Background: Although rare, melanoma is the most common form of skin cancer in children and the incidence is rising in the adolescent population. Similar to adults, the outcome for pediatric patients with advanced or recurrent melanoma is poor. Many adult studies of melanoma exclude patients under the age of 18 years. Approximately 50% of melanomas carry a mutation in the BRAF gene and the oral BRAF inhibitor vemurafenib (VEM) has demonstrated improved rates of overall and progression-free survival in adult melanoma patients who carry this mutation (Chapman et al; NEJM 2011). The current study is designed to determine the maximum tolerated dose (MTD)/recommended dose (RD), pharmacokinetics, safety, tolerability, and efficacy of VEM in pediatric patients with surgically incurable and unresectable stage IIIC/IV melanoma harboring BRAF^V600mutations. Methods: Patients aged 12 through 17 years with newly diagnosed or previously treated measurable disease are eligible. Patients with radiographically stable, asymptomatic previously treated central nervous system lesions are also eligible. In the dose-escalation phase, patients will be enrolled sequentially to increasing dose cohorts of VEM following a 3+3 design. Dose-limiting toxicity will be assessed during the first cycle (defined as the first 28 days). The initial dose will be 720 mg BID (patients ≥45 kg) or 480 mg BID (patients <45 kg). Once the MTD/RD for the extension phase is defined based on the dose-escalation window, all patients will be eligible to receive the MTD/RD. The efficacy tail of the trial will enroll additional pediatric patients at the MTD/RD. Patients will receive VEM until disease progression, death, unacceptable tolerability, discontinuation from the study, or other protocol-specified criteria. The study aims to treat approximately 20 patients at the RD with 3-15 additional patients treated at other dose levels during the dose-escalation phase. This study is currently open at 18 sites in the USA, UK, Germany, Italy, and Australia. As of January 24, 2013, one patient has been enrolled. Clinical trial information: NCT01519323.