Cabozantinib and Nivolumab for Carcinoid Tumors

Inclusion Criteria:

• Patients with locally unresectable or metastatic well-differentiated neuroendocrinetumor of non-pancreatic (ie, carcinoid) origin

• Participants must have measurable disease, defined as at least one lesion that canbe accurately measured in at least one dimension (longest diameter to be recordedfor non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventionaltechniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. SeeSection 11 for the evaluation of measurable disease.

• Patients must have evidence of radiographic disease progression within the past 12months.

• Patients who have received at least one line of therapy, which can includesomatostatin analog therapy. Participants should be adequately recovered from acutetoxicities of prior treatment.

• Prior somatostatin analog therapy is allowed. Continuation of somatostatinanalog therapy is allowed provided that the dose has been stable for 2 months.

• Prior chemotherapy: Participants must have been off treatment with cytotoxicchemotherapy for at least 14 days prior to registration.

• Prior biologic therapy: Patients must have discontinued all biologic therapy atleast 28 days prior to registration. Duration may be shorted to 14 days foragents with short half-lives.

• Prior radiolabeled somatostatin analog therapy: Participants must havecompleted radiolabeled somatostatin analog therapy at least 6 weeks prior toregistration.

• Prior hepatic artery embolization or ablative therapies is allowed ifmeasurable disease remains outside the treated area or there is documenteddisease progression in a treated site. Prior liver-directed or ablativetreatment must be completed at least 28 days prior to registration.

• Prior radiation therapy: Radiation therapy must be completed per the followingtimelines

• i) Radiotherapy to the thoracic cavity or abdomen within 4 weeks prior toregistration.

• 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 ongoingcomplications 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 ULNin patients with documented Gilbert's Syndrome)

• AST (SGOT)/ALT (SGPT) ≤2.5 × ULN or ≤ 3 × ULN for participants with documentedliver metastases

• creatinine <1.5 × ULN Or creatinine clearance ≥40 mL/min (using Cockcroft-Gaultformula) 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 ULNwithin 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 hassigned the informed consent document.

Exclusion Criteria:

• Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeksbefore first dose of study treatment. Complete wound healing from major surgery musthave occurred 1 month before first dose and from minor surgery (eg, simple excision,tooth extraction) at least 10 days before first dose. Subjects with clinicallyrelevant 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 ordrug specifically targeting T-cell co-stimulation or checkpoint pathways)

• Participants with known brain metastases should be excluded from this clinical trialbecause of their poor prognosis and because they often develop progressiveneurologic dysfunction that would confound the evaluation of neurologic and otheradverse events.

• The participant has tumor in contact with, invading, or encasing major blood vesselsor radiographic evidence of significant cavitary pulmonary lesions.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to cabozantinib or nivolumab.

• Participants receiving any strong inhibitors or inducers of CYP3A4 within 14 daysprior to registration are ineligible. Chronic treatment with strong inhibitors orinducers 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 antihypertensivetreatment 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 ischemicevent);

• myocardial infarction;

• GI disorders particularly those associated with a high risk of perforation orfistula formation including:

• Tumors invading the GI tract, active peptic ulcer disease, active inflammatorybowel disease (eg, Crohn's disease), active diverticulitis, cholecystitis,symptomatic cholangitis or appendicitis, acute pancreatitis or acuteobstruction of the pancreatic duct or common bile duct, or gastric outletobstruction

• Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscesswithin 6 months before screening

• Thromboembolic events within 6 months of registration.

• Note: Low dose aspirin ≤ 81 mg/day is allowed. Anticoagulation with therapeuticdoses of LMWH is allowed in patients who are on a stable dose of LMWH for atleast 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 thefirst dose of study treatment

• Clinically significant hemoptysis (> 0.5 teaspoon) within 3 months of the firstdose of study treatment

• Any other signs indicative of pulmonary hemorrhage within 3 months before thestart of study treatment

• Individuals with a history of different malignancy are ineligible except forthe following circumstances: Individuals with a history of other malignanciesare eligible if they have been disease-free for at least 3 years or are deemedby 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 Idiabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, orconditions not expected to recur in the absence of an external trigger (e.g. celiacdisease) are permitted to enroll.

• Patient has a medical condition that requires chronic systemic steroid therapy or onany other form of immunosuppressive medication. Adrenal replacement steroid diseaseare 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 oncombination antiretroviral therapy are ineligible because of the potential forpharmacokinetic interactions with cabozantinib and nivolumab.

• The participant has received a live vaccine within 28 days prior to the first doseof trial treatment and while participating in the trial. Examples of live vaccinesinclude, but are not limited to, the following: measles, mumps, rubella,varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The use of theinactivated seasonal influenza vaccine (Fluzone®) is allowed.

• Pregnant or lactating females are excluded from this study because cabozantinib andnivolumab are agents with the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with cabozantinib and nivolumab, breastfeedingshould 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 medicallyaccepted methods of contraception (eg, barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfollowing treatment. Women of childbearing potential receiving nivolumab will beinstructed to adhere to contraception for a period of 5 months after the last doseof nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will beinstructed to adhere to contraception for a period of 7 months after the last doseof nivolumab. Contraception must be used for 4 months after last dose ofcabozantinib.