Trametinib With GSK2141795 in BRAF Wild-type Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: Trametinib (GSK1120212); GSK2141795
Intervention description: Trametinib is a highly selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.; 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. Since phosphorylation 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.
Intervention MeSH terms: Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melanoma; Wild-type; BRAF

Summary:

      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.
    

Eligibility criteria:

        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