lgx818 in combination with agents (mek162; bkm120; lee011; bgj398; inc280) in advanced braf melanoma

Conditions: Melanoma

Summary: the primary purpose of the phase ii clgx818x2102 study is to assess the anti-tumor activity of lgx818 in combination with selected agents.

this is a phase ii two part multi-center, open-label study. part i: lgx818 single agent treatment until progression part ii: combination treatments of lgx818 + mek162, or bkm120, or bgj398, or inc280, or lee01 to assess the clinical efficacy, to further evaluate the safety of the drug combinations in patients with locally advanced or metastatic braf mutant melanoma after relapse on lgx818, and to determine the maximum tolerated dose of the combinations (when not established previously). these drug combinations are selected and assigned to patients based on documentation of molecular resistance mechanism. patients with braf mutant melanoma treated by lgx818 single agent in other studies can be enrolled directly in part ii of clgx818x2102 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. after careful evaluation of slow enrollment and the braf-mutant melanoma treatment landscape, recruitment was permanently halted on 26-jul-2014. this recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.

Eligibility criteria:
inclusion criteria: * locally advanced or metastatic melanoma * confirmed braf v600 mutation * patients naïve to a selective braf inhibitor * fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time of relapse * life expectancy ≥ 3 months * world health organization (who) performance status ≤ 2. exclusion criteria: * previous treatment with raf-inhibitor * symptomatic or untreated leptomeningeal disease * symptomatic brain metastases. * known acute or chronic pancreatitis * clinically significant cardiac disease * ast/sgot and alt/sgpt \> 2.5 x uln, or \> 5 x uln if liver metastases are present * impairment of gastrointestinal (gi) function or gi disease that may significantly alter the absorption of oral interventional drug * previous or concurrent malignancy. * other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation specific exclusion criteria for each treatment arm: lgx818/mek162: history or current evidence of retinal disease history of gilbert's syndrome. lgx818/bkm120: patients with diabetes mellitus requiring insulin treatment patient has mood disorders lgx818/bgj398: history and/or current evidence of ectopic mineralization/ calcification current evidence of corneal disorder/ keratopathy patients with current evidence of endocrine alteration of calcium/phosphate homeostasis. history of congenital long qt- syndrome and/or hypokalaemia ctcae grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry. ionized (i) calcium (ca) \> uln serum inorganic phosphorus (pi) \> uln lgx818/lee011 history of congenital long qt- syndrome and/or hypokalaemia ctcae grade ≥ 3 and/or magnesium levels below the clinically relevant lower limits before study entry.

Keywords: open-label study braf inhibitor lgx818 mek1620 mapk1/2 inhibitor pi3k inhibitor fgfr c-met cdk4/6 metastatic melanoma braf v600