Binimetinib and Nivolumab for the Treatment of Locally Advanced Unresectable or Metastatic BRAF V600 Wildtype Melanoma

Inclusion Criteria:

• Males or females age >= 18 years

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

• Histologically confirmed locally advanced/unresectable or metastatic cutaneousmelanoma

• Measurable disease per RECIST version (v.) 1.1 criteria using imaging scans, ORperipheral lesions that can be adequately documented with a picture and a ruler evenif they do not meet RECIST criteria

• Patient must have failed prior alphaPD-1 or alphaPD-1 + alphaCTLA-4 therapy in themetastatic setting

• V600BRAF wildtype tumor status confirmed by Clinical Laboratory Improvement Act (CLIA) approved lab

• Hemoglobin >= 8.0 g/dL

• Whole blood cell count (WBC) >= 2,000/mm^3

• Absolute neutrophil count >= 1,500/mm^3

• Platelet count >= 75,000/mm^3

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 xinstitutional upper limit of normal (ULN), (=< 5.0 x ULN in those with hepaticmetastases)

• Bilirubin =< 1.5 x ULN; for subjects with documented/suspected Gilbert's disease,bilirubin =< 3 x ULN

• Albumin >= 2.5 g/dl

• Serum creatinine =< 2.0 x upper limit of normal (ULN)

• Left ventricular ejection fraction (LVEF) >= 50% assessed by echocardiogram (ECHO)or multiple-gated acquisition (MUGA) scan completed =< 180 days (6 months) beforeinitiation of protocol treatment

• Patients must be willing to submit blood and tissue specimens for translationalmedicine studies

• Patients must have a site of disease amenable to biopsy and be a candidate forbiopsy

• Women of childbearing potential (WOCBP) must have a negative serum or urinepregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionicgonadotropin [HCG]) at screening and within 24 hours prior to the start of studydrug

• Women of childbearing potential (WOCBP) must be willing to use either two adequatebarrier methods or a barrier method plus a hormonal method of contraception toprevent pregnancy, or to abstain from heterosexual activity (complete abstinence)throughout the study, starting with visit 1 through 5 months after the last dose ofstudy therapy. Approved contraceptive methods include, for example, intrauterinedevice, diaphragm with spermicide, cervical cap with spermicide, male condoms,female condoms with spermicide, or oral contraceptives. Spermicides alone are not anacceptable method of contraception. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately

• Male patients must agree to use an adequate method of contraception, or to abstainfrom heterosexual activity (complete abstinence) starting with the first dose ofstudy drug through 5 months after the last dose of study therapy

Exclusion Criteria:

• Contraindications to tumor biopsy (coagulopathy, known history of keloid formation,etc.)

• Women who are pregnant or breastfeeding

• Prior therapy with a MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib)

• Known hypersensitivity or contraindication to any component of binimetinib or itsexcipients

• Inability to swallow and retain study drug

• Patients who have received prior lines of systemic therapy in theadvanced/metastatic setting (not including, neoadjuvant, adjuvant, or maintenancetherapy)

• Received anticancer therapy including chemotherapy, immunotherapy, or antineoplasticbiologic therapy (e.g., erlotinib, cetuximab, bevacizumab etc.), within 14 daysprior to start of study treatment or exposure to any investigational drug within 7days prior to screening visit or for which 5 half-lives have not elapsed

• Participants who have undergone major surgery (e.g., in-patient procedures) =< 6weeks prior to start of study treatment or who have not recovered from side effectsof such procedure

• Participants who have had radiotherapy =< 14 days prior to start of study treatmentor who have not recovered from side effects of such procedure. Note: Palliativeradiation therapy must be complete 7 days prior to the first dose of study treatment

• Participants who have not recovered to =< grade 1 from toxic effects of priortherapy before starting study treatment

• Note: Stable chronic conditions (=< grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies)are exceptions and may enroll

• Uncontrolled or symptomatic brain metastases or leptomeningeal carcinomatosis thatare not stable, require steroids, are potentially life-threatening or have requiredradiation within 28 days prior to starting study drug. Note: Patients withpreviously treated brain metastases may participate provided they are stable (e.g.,without evidence of progression by radiographic imaging for at least 28 days beforethe first dose of study treatment and neurologic symptoms have returned tobaseline), and have no evidence of new or enlarging brain metastases or centralnervous system (CNS) edema, and does not require steroids at least 7 days before thefirst dose of study treatment

• Subjects with active, known, or suspected autoimmune disease. Subjects 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 are permittedto enroll

• Uncontrolled or significant cardiovascular disease including, but not limited to,any of the following:

• Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent

• Uncontrolled angina within the 3 months prior to consent

• Any history of clinically significant arrhythmias (such as ventriculartachycardia, ventricular fibrillation, torsades de pointes, or poorlycontrolled atrial fibrillation)

• Corrected QT (QTc) prolongation > 480 msec

• History of other clinically significant cardiovascular disease (i.e.,cardiomyopathy, congestive heart failure with New York Heart Association [NYHA]functional classification III-IV, pericarditis, significant pericardialeffusion, significant coronary stent occlusion, poorly controlled deep venousthrombosis, etc)

• Cardiovascular disease-related requirement for daily supplemental oxygen

• History of two or more myocardial infarctions OR two or more coronaryrevascularization procedures

• Subjects with history of myocarditis, regardless of etiology

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

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

• Note: Patients with thromboembolic events related to indwelling cathetersor other procedures may be enrolled

• A confirmed history of encephalitis, meningitis, or uncontrolled seizures in theyear prior to informed consent

• Participants with a condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent)

• Subjects receiving any other investigational or standard antineoplastic agents

• Patients with severe grade 3-4 toxicities due to anti-PD-1 monotherapy during firstline. Toxicities due to combination PD-1/CTLA-4 blockade will not be exclusionary

• Inability to give informed consent

• History of malignancies except cured basal cell carcinoma, cutaneous squamous cellcarcinoma, melanoma in situ, superficial bladder cancer or carcinoma in situ of thecervix; for other malignancies, must be documented to be free of cancer for >= 2years. All other cases can be considered on a case by case basis at the discretionof the principal investigator

• Any condition that might interfere with the subject's participation in the study,safety, or in the evaluation of the study results

• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventionalstudy

• Active or prior documented inflammatory bowel disease

• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis thatrequired steroids or has current ILD/pneumonitis or where suspected ILD/pneumonitiscannot be ruled out by imaging at screening

• Impairment of gastrointestinal function or disease which may significantly alter theabsorption of study drug (e.g., active ulcerative disease, uncontrolled vomiting ordiarrhea, malabsorption syndrome, small bowel resection with decreased intestinalabsorption), or recent (=< 3 months) history of a partial or complete bowelobstruction, or other conditions that will interfere significantly with theabsorption of oral drugs

• Concurrent neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateralsclerosis, spinal muscular atrophy)

• History or current evidence of retinal venous occlusion (RVO) or current riskfactors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history ofhyperviscosity or hypercoagulability syndromes); history of retinal degenerativedisease

• Prisoners or subjects who are involuntarily incarcerated

• Note: under certain specific circumstances a person who has been imprisoned maybe included or permitted to continue as a subject

• Subjects who are compulsorily detained for treatment of either a psychiatric orphysical (e.g., infectious disease) illness