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

A Phase 2 Trial of the BRAF Inhibitor, LGX818, Utilizing a Pulsatile Schedule in Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation

The purpose of this phase II study is to find out if an investigational drug called LGX818 can stop the melanoma from growing.

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