BRAF Inhibitor, LGX818, Utilizing a Pulsatile Schedule in Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation

Inclusion Criteria:

- Stage IV, or unresectable stage III melanoma that harbors a BRAFV600 mutation

- Any prior therapy allowed except a BRAF or MEK inhibitor,.

- Patients must provide written informed consent prior to any screening procedures.

- Age 18 years or older.

- Willing and able to comply with scheduled visits, treatment plan and laboratory tests

- Patient is able to swallow and retain oral medication

- Measurable disease according to RECIST v1.1

- ECOG performance status ≤ 1

Exclusion Criteria:

- Brain metastasis or leptomeningeal disease

- Known acute or chronic pancreatitis

- Prior colectomy

- Clinically significant cardiac disease including any of the following:

- CHF requiring treatment (NYHA Classification ≥ 2) in which patients have a history of
LVEF < 45% as determined by MUGA scan or ECHO, or uncontrolled hypertension (please
refer to WHO-ISH guidelines)

- 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

- Serum total bilirubin >1.5 x ULN

- AST/SGOT and/or ALT/SGPT > 2.5 x ULN

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral LGX818 (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, small bowel resection).

- Previous or concurrent malignancy. Exceptions: adequately treated basal cell or
squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and
without evidence of recurrence for at least 3 years prior to study entry; or other
solid tumor treated curatively, and without evidence of recurrence for at least 3
years prior to study entry.

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (> 5 mIU/mL).

Women of child-bearing potential, defined as all women physiologically capable of becoming
pregnant, are not allowed to participate in this study UNLESS they are using highly
effective methods of contraception throughout the study and for 3 months after study drug
discontinuation. Highly effective contraception methods include:

Total abstinence or

- Male or female sterilization

- Combination of any two of the following (a+b or a+c or b+c)

1. Use of oral, injected, or implanted hormonal methods of contraception

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

- Post-menopausal women are allowed to participate in this study. Women are
considered post-menopausal and not of child bearing potential if they have
had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g. age appropriate, history of vasomotor symptoms) or
six months of spontaneous amenorrhea with serum Follicle-Stimulating Hormone
(FSH) levels > 40 mIU/mL or have had surgical bilateral oophorectomy (with
or without hysterectomy) or tubal ligation at least six weeks prior to
screening. In the case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment
is she considered not of child bearing potential.

Sexually active males must use a condom during intercourse while taking the drug and for 5
T1/2 after stopping treatment and should not father a child in this period. A condom is
required to be used also by vasectomized men in order to prevent delivery of the drug via
seminal fluid.

History of thromboembolic or cerebrovascular events within the last 6 months, including
transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary
embolism.

- Patients who have undergone any major surgery within the last 2 weeks prior to
starting study drug or who would not have fully recovered from previous surgery.

- Known Human Immunodeficiency Virus (HIV) infection

- Other severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or that may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient inappropriate for the
study.

- Treatment with a prior BRAF or MEK inhibitor