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 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 signific