Trametinib With GSK2141795 in BRAF Wild-type Melanoma

• Progression-Free Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Overall Survival of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Time-to-Progression of patients treated with the combination of trametinib and GSK 2141795 [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Number of severe adverse events (Grade 3 and 4) reported by patients related with the treatment of Trametinib and GSK2141795. [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
  SAEs will be collected to assess the tolerability, safety and toxicity profile of this treatment.

• Biomarkers of response in biopsy tissue from patients on trial [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Biomarkers of response in peripheral blood from patients on trial [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Biomarkers of resistance in biopsy tissue from patients on trial [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
• Biomarkers of resistance in peripheral blood from patients on trial [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

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 assessments will be performed every week through cycle 3 day 1, and on day 1 for every cycle thereafter. AEs and SAEs will be monitored by UCSF's Data Safety Monitoring Committee.

Safety assessments will include medical history, physical examination, CBC with differential, chemistries panel, thyroid function and pregnancy tests, ECGs, and ophthalmology evaluations. Screening assessments will also include a transthoracic echocardiogram or MUGA scan, and brain imaging.

It is estimated that 48 patients will complete the study.

• Drug: Trametinib (GSK1120212)
  Trametinib is a highly selective allosteric inhibitor of MEK1 andMEK2 activation and kinase activity.
  Other Name: MEKINIST
• Drug: GSK2141795
  GSK 2141795 is an ATP competitive subnanomolar pan-AKT inhibitor. In order to measure the true potency of GSK 2141795, potency (Ki*) values were determined in a filter binding assay using lower enzyme concentrations (0.1, 0.7, and 0.2 nM for human AKT1, AKT2, and AKT3, respectively). Using a sandwich ELISA, GSK 2141795 inhibited phosphorylation of GSK-3β in BT474 and LNCaP cell lines with EC50 values of 143 and 34 nM, respectively. Sincephosphorylation of GSK-3β can be modulated by other enzymes (PKA, PKC, and RSK),cellular activity of GSK 2141795 was evaluated using a phospho-PRAS40 ELISA.GSK 2141795 inhibited the phosphorylation of PRAS40 with EC50 values of 39 and 55 nM for BT474 and LNCaP cells, respectively.

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