Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer
Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer
This phase II trial studies how well encorafenib and binimetinib given with or without
 nivolumab works in treating patients with BRAF V600 mutation positive thyroid cancer that has
 spread to other places in the body (metastatic) and does not respond to radioiodine treatment
 (refractory). Encorafenib and binimetinib may stop the growth of tumor cells by blocking some
 of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as
 nivolumab, may help the body?s immune system attack the cancer, and may interfere with the
 ability of tumor cells to grow and spread. The trial aims to find out if the combination of
 encorafenib and binimetinib, with and without study nivolumab, is a safe and effective way to
 treat metastatic radioiodine refractory thyroid cancer.
PRIMARY OBJECTIVES:

 I. To assess the overall rate of response among study participants treated with the
 combination of encorafenib and binimetinib, with or without nivolumab.

 SECONDARY OBJECTIVES:

 I. To assess the progression-free survival (PFS) among study participants treated with the
 combination of encorafenib and binimetinib with or without nivolumab.

 II. To assess the overall survival (OS) among study participants treated with the combination
 of encorafenib and binimetinib with or without nivolumab.

 III. To evaluate the duration of response (DOR). IV. To evaluate the safety and tolerability
 of study participants treated with the combination of encorafenib and binimetinib with or
 without nivolumab.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM I: Patients receive encorafenib orally (PO) once daily (QD) and binimetinib PO twice
 daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression
 or unacceptable toxicity.

 ARM II: Patients receive encorafenib PO QD and binimetinib PO BID as in arm I. Patients also
 receive nivolumab intravenously (IV) over 30 minutes on day 1. Cycles with nivolumab repeat
 every 28 days for up to 2 years in the absence of disease progression or unacceptable
 toxicity.

 After completion of study treatment patients are followed up at 30 days and then every 6
 months for up to 12 months.
Inclusion Criteria:

 -  Ability to understand and the willingness to sign a written informed consent document

 -  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 body
 scan, or a post-treatment RAI scan in measurable lesions

 -  Radiographic progression of disease within 12 months of the last course of
 RAI treatment, or

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

 -  Measurable disease meeting the following criteria and confirmed by radiography review:

 -  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 is serially
 measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
 using computed tomography/magnetic resonance imaging (CT/MRI). If there is only 1
 target lesion and it is a non-lymph node, it should have a longest diameter of >=
 1.5 cm

 -  Lesions that have had external beam radiotherapy or locoregional therapies such
 as radiofrequency (RF) ablation must show evidence of progressive disease based
 on 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 x upper
 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 allowed if
 their indirect bilirubin level is =< 1.5 x ULN (i.e., participants with suspected
 or known diagnosis of Gilbert?s syndrome)

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

 -  Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated
 acquisition (MUGA) scan or echocardiogram

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

 -  Participants of childbearing potential must have a negative serum or urine pregnancy
 test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
 [HCG]) within 72 hours prior to the start of assigned study intervention

 -  Participants of child-bearing potential agree to use highly effective methods of
 contraception starting with the first dose of assigned study intervention through 6
 months 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 hormonal
 treatments

 -  Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
 post-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 starting with
 the first dose of study therapy through 6 months after the last dose of study therapy

 Exclusion Criteria:

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

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

 -  Participants with active, known, or suspected autoimmune disease. Participants with
 type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
 requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or
 alopecia) 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 study
 participation.

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

 -  Participants with a condition requiring systemic treatment with either corticosteroids
 (>= 10 mg daily prednisone or equivalent) or other immunosuppressive medications
 within 14 days of study drug administration. Inhaled or topical steroids are 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 factors to
 RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
 hypercoagulability syndromes); history of retinal degenerative disease

 -  Previous or concurrent malignancy within 3 years of study entry, with the following
 exceptions:

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

 -  Other solid tumors treated curatively in which the expected rate of recurrence
 within 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, unstable
 angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6
 months prior to screening

 -  Symptomatic congestive heart failure (i.e. grade 2 or higher), history or current
 evidence of clinically significant cardiac arrhythmia and/or conduction
 abnormality < 6 months prior to screening. Exceptions include
 asymptomatic/well-controlled atrial fibrillation/flutter or paroxysmal
 supraventricular tachycardia

 -  Uncontrolled hypertension defined as persistent elevation of systolic blood
 pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg, despite medical
 therapy

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

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

 -  Note: Individuals with thromboembolic events related to indwelling catheters or
 other 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 the
 absorption of encorafenib or binimetinib (e.g., uncontrolled vomiting or malabsorption
 syndrome)

 -  Concurrent neuromuscular disorder that is associated with the potential of elevated
 creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic
 lateral 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 the start
 of study treatment

 -  Any other condition that would, in the investigator?s judgment, contraindicate an
 individual?s participation in the clinical study due to safety concerns or compliance
 with clinical study procedures, e.g., infection/inflammation, intestinal obstruction,
 unable to swallow medication, social/ psychological issues, etc

 -  Participants who have undergone major surgery (e.g., intracranial, intrathoracic, or
 intra-abdominal surgery) =< 3 weeks prior to starting study drug or who have not
 recovered 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 the
 participant?s ability to understand the patient information, give informed consent,
 comply with the study protocol or complete the study