Dabrafenib, Trametinib, and Digoxin in Treating Patients with BRAF V600 Mutant Melanoma That Is Metastatic or Cannot Be Removed by Surgery

Inclusion Criteria

• Histologic diagnosis of unresectable or metastatic BRAF V600 mutant melanoma
• Naive or any number of prior systemic therapeutic regimens for unresectable stage III or stage IV melanoma, except prior BRAF or MEK inhibitor agents; this includes chemotherapy, immunotherapy, biochemotherapy, or investigational treatments; patients may also have received therapies in the adjuvant setting
• Performance status Eastern Cooperative Oncology Group (ECOG) 0-2
• Total bilirubin =< 3 x institutional upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SPGT]) =< 5 X institutional upper limit of normal
• Creatinine =< 3 mg/dL
• Cardiac ejection fraction >= 50%
• Corrected QT using Fridericia's correction formula (QTcF) =< 480 msec
• Prothrombin time (PT)/ international normalized ratio (INR)/activated partial thromboplastin time (aPTT) =< 1.5 x institutional upper limit of normal
• 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 (RECIST) version (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 IL2, interferon, ipilimumab, anti-PD-1 or anti-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 >= 2 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, uncontrolled thyroid disease, or psychiatric illness/social situations that would limit compliance with study requirements; acute coronary syndrome within 24 weeks; note atrial fibrillation controlled > 30 days is not an exclusion
• History of predisposition to retinal vein occlusion or central serous retinopathy
• Prior BRAF or MEK inhibitor therapy
• Wolff-Parkinson White syndrome 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
• Patients requiring concomitant medications that are not able to be switched to a reasonable alternative