GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: GSK1120212; Chemotherapy
Intervention description: MEK inhibitor; Investigator Choice of DTIC or paclitaxel
Intervention MeSH terms: Trametinib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 322.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MEK inhibitor; Cancer; Metastatic Melanoma; BRAF mutant metastatic melanoma; GSK1120212

Summary:

      This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212
      to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV
      malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample.
      Subjects who have received up to one prior regimen of chemotherapy in the advanced or
      metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or
      MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1
      randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy
      arm). The primary endpoint for the statistical analysis will be a comparison of progression
      free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have
      progression on chemotherapy will be offered the option to receive GSK1120212.
    

Eligibility criteria:

        Inclusion Criteria:

          -  ≥18 years of age

          -  Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which
             is also determined to be BRAF V600E/K mutation-positive by the central laboratory

          -  Received no prior treatment or up to one prior regimen of chemotherapy for advanced or
             metastatic melanoma. Prior treatment with immunotherapy (with the exception of prior
             ipilimumab, which is only allowed if given in the adjuvant setting), cytokine therapy,
             biological or vaccine regimen is permitted. Prior use of sorafenib is allowed

          -  Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST
             1.1)

          -  Women of childbearing potential and men with reproductive potential must agree to use
             effective contraception during the study. Additionally women of childbearing potential
             must have a negative serum pregnancy test within 14 days prior to randomization

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1

          -  Adequate screening organ function

        Exclusion Criteria:

          -  Any prior use of BRAF inhibitors or MEK inhibitors.

          -  Subjects who have received dacarbazine or paclitaxel prior to randomization will not
             be eligible to receive the same chemotherapy as study medication (i.e. a subject who
             received prior dacarbazine cannot receive dacarbazine on this trial and would thus
             receive paclitaxel if randomized to the control arm)

          -  History of another malignancy. Exception: Subjects who have been disease-free for 3
             years, or subjects with a history of completely resected non-melanoma skin cancer or
             successfully treated in situ carcinoma are eligible. Subjects with second malignancies
             that are indolent or definitively treated may be enrolled. Consult GSK Medical Monitor
             if unsure whether second malignancies meet requirements specified above

          -  Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
             Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection
             which will be allowed)

          -  Brain metastases with the following exceptions that are ALL confirmed by the GSK
             Medical Monitor:

        All known lesions must be previously treated with surgery or stereotactic radiosurgery, and
        Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion
        size) for ≥90 days prior to randomization (must be documented with two consecutive MRI or
        CT scans using contrast), and asymptomatic with no corticosteroids requirement for ≥ 30
        days prior to randomization, and no enzyme-inducing anticonvulsants for ≥ 30 days prior to
        randomization

          -  History or evidence of cardiovascular risk including any of the following:

               -  QTcB ≥ 480 msec.

               -  History or evidence of current clinically significant uncontrolled arrhythmias.
                  Exception: Subjects with controlled atrial fibrillation for >30 days prior to
                  randomization are eligible

               -  History of acute coronary syndromes (including myocardial infarction and unstable
                  angina), coronary angioplasty, or stenting within 6 months prior to
                  randomization.

               -  History or evidence of current ≥ Class II congestive heart failure as defined by
                  New York Heart Association

          -  History of interstitial lung disease or pneumonitis

          -  History or current evidence / risk of retinal vein occlusion (RVO) or central serous
             retinopathy (CSR):

               -  History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled
                  glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes
                  mellitus, or history of hyperviscosity or hypercoagulability syndromes).

               -  Visible retinal pathology as assessed by ophthalmic exam that is considered a
                  risk factor for RVO or CSR such as:

          -  Evidence of new optic disc cupping.

          -  Intraocular pressure > 21 mm Hg as measured by tonography