Testing the Combination of Cabozantinib, Nivolumab, and Ipilimumab (CaboNivoIpi) for Advanced Differentiated Thyroid Cancer

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed papillary thyroidcancer (PTC), follicular thyroid cancer (FTC), or Hurthle cell thyroid cancer (HTC).Follicular variant of PTC or any of the above mixed histology will be allowed, aswell as tall cell, insular, or poorly-differentiated thyroid cancers. Patients withanaplastic thyroid cancers (ATC) or medullary thyroid cancers (MTC) are not eligible

• Patients must have measurable disease as defined by Response Evaluation Criteria inSolid Tumors (RECIST) v1.1

• Patients must have radioactive iodine (RAI)-refractory/resistant disease as definedby one or more of the following criteria:

• One or more measurable lesions that do not demonstrate RAI uptake,

• Progressive disease (PD) (new lesion or progression of previously knownlesions), as defined by RECIST v1.1, within 12 months of prior RAI therapy,

• One or more measurable lesion present after cumulative RAI dose of > 600 mCi,or

• Fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan-positivedisease (SUV >= 5 in tumor lesion)

• The patient's disease must have progressed on one line of VEGFR-targeted therapy (including, but not limited to, sorafenib, sunitinib, vandetanib, pazopanib, orlenvatinib, etc.) as defined by PD per RECIST v1.1 while receiving VEGFR-targetedtherapy. Patients who have received more than one line of prior VEGFR-targetedtherapy will not be eligible

• Prior external beam radiation to extra-osseous disease, systemic cytotoxicchemotherapy or BRAF- or non-VEGFR-targeted therapies will be allowed, provided that > 4 weeks has elapsed since receiving prior treatment. Radiation to bone metastasesis allowed up to 2 weeks prior to initiation of study treatment

• Patients must be >= 18 years of age. Because no dosing or adverse event data arecurrently available on the use of XL184 (cabozantinib), nivolumab, or ipilimumab inpatients <18 years of age, children are excluded from this study, but may beeligible for future pediatric trials.

• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Patients must have recovered to baseline or =< Common Terminology Criteria forAdverse Events (CTCAE) v5.0 grade 1 from toxicities related to any prior treatments,unless adverse event (AE)(s) are clinically nonsignificant and/or stable onsupportive therapy

• Absolute neutrophils >= 1,500/mcL

• Platelets >= 100,000/mcL

• Hemoglobin >= 9 g/dL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); =< 3.0 x ULN forpatients with Gilbert's syndrome

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN

• Alkaline phosphatase =< 3.0 x institutional ULN; =< 5.0 x ULN with documented bonemetastases

• Creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using theCockcroft-Gault formula)

• Serum albumin >= 2.8 g/dL

• Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg

• Serum phosphorus, calcium, magnesium, and potassium within institutional normallimits

• Prothrombin time (PT)/international normalized ratio (INR) and partialthromboplastin time (PTT) test < 1.3 x ULN

• Patients with a history of human immunodeficiency virus (HIV) infection must be onan effective anti-retroviral regimen utilizing agents that do not strongly induce orinhibit cytochrome P450 (CYP) 3A4, and must have an undetectable viral load measuredwithin 6 months prior to study registration

• Patients with evidence of chronic hepatitis B virus (HBV) infection must haveundetectable HBV viral load on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. Patients with HCV infection who are currently on treatment are eligibleif they have an undetectable HCV viral load

• The effects of XL184 (cabozantinib), nivolumab, and ipilimumab on the developinghuman fetus are unknown. For this reason, women of child-bearing potential (WOCBP)and men must agree to use adequate contraception (hormonal or barrier method ofbirth control; abstinence) prior to study entry and for the duration of studyparticipation. WOCBP should use an adequate method to avoid pregnancy for 5 monthsafter the last dose of study therapy. Women of childbearing potential must have anegative serum or urine pregnancy test (minimum sensitivity: 25 IU/L or equivalentunits of human chorionic gonadotropin [hCG]) within 24 hours prior to the start ofstudy therapy. Women must not be breastfeeding. Men who are sexually active withWOCBP must use any contraceptive method with a failure rate of < 1% per year. Menwho receive study therapy and who are sexually active with WOCBP will be instructedto adhere to contraception for a period of 7 months after the last dose of studytherapy. Women who are not of childbearing potential (i.e., who are postmenopausalor surgically sterile) as well as azoospermic men do not require contraception

