1. Provide written informed consent obtained prior to the initiation of study
2. Male and female subjects who are at least 18 years of age.
3. Histologically confirmed unresectable stage III or stage IV melanoma (AJCC 7th
edition classification). Cutaneous melanoma and mucosal melanoma will be eligible.
4. Only patients with BRAF V600E or V600K mutated tumors will be enrolled.
5. Baseline skin exam is required for all patients. Note: Cutaneous squamous cell
carcinoma (SCC) lesions identified at baseline must be excised.
6. Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors
(RECIST v1.1). Baseline measurements must be obtained within 4 weeks prior to
7. Adequate hematologic, renal, and liver function as evidenced by the following (within
4 weeks prior to starting the study drugs):
- WBC 3,000/mm3
- ANC 1500
- Hemoglobin 9g/dL (women) or 11g/dL (men) Platelets 100,000/mm3 Serum
Creatinine 1.5 x upper limit of normal (ULN)
- Serum Bilirubin 1.5 x ULN
- Serum AST and ALT 2.5 x ULN
Note: (supportive transfusions will be allowed during screening and during treatment
as deemed necessary by the treating physician)
8. EKG documenting QTc interval < 480 msec and no clinically significant arrhythmia
9. Fully recovered from any effects of major surgery, and be free of significant
10. ECOG performance status of 0 or 1.
11. Patients must be free of active brain metastases by contrast-enhanced CT/MRI scans
within 4 weeks prior to starting the study drugs. If known to have prior brain
metastases, must not have evidence of active (enlarging and/or symptomatic lesions)
brain disease on MRI evaluations within 4 weeks apart (one of which is at least 4
weeks from SRS or WBRT treatment.
12. Female patients of child bearing potential must have a negative pregnancy test within
7 days from the time of registration .
13. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
14. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
course of the study through 26 weeks after the last dose of study medication
(Reference Section 5.7.2). Subjects of childbearing potential are those who have not
been surgically sterilized or have not been free from menses for greater than 1 year.
15. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 26 weeks after the last dose of study
1. Serious clinically significant illnesses, such as: cardiovascular disease
(uncontrolled congestive heart failure, uncontrolled hypertension, cardiac ischemia,
myocardial infarction, and severe cardiac arrhythmia), bleeding disorders,
symptomatic autoimmune diseases (such as inflammatory bowel disease, autoimmune
hepatitis, uncontrolled hypo or hyperthyroidism), severe obstructive or restrictive
pulmonary diseases, retinopathy, active systemic infections, and inflammatory bowel
2. Known HIV or AIDS-related illness, or active HBV and HCV.
3. Has a known history of active TB (Bacillus Tuberculosis)
4. History of grade 4 immune-related adverse events requiring treatment with prednisone,
or grade 3 immune-related adverse events requiring prednisone >10 mg/kg for >12
weeks, if previously treated with ipilimumab.
5. Patients with brain metastases will be excluded if metastases have been symptomatic
or actively treated within 4 weeks prior to enrollment.
6. Prior therapy with a BRAF and/or MEK and/or ERK inhibitors.
7. Refractory nausea, vomiting, small bowel resection or any other gastrointestinal
ailment that would preclude study drug absorption.
8. Cardiac abnormalities
- Mean QTc interval 480 msec at screening.
- ACS/AMI -within 24 weeks prior to screening.
- PCI/PTCA -within 24 weeks prior to screening.
- Symptomatic heart failure - NYHA Class II symptoms.
9. Active infection within one-week prior to study, including unexplained fever
10. Systemic steroid or other immunosuppressive therapy within 4 weeks of starting the
11. Lactating females and/or pregnant females.
12. Any significant psychiatric disease, medical or other condition, which in the opinion
of the principal investigator could prevent adequate informed consent or compromise
participation in the clinical trial.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both