['malignant melanoma']
['dabrafenib + trametinib']

        Inclusion Criteria:

          1. 18 years of age and signed written informed consent.

          2. Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable)
             or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive.

          3. Subjects must have failed at least two prior systemic anti-cancer treatments for Stage
             IIIC (unresectable) or Stage IV (metastatic) melanoma that must have included:

               -  Treatment with a BRAF inhibitor (including but not limited to dabrafenib,
                  vemurafenib, and LGX818) and progression of disease per RECIST, version 1.1
                  [Eisenhauer, 2009] must have been documented during this treatment.

               -  Treatment with ipilimumab (or an alternative experimental immunotherapy) and
                  progression of disease per immune related response criteria [Wolchock Clin Cancer
                  Res December 1, 2009 15; 7412] must have been documented during this treatment.

          4. Documented progression of disease per RECIST, version 1.1 [Eisenhauer, 2009]) or per
             immune related response criteria [Wolchock Clin Cancer Res December 1, 2009 15; 7412]
             if the latest systemic therapy administered was ipilimumab, an anti-PD1 or anti-PD-L1
             therapy, or any other experimental immunotherapy.

          5. The presence of at least one measurable lesion per RECIST, version 1.1 [Eisenhauer,
             2009]).

          6. Interval between the date of the last administration of prior therapy for melanoma and
             the date of recruitment:

               -  > 12 weeks following the date of the last administration of a BRAF-inhibitor;

               -  > 12 weeks following the date of the first administration and > 4 weeks following
                  the date of the last administration of ipilimumab, or an anti-PD1, or anti-PD-L1
                  therapy;

               -  > 4 weeks following the date of the last administration of chemotherapy (> 6
                  weeks in case of a nitrosurea or mitomycin C containing regimen);

               -  > 4 weeks following major surgery or extensive radiotherapy.

          7. Subjects with ocular melanoma are not eligible.

          8. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory
             values as listed on Table 2) must be ≤ Grade 1 according to the Common Terminology
             Criteria for Adverse Events version 4 (CTCAE version 4.0; National Cancer Institute (
             NCI,) 2009) at the time of recruitment.

          9. Able to swallow and retain oral medication and must not have any clinically
             significant gastrointestinal abnormalities that may alter absorption such as
             malabsorption syndrome or major resection of the stomach or bowels.

         10. Women of childbearing potential must have a negative serum pregnancy test within 7
             days prior to recruitment and agree to use effective contraception, as defined in
             Section 7.3.3.1, throughout the treatment period, and for 4 months after the last dose
             of study treatment.

         11. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 [Oken,
             1982]. Refer to Appendix 1 for details.

         12. Adequate baseline organ function as defined in Table 2.

        Exclusion Criteria:

          1. Grade 4 or repetitive grade 3 adverse event(s) related to prior treatment with a BRAF-
             and/or MEK inhibitor.

          2. Any contra-indication for evaluation by whole body CT and MRI of the brain.

          3. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days),
             whichever is shorter, prior to recruitment.

          4. Current use of a prohibited medication as described in Section 6 or requires any of
             these medications during treatment.

          5. History of another malignancy, including any malignancy with confirmed activating RAS
             mutation. Note: Prospective RAS testing is not required. However, if the results of
             previous RAS testing are known, they must be used in assessing eligibility. Exception:
             Subjects who have been disease-free for 3 years, (i.e. subjects with second
             malignancies that are indolent or definitively treated at least 3 years ago) not
             including malignancy with confirmed activating RAS mutation, or subjects with a
             history of completely resected non-melanoma skin cancer.

          6. Any serious or unstable pre-existing medical conditions (aside from malignancy
             exceptions specified above), psychiatric disorders, or other conditions that could
             interfere with the subject's safety, obtaining informed consent, or compliance with
             study procedures.

          7. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
             Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV
             infection will be permitted).

          8. Patients with progressive symptoms from active brain metastasis or in need of an
             increase in corticosteroids dose to control symptoms within 4 weeks prior to
             recruitment are excluded

          9. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment

         10. A history or evidence of cardiovascular risk including any of the following:

               -  Current LVEF < LLN

               -  A QT interval corrected for heart rate using the Bazett's formula (QTcB; Section
                  5.6.3.3) ≥480 msec;

               -  A history or evidence of current clinically significant uncontrolled arrhythmias;
                  Exception: Subjects with atrial fibrillation controlled for > 30 days prior to
                  recruitment are eligible.

               -  A history (within 6 months prior to recruitment) of acute coronary syndromes
                  (including myocardial infarction or unstable angina), coronary angioplasty or
                  stenting;

               -  A history or evidence of current ≥Class II congestive heart failure as defined by
                  the New York Heart Association (NYHA) guidelines (Appendix 4);

               -  Treatment refractory hypertension defined as a blood pressure of systolic >140
                  mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive
                  therapy;

               -  Patients with intra-cardiac defibrillators;

               -  Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram
                  (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be
                  entered on study). Subjects with moderate valvular thickening should not be
                  entered on study.

         11. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia,
             hypocalcaemia), long QT syndrome or taking medicinal products known to prolong the QT
             interval.

         12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study treatments, their excipients, and/or dimethyl
             sulfoxide (DMSO).

         13. Females who are pregnant or nursing.

         14. Interstitial lung disease or pneumonitis

         15. Patients with a prior history of central serous retinopathy or retinal vein occlusion
             are excluded. Patients with a preexisting major ocular pathology are not eligible.
      