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

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

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.