Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consentdocument

• Histologically (or cytologically) confirmed diagnosis of metastatic, radioiodine (RAI) refractory, BRAFV600E/M mutant differentiated thyroid cancer (DTC)

• Note: RAI refractoriness is defined as:

• The absence of uptake of RAI on either a low-dose diagnostic whole bodyscan, or a post-treatment RAI scan in measurable lesions

• Radiographic progression of disease within 12 months of the last course ofRAI treatment, or

• Having a cumulative lifetime administered dose of > 600 mCi of RAI

• Measurable disease meeting the following criteria and confirmed by radiographyreview:

• At least 1 lesion of >= 1.0 cm in the longest diameter for a non-lymph node or > 1.5 cm in the short-axis diameter for a lymph node metastasis that isserially measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 using computed tomography/magnetic resonance imaging (CT/MRI). Ifthere is only 1 target lesion and it is a non-lymph node, it should have alongest diameter of >= 1.5 cm

• Lesions that have had external beam radiotherapy or locoregional therapies suchas radiofrequency (RF) ablation must show evidence of progressive disease basedon RECIST 1.1 to be deemed a target lesion.

• Eastern Cooperative Oncology Group (ECOG) performance status =< 1

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

• Hemoglobin (Hgb) >= 9 g/dL

• Platelets (PLT) >= 75 x 10^9/L

• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 2.5 xupper limit of normal (ULN); participants with liver metastases =< 5 x ULN

• Total bilirubin =< 1.5 x ULN

• Note: Individuals who have a total bilirubin level > 1.5 x ULN will be allowedif their indirect bilirubin level is =< 1.5 x ULN (i.e., participants withsuspected or known diagnosis of Gilbert?s syndrome)

• Serum creatinine =< 1.5 x ULN, or calculated creatinine clearance (determined as perCockcroft-Gault) >= 40 mL/min at screening

• Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigatedacquisition (MUGA) scan or echocardiogram

• Triplicate average baseline corrected QT (QTc) interval =< 480 ms

• Participants of childbearing potential must have a negative serum or urine pregnancytest (minimum sensitivity 25 IU/L or equivalent units of human chorionicgonadotropin [HCG]) within 72 hours prior to the start of assigned studyintervention

• Participants of child-bearing potential agree to use highly effective methods ofcontraception starting with the first dose of assigned study intervention through 6months after the last dose of study therapy

• Participants of childbearing potential are those who are not proven postmenopausal.Postmenopausal is defined as any of the following:

• Amenorrheic for 1 year or more following cessation of exogenous hormonaltreatments

• Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in thepost-menopausal range for women under 50

• Radiation-induced oophorectomy with last menses > 1 year ago

• Chemotherapy-induced menopause with > 1 year interval since last menses

• Surgical sterilization (bilateral oophorectomy or hysterectomy)

• Male participants must agree to use an adequate method of contraception startingwith the first dose of study therapy through 6 months after the last dose of studytherapy

Exclusion Criteria:

• Currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigationalagent/device within 4 weeks of first dose of study intervention

• Note: Individuals in the follow-up phase of a prior investigational study mayparticipate as long as it has been 4 weeks since last dose of the previousinvestigational agent of device

• Participants with active, known, or suspected autoimmune disease. Participants withtype I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis onlyrequiring hormone replacement, skin disorders (such as vitiligo, psoriasis, oralopecia) not requiring systemic treatment are permitted to enroll

• Prior treatment with selective/potent BRAF/MEK inhibitors including vemurafenib,dabrafenib, encorafenib, selumetinib, trametinib, cobimetinib, binimetinib.

• Note: Prior therapy with oral multikinase inhibitors (e.g., lenvatinib,sorafenib, cabozantinib, pazopanib, sunitinib, etc.) remain eligible for studyparticipation.

• Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4antibody (including ipilimumab or any other antibody or drug specifically targetingT cell co-stimulation or immune checkpoint pathways)

• Participants with a condition requiring systemic treatment with eithercorticosteroids (>= 10 mg daily prednisone or equivalent) or other immunosuppressivemedications within 14 days of study drug administration. Inhaled or topical steroidsare permitted in the absence of active autoimmune disease

• History of allergy or hypersensitivity to any monoclonal antibody

• History or current evidence of retinal vein occlusion (RVO) or current risk factorsto RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosityor hypercoagulability syndromes); history of retinal degenerative disease

• Previous or concurrent malignancy within 3 years of study entry, with the followingexceptions:

• Adequately treated basal or squamous cell skin cancer, superficial bladdercancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, orother noninvasive or indolent malignancy; OR

• Other solid tumors treated curatively in which the expected rate of recurrencewithin 5 years is < 5%

• Impaired cardiovascular function or clinically significant cardiovascular diseases,including any of the following:

• History of acute coronary syndromes (including myocardial infarction, unstableangina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6months prior to screening

• Symptomatic congestive heart failure (i.e. grade 2 or higher), history orcurrent evidence of clinically significant cardiac arrhythmia and/or conductionabnormality < 6 months prior to screening. Exceptions includeasymptomatic/well-controlled atrial fibrillation/flutter or paroxysmalsupraventricular tachycardia

• Uncontrolled hypertension defined as persistent elevation of systolic bloodpressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg, despite medicaltherapy

• History of thromboembolic or cerebrovascular events =< 12 weeks prior to the firstdose of study treatment. Examples include transient ischemic attacks,cerebrovascular accidents, hemodynamically significant (i.e., massive orsub-massive) deep vein thrombosis or pulmonary emboli

• Note: Individuals with either deep vein thrombosis or pulmonary emboli thatdoes not result in hemodynamic instability are allowed to enroll as long asthey are on a stable dose of anticoagulants for at least 4 weeks

• Note: Individuals with thromboembolic events related to indwelling catheters orother procedures may be enrolled

• Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,and/or active hepatitis C infection

• Known history of acute or chronic pancreatitis

• Impaired gastrointestinal function or disease that may significantly alter theabsorption of encorafenib or binimetinib (e.g., uncontrolled vomiting ormalabsorption syndrome)

• Concurrent neuromuscular disorder that is associated with the potential of elevatedcreatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophiclateral sclerosis, spinal muscular atrophy)

• Current use of a prohibited medication (including herbal medications, supplements,or foods), as described, or use of a prohibited medication =< 1 week prior to thestart of study treatment

• Any other condition that would, in the investigator?s judgment, contraindicate anindividual?s participation in the clinical study due to safety concerns orcompliance with clinical study procedures, e.g., infection/inflammation, intestinalobstruction, unable to swallow medication, social/ psychological issues, etc

• Participants who have undergone major surgery (e.g., intracranial, intrathoracic, orintra-abdominal surgery) =< 3 weeks prior to starting study drug or who have notrecovered from side effects of such procedure

• Participants that are pregnant or nursing (lactating)

• Prisoners or individuals who are involuntarily incarcerated

• Medical, psychiatric, cognitive or other conditions that may compromise theparticipant?s ability to understand the patient information, give informed consent,comply with the study protocol or complete the study