Dabrafenib Alone and in Combination With Trametinib Before Surgery in Treating Patients With Locally or Regionally Advanced Melanoma That Can Be Removed By Surgery
Condition: Recurrent Melanoma; Stage IIB Melanoma (Locally Advanced); Stage IIC Melanoma (Locally Advanced); Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma (Limited, Resectable)
MeSH terms: Melanoma
Intervention: dabrafenib; trametinib; laboratory biomarker analysis
Intervention description: 150 mg given PO; 2 mg given PO; Correlative studies
Intervention MeSH terms: Trametinib; Dabrafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 13.0
Sex: All
Minimum age: 18 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: Melanoma, B-RAF, biomarkers, targeted therapy, resistance

Summary:

      This phase II trial studies how well giving dabrafenib alone and in combination with
      trametinib before surgery works in treating patients with advanced melanoma that can be
      removed by surgery. Studying samples of tumor tissue in the laboratory from patients
      receiving dabrafenib and trametinib may help doctors learn more about the effects of these
      drugs on cells and help identify biomarkers that determine which patients will respond to
      these drugs best.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed written informed consent

          -  Patients with locally-or regionally advanced melanoma being considered for resection
             of the lesion(s) for local-regional control and potential cure

               -  Patients with limited, resectable metastatic disease (three or fewer lesions) are
                  eligible if surgical resection is considered to be the best therapeutic option

               -  Patients with AJCC clinical stage IIb-IV disease at initial diagnosis, or
                  patients with melanoma of any stage with advanced local or regional recurrence,
                  with or without limited resectable metastatic disease, would be eligible

          -  B-RAF V-600 mutation positive by snapshot molecular analysis

               -  Individuals with B-RAF V-600 mutations other than V600E are eligible

          -  Measurable disease, i.e. presenting with at least one measurable lesion per Response
             Evaluation Criteria in Solid tumors (RECIST) 1.1

          -  All prior treatment related toxicities must be Common Terminology Criteria for Adverse
             Events (CTCAE) (Version 4.0) =< Grade 1 at the time of enrollment

          -  Adequate baseline organ function defined by the criteria below:

               -  Absolute Neutrophil Count (ANC) >= 1.5 X 10^9/L

               -  Platelet Count >= 60 X 10^9/L

               -  Hemoglobin >= 9 g/dl

               -  Creatinine =< 2 mg/dl

               -  Aspartate aminotransferase (AST) =< 100 U/L

               -  Alanine aminotransferase (ALT) =< 100 U/L

               -  Alkaline Phosphatase =< 380 U/L

               -  Total Bilirubin =< 2.0 mg/dl

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days of first dose of study treatment and agree to use effective contraception during
             the study and for 7 days following the last dose of study treatment

          -  Men with a female partner of childbearing potential must have either had a prior
             vasectomy or agree to use effective contraception from 1 day prior to administration
             of the first dose of study treatment until 7 days after the last dose of study
             treatment

        Exclusion Criteria:

          -  ECOG Performance Status > 2

          -  Lactating female

          -  Any serious and/or unstable pre-existing medical, psychiatric disorder, or other
             conditions that could interfere with subject's safety, obtaining informed consent or
             compliance to the study procedures

          -  Any serious medical condition that would render the patient unable to undergo surgical
             resection or would limit life expectancy to less than 1 year

          -  Any prohibited medication

          -  Administration of an investigational drug within 30 days or 5 half-lives, whichever is
             longer, preceding the first dose of study treatment

          -  A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to GSK-2118436 (dabrafenib) or GSK-1120212 (trametinib) or
             excipient that contraindicates their participation

          -  Patients with a history of severe cardiovascular disease as defined:

               -  Symptomatic or uncontrolled cardiac arrhythmias

               -  Treatment refractory hypertension, defined as a systolic blood pressure > 160mm
                  Hg and/or diastolic > 100 mmHg which cannot be controlled by antihypertensive
                  therapy.

               -  Current ≥ NYHA Class II congestive heart failure

               -  History of myocardial infarction or unstable angina within 6 months prior to
                  study entry.

               -  History of stroke or TIA within 6 months prior to study entry

               -  QTc ≥ 480 msec

               -  Cardiac valvular disease ≥ grade 2.

          -  Patients with a history of interstitial lung disease or interstitial pneumonitis

          -  A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or
             Hepatitis C Virus (HCV) infection.

          -  History of another active malignancy within the past 5 years, or any malignancy with a
             confirmed activating RAS mutation. Please note that prospective RAS mutation testing
             is not required, however, if results of previous RAS testing are known, they must be
             used in assessing eligibility. Subjects with a history of completely resected
             non-melanoma skin cancer are eligible.

          -  A history or current evidence/risk of retinal vein occlusion (RVO) or CSR including:

          -  a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or
             ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a
             history of hyperviscosity or hypercoagulability syndromes); or

          -  b. Visible retinal pathology as assessed by ophthalmic examination that is considered
             a risk factor for RVO or CSR such as:

               -  i. Evidence of new optic disc cupping;

               -  ii. Evidence of new visual field defects on automated perimetry;

               -  iii. Intraocular pressure >21 mmHg as measured by tonography.