This is a multicenter phase II clinical study of trametinib in combination with GSK2141795 in patients with BRAF wild-type mutation melanoma. All patients will receive continuous dosing of trametinib (2 mg) in combination with GSK2141795 (25 mg) oral daily until progression of disease, withdrawal of consent, or the development of intolerable treatment associated toxicity. Imaging (CT or MRI) will be performed within 7 days prior to day 1 of Odd Cycles, starting with Cycle 3.

Patients may continue treatment with trametinib in combination with GSK2141795 on trial until disease progression or the development of unacceptable toxicity that does not improve with maximal supportive care or dose reduction per protocol.

Treatment-associated adverse events will be assessed based on clinical and laboratory findings using the Common Toxicity Criteria for Adverse Events, version 4.0. Adverse event (AE) assessments will be performed every week through cycle 3 day 1, and on day 1 for every cycle thereafter. AEs and Serious adverse events (SAE)s will be monitored by UCSF's Data Safety Monitoring Committee.

Safety assessments will include medical history, physical examination, Complete Blood Count (CBC) with differential, chemistries panel, thyroid function and pregnancy tests, ECGs, and ophthalmology evaluations. Screening assessments will also include a transthoracic echocardiogram or multiple-gated acquisition (MUGA) scan, and brain imaging.

It is estimated that 48 patients will complete the study.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Histologically or cytologically confirmed Malignant Melanoma.

3. Unresectable Stage III or Stage IV disease.

4. Measureable disease by RECIST 1.1

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

6. Resolution of all acute toxic effects of prior radiotherapy, chemotherapy or surgical procedures to NCI CTCAE Version 4.0 grade ≤1. At least 2 weeks must have elapsed since the end of prior systemic treatment, radiotherapy, or major surgical procedure.

7. Evidence of tumor DNA showing either NRAS mutation or NRAS Wild-Type (WT)/BRAF WT. BRAF genotype must be determined by a CLIA-approved assay. NRAS genotyping may be determined by Sanger sequencing, melting point polymerase chain reaction (PCR) assay, Sequenome, or NextGen sequencing.

8. Adequate Bone Marrow and Organ function as defined:

   • Hemoglobin ≥ 9 g/dL
   • Absolute neutrophil count ≥ 1,500/mm3
   • Platelet count ≥ 100,000/mm3
   • Bilirubin ≤ 1.5 times normal limit
   • aspartate aminotransferase (AST) /alanine aminotransferase (ALT) ≤ 5 times the upper limit of normal if liver metastasis present or ≤2.5 X upper limit of normal (ULN) if no liver metastases are present.
   • Creatinine ≤ 2 mg/dL

Exclusion Criteria:

1. Progressive central nervous system (CNS) metastatic disease. Patients with CNS metastases are allowed only if previously treated and stable for 8 weeks or more, and patient is neurologically intact off steroids. The stability must be documented by MRI/CT over a period of 8 weeks or greater.
2. Congestive Heart Failure with significant limitation of activity New York Heart Association (NYHA) class III or IV
3. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism.
4. QTc >480 mSec , unless presence of bundle branch block. In this case, observed QTc - (QRS-150) should be ≤ 480 msec.
5. More than 1 prior chemotherapy regimen. Patients may have had any prior immunotherapy regimens but must be at least 6 weeks out from anti-CTLA4 or anti-PD-1 antibody treatment and show progression based on immune response evaluation criteria.
6. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy and for 4 months following last dose.
7. Prior treatment with any AKT or MEK inhibitor
8. Retinal or Fundal disease (including macular degeneration, retinal vein occlusion, hypertensive or diabetic retinopathy).
9. Inflammatory Bowel Disease, malabsorption syndrome or diarrhea > Grade 1.
10. Need for treatment with drugs that are known potent CYP3A inhibitors. Current use or anticipated need for treatment with drugs that are known potent CYP3A or CYP1A2 inducers.
11. Prior malignancy will be allowed as long as the patient is known to be free of disease for at least 5 years. Prior Squamous cell carcinoma (SCC), Basal Cell, cervical cancer, early stage prostate cancer, ductal carcinoma in situ (DCIS) or melanoma (second primary) are allowed even if <5 years from diagnosis

Patients with NRAS exon 1 and 2 mutations (NRAS mutant) identified by Sanger sequencing or exon-capture next-generation equencing and patients without these mutations (wild-type (WT)). The sample size for each arm was based on a Simon 2-stage stage design.

Patient toxicity will be collected from time of first treatment at weekly scheduled study visits. Patients will be followed for toxicity for 30 days after last dose of study drug or removal from study, or until death, whichever occurs first. Patients removed from study for unacceptable treatment related adverse event(s) will be followed additionally until resolution or stabilization of all treatment related adverse events to Grade 2 or lower