• WOCBP is defined as any female who has experienced menarche and who has notundergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who isnot postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in awoman over 45 in the absence of other biological or physiological causes. Inaddition, women under the age of 55 must have a documented serum folliclestimulating hormone (FSH) level < 40 mIU/mL

• WOCBP and men who are sexually active with WOCBP will be instructed to adhere tocontraception for a period of 5 and 7 months, respectively, after the last dose ofstudy therapy. These durations have been calculated using the upper limit of thehalf-life for nivolumab (25 days) and are based on the protocol requirement thatWOCBP use contraception for 5 half-lives plus 30 days and men who are sexuallyactive with WOCBP use contraception for 5 half-lives plus 90 days

• Should a woman become pregnant or suspect she is pregnant while she or her partneris participating in this study, she (or the participating partner) must inform thetreating physician immediately

• Patients must be able to swallow tablets

• Patients must be able to understand be willing to sign a written informed consentdocument

• Patients with impaired decision-making capacity (IDMC) will be eligible if they havea legally authorized representative (LAR) or caregiver available to assist them

Exclusion Criteria:

• Patients must not have had prior treatment with XL184 (cabozantinib), anyMET-targeting tyrosine kinase inhibitor (TKI), or any MET-targeting monoclonalantibody (MetMAb), such as onartuzumab

• Patients must not have had prior treatment with an anti-PD-1, anti-PD-L1,anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specificallytargeting T cell co-stimulation or immune checkpoint pathways

• Patients must not have a tumor invading or encasing any major blood vessels, andmust not have evidence of tumor invading the gastrointestinal (GI) tract (esophagus,stomach, small or large bowel, rectum, or anus), or any evidence of endotracheal orendobronchial tumor within 28 days before the first dose of XL184 (cabozantinib)

• Patients must not have a diagnosis of another malignancy within 2 years before thefirst dose of study treatment, except for superficial skin cancers, or localized,low grade tumors deemed cured and not treated with systemic therapy. Adjuvanthormonal therapy for history of prostate or breast cancer is allowed

• Patients must not have received cytotoxic chemotherapy (including investigationalcytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4weeks, or nitrosoureas/ mitomycin C within 6 weeks, before the first dose of studytreatment. Patients may continue on bone-modifying agents (denosumab orbisphosphonates) with caution

• Patients must not have received radiation therapy:

• To the thoracic cavity, abdomen, or pelvis within 4 weeks before the first doseof study treatment;

• To bone metastases within 14 days before the first dose of study treatment;

• To any other sites within 4 weeks before the first dose of study treatment

• Patients must not have clinically relevant, ongoing complications from priorradiation therapy. Palliative (limited-field) radiation therapy is permitted as longas the patient does not have disease progression according to RECIST v 1.1

• Patients must not have received any type of small molecule kinase inhibitor (including investigational kinase inhibitors) within 4 weeks before the first doseof study treatment

• Patients must not have received any other type of investigational agent within 4weeks before the first dose of study treatment

• Patients must not have a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 msec by electrocardiogram (EKG) within 28 days before the first dose ofstudy treatment

• Note: if a single EKG shows a QTcF with an absolute value > 500 msec, twoadditional EKGs at intervals of approximately 3 min must be performed within 30min after the initial EKG, and the average of these three consecutive resultsfor QTcF will be used to determine eligibility

• Patients should not have known, untreated brain metastases or leptomeningealmetastases because of poor prognosis and concerns that progressive neurologicdysfunction could confound the evaluation of neurologic and other adverse events.However, patients will be eligible if metastases have been treated, and there is nomagnetic resonance imaging (MRI) evidence of progression for at least 4 weeks aftertreatment for metastases is complete and within 28 days prior to the first dose ofstudy treatment

• Patients must not require concomitant treatment with oral anticoagulants (e.g.,warfarin, direct thrombin, and factor Xa inhibitors) or platelet inhibitors (e.g.,clopidogrel). The following anticoagulants are allowed:

• Low-dose aspirin for cardioprotection (per local applicable guidelines),

• Low-dose low molecular weight heparins (LMWH),

• Therapeutic doses of LMWH are allowed in patients without known brainmetastases who are on a stable dose of LMWH for at least 6 weeks before thefirst dose of study treatment, and who have had no clinically significanthemorrhagic complications from the anticoagulation regimen or the tumor

• Patients must not require systemic corticosteroids treatment (>= 10 mg/dayprednisone equivalents) or other immunosuppressive medications within 14 days priorto study drug administration. Inhaled or topical steroids and adrenal replacementdoses < 10 mg/day prednisone equivalents are permitted in the absence of activeautoimmune disease. Patients are permitted to use topical, ocular, intra-articular,intranasal, and inhalational corticosteroids (with minimal systemic absorption).Physiologic replacement doses of systemic corticosteroids are permitted, even if >= 10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxisor for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivityreaction caused by contact allergen) is permitted, as is steroid pre-medication forcontrast allergy

• Patients must not have a history of severe hypersensitivity reactions to anymonoclonal antibodies

• Patients must not have a history of allergic reactions attributed to compounds ofsimilar chemical or biologic composition to agents used in study

• Patients must not require concomitant treatment with strong CYP3A4 inducers (e.g.,dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin,phenobarbital, or St. John's wort). Because lists of these agents are constantlychanging, it is important to regularly consult a frequently-updated list. Medicalreference texts such as the Physicians' Desk Reference may also provide thisinformation. As part of the enrollment/informed consent procedures, patients will becounseled on the risk of interactions with other agents, and what to do if newmedications need to be prescribed or if the patient is considering a newover-the-counter medicine or herbal product

• Patients must not have uncontrolled, significant intercurrent or recent illnessincluding, but not limited to, the following conditions:

• Cardiovascular disorders:

• Congestive heart failure New York Heart Association (NYHA) class 3 or 4,unstable angina pectoris, serious cardiac arrhythmias

• Uncontrolled hypertension defined as sustained blood pressure (BP) > 140mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensivetreatment within seven days prior to the first dose of study treatment

• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venousthrombosis [DVT], pulmonary embolism [PE]) within 6 months before firstdose

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

• The patient has evidence of tumor invading the GI tract, active pepticulcer disease, inflammatory bowel disease (e.g., Crohn's disease),diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,acute pancreatitis, acute obstruction of the pancreatic duct or commonbile duct, or gastric outlet obstruction

• Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominalabscess within 6 months before first dose. Complete healing of anintra-abdominal abscess must be confirmed before first dose

• Clinically significant hematuria, hematemesis, or hemoptysis or other historyof significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks beforefirst dose

• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation

• Lesions invading or encasing any major blood vessels

• Other clinically significant disorders that would preclude safe studyparticipation

• Serious non-healing wound/ulcer/bone fracture

• Uncompensated/symptomatic hypothyroidism

• Moderate to severe hepatic impairment (Child-Pugh B or C)

• Patients must not have had major surgery (e.g., GI surgery or removal or biopsy ofbrain metastasis) within 8 weeks before first dose of study treatment. Completewound healing from major surgery must have occurred 1 month before the first dose ofstudy treatment and from minor surgery (e.g., simple excision or tooth extraction)at least 10 days before the first dose. Patients with clinically relevant ongoingcomplications from prior surgery are not eligible

• Pregnant women are excluded from this study because XL184 (cabozantinib) has thepotential for teratogenic or abortifacient effects, and the effects of nivolumab andipilimumab on the developing fetus are not well known. Because there is an unknownbut potential risk for AEs in nursing infants secondary to treatment of the mother,breastfeeding must be discontinued if the mother is treated with XL184 (cabozantinib), nivolumab, or ipilimumab

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding high dose systemic corticosteroids, should be excluded. These include butare not limited to: immune-related neurologic disease, such as multiple sclerosis,autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, or myastheniagravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE),connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's,ulcerative colitis, or autoimmune hepatitis. Patients with a history of toxicepidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndromeshould be excluded because of the risk of recurrence or exacerbation of disease.Patients with vitiligo, type I diabetes mellitus (DM), or endocrine deficiencies (e.g., thyroiditis) managed with replacement hormones, including physiologiccorticosteroids, are eligible

• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome andpsoriasis controlled with topical medication, and patients with positive serology, (e.g., antinuclear antibodies [ANA] or anti-thyroid antibodies) should be evaluatedfor the presence of target organ involvement and potential need for systemictreatment but should otherwise be eligible