lgx818 and mek162 in combination with a third agent (bkm120, lee011, bgj398 or inc280) in advanced braf melanoma

Conditions: Melanoma

Summary: the primary purpose of this study is to assess the anti-tumor activity of lgx818/mek162 in combination with targeted agents after progression on lgx818/mek162 combination therapy, as well as the safety and tolerability of the novel triple combinations.

this study consists of two parts: in part i/run-in, patients naïve to selective braf and mek inhibitors will be treated with the lgx818/mek162 combination until disease progression (as defined per recist v1.1). based on the genetic analysis of a tumor biopsy obtained at that time, patients will enter part ii of the study for tailored combination treatment in one of four arms of lgx818/mek162 + either bkm120, bgj398, inc280 or lee011 patients with braf mutant melanoma treated by lgx818/mek162 combination in other studies can be enrolled directly in part ii of clgx818x2109 after relapse. dose-escalations in the combination arms for which no mtd has been established will be based on the recommendations of a bayesian logistic regression model guided by an escalation with overdose control criterion

Eligibility criteria:
inclusion criteria: * age ≥ 18 years * histologically confirmed diagnosis of unresectable stage iii or metastatic melanoma (stage iiic to iv per american joint committee on cancer \[ajcc\]) * documented evidence of braf v600 mutation. * newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at the time of progression, if not medically contraindicated. * evidence of measurable disease, as determined by recist v1.1. inclusion criteria for triple combinations: progressive disease following prior treatment with lgx818/mek162 combination. principal exclusion criteria symptomatic or untreated leptomeningeal disease. * symptomatic brain metastases. patients previously treated or untreated for brain metastases that are asymptomatic in the absence of corticosteroid therapy or on a stable dose of steroids for four weeks are allowed to enroll. brain metastases must be stable at least 4 weeks with verification by imaging (e.g. brain mri completed at screening demonstrating no current evidence of progressive brain metastases). patients are not permitted to receive enzyme inducing anti-epileptic drugs. * patients who have developed brain metastases during part i of the study may continue to part ii upon discussion with novartis medical monitor. the brain metastasis must be either asymptomatic or treated and stable for at least 4 weeks and on a stable or tapering dose of steroids for at least 2 weeks. patients with brain metastasis are not eligible for the combination with lee011. * known acute or chronic pancreatitis. * history or current evidence of retinal vein occlusion (rvo) or current risk factors for rvo (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); * clinically significant cardiac disease including any of the following: * chf requiring treatment (nyh grade ≥ 2), * lvef \< 50% as determined by muga scan or echo * history or presence of clinically significant ventricular arrhythmias or atrial fibrillation * clinically significant resting bradycardia * unstable angina pectoris ≤ 3 months prior to starting study drug * acute myocardial infarction (ami) ≤ 3 months prior to starting study drug, * qtcf \> 480 msec. patients with any of the following laboratory values at screening/baseline: * absolute neutrophil count (anc) \<1,500/mm3 \[1.5 x 109/l\] * platelets \< 100,000/mm3 \[100 x 109/l\] * hemoglobin \< 9.0 g/dl * serum creatinine \>1.5 x uln or calculated or directly measured crcl \< 50% lln (lower limit of normal) * serum total bilirubin \>1.5 x uln * ast/sgot or alt/sgpt \> 2.5 x uln, or \> 5 x uln if liver metastases are present additional exclusion criteria for the triple combinations: lgx818/mek162/bkm120: * patients with fasting glucose \> 120 mg/dl or 6.7 mmol/l, and hba1c \> 8 %. * patient has any of the following mood disorders as judged by the investigator or a psychiatrist: * patient has a score ≥ 12 on the phq-9 questionnaire * patient has ≥ ctcae grade 3 anxiety lgx818/mek162/bgj398: * history and/or current evidence of significant ectopic mineralization/ calcification with the exception of calcified lymph nodes and asymptomatic vascular calcification. * current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/ band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits etc., confirmed by ophthalmologic examination lgx818/mek162/lee011: * patients with uncontrolled hypertension (please refer to who-ishguidelines) are excluded from study. * qtcf \>450 ms for males and \>470 ms for females congenital long qt syndrome or family history of unexpected sudden cardiac death and/or hypokalemia ctcae grade ≥ 3 and magnesium levels below the clinically relevant lower limits at study entry * current evidence of brain metastasis or brain metastasis detected by mandatory ct/mri at screening * pt/inr or aptt \> 1.5xuln other protocol-defined inclusion/exclusion criteria may apply.

Keywords: melanoma