study comparing combination of lgx818 plus mek162 versus vemurafenib and lgx818 monotherapy in braf mutant melanoma

Conditions: Melanoma

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

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