Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma
Condition: Melanoma
MeSH terms: Melanoma
Intervention: LGX818; MEK162; vemurafenib
Intervention description: LGX818- Orally 100 mg and 50 mg capsules; MEK162- Orally 15 mg tablets; Tablets in bottles or blisters 240 mg
Intervention MeSH terms: Vemurafenib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 921.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Melanoma; Cutaneous melanoma; Skin disease; Skin cancer; Skin Neoplasms; Neoplasm Metastasis; BRAF mutant; BRAF V600E; BRAF V600K; Cancer; LGX818; MEK162; vemurafenib; combination; BRAF inhibitor; resistance; The combination of a selective BRAF- and a MEK1/2-inhibitor; Prior immunotherapy; MEK inhibitor; Phase III; Combo 300, Combo 450

Summary:

      This is 2-part, randomized, open label, multi-center, parallel group, phase III study
      comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy
      in patients with locally advanced unresectable or metastatic melanoma with BRAF V600
      mutation. A total of approximately 900 patients will be randomized.

      Part 1:

      Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms:

        1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm)

        2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or

        3. vemurafenib 960 mg BID (denoted as vemurafenib arm)

      Part 2:

      Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms:

        1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or

        2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or
             unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV)

          -  Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization

          -  Naïve untreated patients or patients who have progressed on or after prior first line
             immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant
             therapy is permitted (e.g. IFN, IL-2 therapy, any other immunotherapy, radiotherapy or
             chemotherapy), except the administration of BRAF or MEK inhibitors

          -  Evidence of at least one measurable lesion as detected by radiological or photographic
             methods

          -  ECOG performance status of 0 or 1

          -  Adequate bone marrow, organ function, cardiac and laboratory parameters

          -  Normal functioning of daily living activities

        Exclusion Criteria:

          -  Any untreated central nervous system (CNS) lesion

          -  Uveal and mucosal melanoma

          -  History of leptomeningeal metastases

          -  History of or current evidence of central serous retinopathy (CSR), retinal vein
             occlusion (RVO) or history of retinal degenerative disease

          -  Any previous systemic chemotherapy treatment, extensive radiotherapy or
             investigational agent other than immunotherapy, or patients who have received more
             than one line of immunotherapy for locally advanced unresectable or metastatic
             melanoma; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at
             least 6 weeks prior to randomization

          -  History of Gilbert's syndrome

          -  Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor

          -  Impaired cardiovascular function or clinically significant cardiovascular diseases

          -  Uncontrolled arterial hypertension despite medical treatment

          -  HIV positive or active Hepatitis B, and/or active Hepatitis C

          -  Impairment of gastrointestinal function

          -  Patients with neuromuscular disorders that are associated with elevated CK

          -  Pregnant or nursing (lactating) women

          -  Medical, psychiatric, cognitive or other conditions that may compromise the patient's
             ability to understand the patient information, give informed consent, comply with the
             study protocol or complete the study

        Other protocol-defined inclusion/exclusion criteria may apply