Leflunomide and Vemurafenib in Treating Patients With Melanoma That is Metastatic or Cannot Be Removed By Surgery

Inclusion Criteria

• Participants must have histological or cytological confirmed melanoma that is metastatic or unresectable and clearly progressive
• Melanoma must be documented to contain a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation by a Clinical Laboratory Improvement Amendments (CLIA) approved assay
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
• Patients may not have received more than two prior systemic treatment regimens for distant metastatic disease; the following prior therapy is permitted in either the adjuvant or metastatic disease setting: * No prior therapy * Immunotherapy consisting of interferon, interleukin-2, filgrastim (GM-CSF), ipilimumab, anti-programmed death (PD)1 or other experimental agent * Cytotoxic chemotherapy consisting of dacarbazine, temozolomide, carboplatin +/- paclitaxel
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal, and less liver metastases are present in which case =< 5.0 X institutional upper limit of normal is permitted
• Creatinine below 1.5 X upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2 for subjects with creatinine levels about institutional 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 and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• No prior therapy with a BRAF inhibitor or mitogen-activated protein kinase kinase (MEK) inhibitor or leflunomide
• Participants may not be receiving any other study agents
• Participants with known brain metastases that are symptomatic and require corticosteroids are excluded
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to vemurafenib or leflunomide
• Corrected QT (QTc) interval > 500 msec (Bazett formula or Fridericia formula based on institutional standard)
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study; breastfeeding should be discontinued
• Patients who are human immunodeficiency virus (HIV)-positive are excluded from the study
• Individuals with a history of a different malignancy are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible if they were treated with curative intent, are currently disease-free and have an estimated risk of recurrence less than 10% at the time of study entry. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin