1. Has signed informed consent.
2. Age >=18 years of age.
3. Histologically confirmed cutaneous metastatic melanoma (Stage IV), including confirmed
4. BRAF mutation-positive (V600 E/K) melanoma as determined by standardized genetic
5. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
6. Eligible for treatment with dabrafenib. Specific information regarding warnings,
precautions, contraindications, adverse events, and other pertinent information on the
study treatment that may impact subject eligibility is provided in the summary of
product characteristics (SPC) for Tafinlar.
7. No contraindication for performing a CT scan.
8. No contraindications for performing an MRI scan of the brain.
9. Able to swallow and retain oral medication.
10. Women with child-bearing potential and men with reproductive potential must be willing
to practice acceptable methods of birth control, as defined in Section 5.2, from 14
days prior to randomization, throughout the treatment period and for 4 weeks after the
last dose of study treatment.
11. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
12. Must have adequate organ function as defined in Table 1. Table 1 Definitions for
Adequate Baseline Organ Function System Laboratory Values Hematologic ANC >= 1.2 ×
109/L Hemoglobin >= 9 g/dL Platelet count >= 75 x 109/L PT/INRa and PTT <= 1.3 x ULN
Hepatic Total bilirubin <= 1.5 x ULN AST and ALT <= 2.5 x ULN Renal Serum creatininec
<= 1.5 mg/dL Cardial ECG QTc < 480 msec Abbreviations: ALT = alanine transaminase; ANC
= absolute neutrophil count; AST = aspartate aminotransferase; ECG =
electrocardiogram; INR = international normalized ratio; PT = prothrombin time; PTT =
partial thromboplastin time; ULN = upper limit of normal.
1. Subjects receiving anticoagulation treatment may be allowed to participate with
INR established within the therapeutic range prior to randomization.
2. Except subjects with known Gilbert's syndrome.
3. If serum creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard
Cockcroft-Gault formula. Creatinine clearance must be >= 50 mL/min to be
13. Women of child-bearing potential must have a negative urine or serum pregnancy test
(β-HCG) within 14 days of first dose of study treatment.
1. Previous treatment with a BRAF or MEK inhibitor. (previous systemic treatment for
melanoma with other agents is allowed).
2. Previous brain surgery or radiotherapy to the brain.
3. Cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy,
immunotherapy, biologic therapy, vaccine therapy or major surgery) or investigational
anti-cancer drugs within the last 3 weeks, or chemotherapy without delayed toxicity
within the last 2 weeks, preceding the first dose of dabrafenib.
4. Current use of a prohibited medication or requires any of these medications during
treatment with dabrafenib as mentioned in the SPC for Tafinlar.
5. Current use of oral anticoagulant therapy. NOTE: Prophylactic low-dose of low
molecular weight heparin (LMWH) is permitted.
6. Known immediate or delayed hypersensitivity reaction to dabrafenib or excipients.
7. Use of other investigational drugs within 28 days (or five half-lives, whichever is
shorter; with a minimum of 14 days from the last dose) preceding the first dose of
study treatment and during the study.
8. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0 (26) grade 2 or higher from previous anti-cancer
therapy, except alopecia.
9. Presence of active gastrointestinal disease or other condition that will interfere
significantly with the absorption of drugs. If clarification is needed as to whether a
condition will significantly affect absorption of drugs, the Novartis medical monitor
will be contacted.
10. Presence of malignancy other than disease under study within 5 years of study
enrollment, or any malignancy with confirmed activating RAS mutation. Subjects with a
history of completely resected non-melanoma skin cancer or successfully treated in
situ carcinoma are eligible.
11. Leptomeningeal metastases, brain metastases, or metastases causing spinal cord
compression that are symptomatic or not stable for >=4 weeks or requiring
corticosteroids. Subjects on a stable dose of corticosteroids >1 month or who have
been off of corticosteroids for at least 2 weeks can be enrolled with approval of the
Novartis medical monitor.
12. A history or evidence of cardiovascular risk including any of the following:
1. A QT interval corrected for heart rate using the Bazett's formula >=480 msec;
2. A history or evidence of current clinically significant uncontrolled arrhythmias;
3. A history of acute coronary syndromes (including myocardial infarction or
unstable angina), coronary angioplasty, or stenting within 6 months prior to
4. A history or evidence of current >=Class II congestive heart failure as defined
by the New York Heart Association (NYHA) guidelines.
5. Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram
(subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be
entered on study). Subjects with moderate valvular thickening should not be
entered on study.
6. Patients with intra-cardiac defibrillators.
13. A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects
with laboratory evidence of cleared HBV and/or HCV will be permitted).
14. Any serious or unstable pre-existing medical conditions (i.e, diabetes mellitus,
hypertension, etc), psychological, familial, sociological, or geographical conditions
that do not permit compliance with the protocol; or unwillingness or inability to
follow the procedures required in the protocol.
15. Altered mental status, or any psychiatric condition that would prohibit the
understanding or rendering of informed consent, unless a legally acceptable
representative could provide informed consent.
16. Pregnant or nursing females.