who have received at least one line of therapy, which can include somatostatin analog therapy. Participants should be adequately recovered from acute toxicities of prior treatment. * Prior somatostatin analog therapy is allowed. Continuation of somatostatin analog therapy is allowed provided that the dose has been stable for 2 months. * Prior chemotherapy: Participants must have been off treatment with cytotoxic chemotherapy for at least 14 days prior to registration. * Prior biologic therapy: Patients must have discontinued all biologic therapy at least 28 days prior to registration. Duration may be shorted to 14 days for agents with short half-lives. * Prior radiolabeled somatostatin analog therapy: Participants must have completed radiolabeled somatostatin analog therapy at least 6 weeks prior to registration. * Prior hepatic artery embolization or ablative therapies is allowed if measurable disease remains outside the treated area or there is documented disease progression in a treated site. Prior liver-directed or ablative treatment must be completed at least 28 days prior to registration. * Prior radiation therapy: Radiation therapy must be completed per the following timelines * i) Radiotherapy to the thoracic cavity or abdomen within 4 weeks prior to registration. * ii) Radiotherapy to bone lesions within 2 weeks prior to registration. * iii) Radiotherapy to any other site within 4 weeks prior to registration. * NOTE: In all cases, there must be complete recovery and no ongoing complications from prior radiotherapy. * Age ≥ 18 years. * ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A) * Participants must have normal organ and marrow function as defined below: * absolute neutrophil count ≥1,500/mcL * platelets ≥100,000/mcL * total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or 2.0 x ULN in patients with documented Gilbert's Syndrome) * AST (SGOT)/ALT (SGPT) ≤2.5 × ULN or ≤ 3 × ULN for participants with documented liver metastases * creatinine \<1.5 × ULN Or creatinine clearance ≥40 mL/min (using Cockcroft-Gault formula) for participants with creatinine levels above institutional normal * Urine protein/creatinine ratio (UPCR) ≤ 1 * PT/INR or partial thromboplastin time (PTT) test \< 1.3 the laboratory ULN within 7 days before the first dose of study treatment. * Negative urine pregnancy test for women of childbearing potential. * Participant must be able to swallow pills. * The participant is capable of understanding and complying with the protocol and has signed the informed consent document. Exclusion Criteria: * Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. * Participants who are receiving any other investigational agents. * Participants who have received a prior cabozantinib. * Participants who have received prior therapy with an anti-PD-1, anti-PD-L1, anti- PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including nivolumab, pembrolizumab, ipilimumab, and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) * Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * The participant has tumor in contact with, invading, or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib or nivolumab. * Participants receiving any strong inhibitors or inducers of CYP3A4 within 14 days prior to registration are ineligible. Chronic treatment with strong inhibitors or inducers of CYP3A4 is not allowed. * Cardiovascular disorders including: * Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening; * Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic or \> 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment; * Any history of congenital long QT syndrome; * QTcF interval \>500 msec * Any of the following within 6 months before the first dose of study treatment: * unstable angina pectoris; * clinically-significant cardiac arrhythmias; * stroke (including transient ischemic attack (TIA), or other ischemic event); * myocardial infarction; * GI disorders particularly those associated with a high risk of perforation or fistula formation including: * Tumors invading the GI tract, active peptic ulcer disease, active inflammatory bowel disease (eg, Crohn's disease), active diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction * Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before screening * Thromboembolic events within 6 months of registration. * Note: Low dose aspirin ≤ 81 mg/day is allowed. Anticoagulation with therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for at least 6 weeks prior to registration. Treatment with warfarin is not allowed. * The subject has experienced any significant bleeding episodes, including: * Clinically significant gastrointestinal bleeding within 6 months before the first dose of study treatment * Clinically significant hemoptysis (\> 0.5 teaspoon) within 3 months of the first dose of study treatment * Any other signs indicative of pulmonary hemorrhage within 3 months before the start of study treatment * Individuals with a history of different malignancy are ineligible except for the following circumstances: Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years or are deemed by the investigator to be at low risk for recurrence of that malignancy. * Participant has an active infection requiring IV antibiotics * Any active, known, or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (e.g. celiac disease) are permitted to enroll. * Patient has a medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication. Adrenal replacement steroid disease are permitted in the absence of autoimmune disease. * The participant is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA. HIV-positive participants with non-detectable viral loads on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cabozantinib and nivolumab. * The participant has received a live vaccine within 28 days prior to the first dose of trial treatment and while participating in the trial. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The use of the inactivated seasonal influenza vaccine (Fluzone®) is allowed. * Pregnant or lactating females are excluded from this study because cabozantinib and nivolumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib and nivolumab, breastfeeding should be discontinued if the mother is treated with cabozantinib and nivolumab. These potential risks may also apply to other agents used in this study. * Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and following treatment. Women of childbearing potential receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of nivolumab. Contraception must be used for 4 months after last dose of cabozantinib.