Trametinib and Digoxin in Treating Patients with Melanoma That Is Metastatic or Cannot Be Removed by Surgery

Inclusion Criteria

• Histologic diagnosis of unresectable or metastatic melanoma; for unknown primary disease, diagnosis of metastatic disease by cytology fine-needle aspiration (FNA) is not acceptable; BRAF wild-type confirmed, and NRAS mutation assessed
• Failure, ineligible or intolerant of approved therapies; any number of prior systemic therapeutic regimens for unresectable stage III or stage IV melanoma; this includes chemotherapy, immunotherapy, pathway inhibitors, biochemotherapy, or investigational treatments; patients may also have received therapies in the adjuvant setting
• Performance status Eastern Cooperative Oncology Group (ECOG) 0-1
• Leukocytes >= 2,000/mcL
• Absolute neutrophil count >= 1,200/mcL
• Hemoglobin >= 9 g/dL
• Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
• Platelets >= 75,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Creatinine =< 2.0 mg/dL
• Creatinine clearance >= 30 mL/min
• Cardiac ejection fraction >= 50%
• Corrected QT interval (QTc) < 480 msec
• Albumin >= 2.5 g/dL
• Potassium 3.4 – 5.0 mmol/L
• Magnesium 1.6 – 2.6 mg/dL
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; a female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• All sites of disease must be evaluated within 4 weeks prior to beginning therapy; patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1)
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

• Subjects who have had chemotherapy or radiotherapy or any systemic therapy for melanoma within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier; no concomitant therapy is allowed including interleukin-2 (IL2), interferon, ipilimumab, anti-programmed cell death 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) antibody, cytotoxic chemotherapy, immunosuppressive agents, or other investigational therapies
• Active infection with hepatitis B or C or human immunodeficiency virus (HIV)
• Subjects with active central nervous system (CNS) disease are excluded; patient with brain metastases previously treated with surgery or radiation therapy and with confirmed stable disease (SD) for >= 3 weeks are allowed
• Patients are excluded if they have a history of any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix
• Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (>= class II based on New York Heart Association [NYHA]), unstable angina pectoris, clinically significant and uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; cardiac symptoms or events within 24 weeks; note atrial fibrillation controlled > 30 days is not an exclusion
• History of predisposition to retinal vein occlusion or central serous retinopathy
• Inability to assess BRAF or NRAS mutation status; hypersensitivity to digoxin
• Wolff-Parkinson White syndrome or first/second/third degree atrioventricular (AV) block or sinus node dysfunction or the presence of an intra-cardiac defibrillator
• Known cardiac metastases
• History of interstitial lung disease or unresolved pneumonitis
• Immediate or delayed hypersensitivity to digoxin or trametinib
• Treatment refractory hypertension systolic blood pressure (SBP) > 140 mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg