Decitabine, Vemurafenib, and Cobimetinib in Treating Patients with Stage IV Melanoma Who Have a BRAF Mutation

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• Neutrophil count of > 1500/mm^3
• Platelet count of > 100,000/mm^3
• Hemoglobin >= 9 g/dL
• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) or =< 5.0 x ULN if the transaminase elevation is due to disease involvement
• Serum bilirubin =< 1.5 x ULN
• Serum creatinine =< 1.5 x ULN or estimated creatinine clearance >= 50 ml/min by Cockcroft-Gault equation
• Total serum calcium (corrected for serum albumin) >= 8.5 mg/dL or ionized calcium >= 3.8 mg/dL
• Serum potassium >= lower limit of normal (LLN)
• Serum sodium >= LLN
• Serum albumin >= 3 g/dl
• Baseline multi gated acquisition scan (MUGA) or echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) >= the lower limit of the institutional normal
• Thyroid-stimulating hormone (TSH) and free thyroxine (T4) within normal limits (patients may be on thyroid hormone replacement)
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of study treatment and must be willing to use two methods of contraception one of them being a barrier method during the study and for 3 months after last study drug administration
• Any patient with metastatic melanoma from any site whose tumor is BRAF V600E mutation (V600EBRAF) positive, regardless of prior treatment will be eligible; these include untreated patients or those treated with chemotherapy, biochemotherapy or a prior BRAF-inhibitor
• Patients who have been treated with vemurafenib will be allowed in this study
• Must not have taken a hypomethylating agent
• Patients must have had disease progression on or following their most recent treatment regimen or on presentation for the first time with metastatic disease
• Patients with central nervous system (CNS) disease are eligible for treatment only after their CNS disease has been directly addressed with radiation therapy

Exclusion Criteria

• Prior decitabine for the treatment of cancer
• Screening electrocardiogram (ECG) with a corrected QT interval (QTc) > 460 msec confirmed by central laboratory prior to enrollment to the study
• Patients with congenital long QT syndrome
• History of sustained ventricular tachycardia
• Any history of ventricular fibrillation or torsades de pointes
• Bradycardia defined as heart rate < 50 beats per minute; patients with a pacemaker and heart rate >= 50 beats per minute are eligible
• Patients with a myocardial infarction or unstable angina within 6 months of study entry
• Congestive heart failure (New York Heart Association class III or IV)
• Right bundle branch block and left anterior hemiblock (bifascicular block)
• Uncontrolled hypertension
• Concomitant use of drugs with a risk of causing torsades de pointes
• Concomitant use of drugs that are cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4), cytochrome P, family 1, subfamily A, polypeptide 2 (CYP1A2), or cytochrome P, family 2, subfamily D, polypeptide 6 (CYP2D6) substrates
• Patients with unresolved diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade 1
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral vemurafenib
• Other concurrent severe and/or uncontrolled medical conditions
• Patients who have received prior therapies will be allowed to enroll after a wash-out period as follows assuming they have recovered from the side effects of such therapies: * Chemotherapy – 3 week wash-out period * Oral agents – 2 week wash-out period (except vemurafenib, which will require no wash-out period) * Investigational agents – 3 week wash-out period * Immunotherapy – 4 week wash-out period * Palliative radiation therapy to bone/brain – 2 week wash-out period * Major radiation or surgical procedure – 3 week wash-out period
• Concomitant use of any anti-cancer therapy or radiation therapy
• Patients who have no measurable disease
• Women who are pregnant or breast feeding or WOCBP not willing to use a double barrier method of contraception during the study and 3 months after the end of treatment; one of these methods of contraception must be a barrier method; WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months); WOCBP must have a negative serum pregnancy test within 7 days of the first administration of decitabine
• Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment; one of these methods must be a condom
• Patients with a history of another primary malignancy within 5 years other than curatively treated carcinoma in situ (CIS) of the cervix, or basal or squamous cell carcinoma of the skin
• Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
• Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent