Trametinib With GSK2141795 in BRAF Wild-type Melanoma

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. 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 WT/BRAF WT. BRAF genotype must be determined by a CLIA-approved assay. NRAS genotyping may be determined by Sanger sequencing, melting point 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
   • AST/ALT ≤ 5 times the upper limit of normal if liver metastasis present or ≤2.5 X ULN if no liver metastases are present.
   • Creatinine ≤ 2 mg/dL

Exclusion Criteria:

1. Progressive 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 SCC, Basal Cell, cervical cancer, early stage prostate cancer, DCIS or melanoma (second primary) are allowed even if <5 years from diagnosis