LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma

Exclusion Criteria

• •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.
• •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
• •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