Background: Combined BRAF and MEK inhibition yields improved response rates and overall survival compared with BRAF inhibitor monotherapy in BRAF mutant melanoma patients(Robert et al., 2015), but the median progression-free survival is less than one year. Recent preclinical data suggest that resistant BRAF mutant melanoma cells adapt to the presence of BRAF inhibitors, but these adaptations may be disadvantageous in the absence of drug(Das Thakur et al., 2013; Moriceau et al., 2015). Further in vitro and in vivo studies suggest that intermittent dosing of BRAF inhibitors and especially BRAF + MEK inhibitor combinations may extend disease control in BRAF mutant melanoma. Based on these findings, S1320, an intergroup SWOG/ECOG randomized phase 2 clinical trial, was designed to determine whether an intermittent dosing schedule of dabrafenib and trametinib improves progression-free survival (PFS) in BRAF mutant melanoma patients treated with a standard, continuous dosing regimen. Methods: ELIGIBILITY: Patients with unresectable or metastatic BRAF^V600E/K melanoma who have not been treated previously with BRAF or MEK inhibitors are eligible. Patients must have adequate end organ function and any known brain metastases must be treated prior to enrollment. DESIGN: Patients will be treated with dabrafenib at 150 mg twice daily and trametinib 2 mg twice daily during an 8 week lead in period. Patients without disease progression at the end of the lead in period will be randomized 1:1 to either continuous dosing or intermittent dosing according to a 5 weeks on, 3 weeks off schedule. Reimaging will be performed once every 8 weeks. ENDPOINTS: The primary endpoint of this study is the PFS in the continuous versus intermittent dosing arms. Secondary endpoints include the toxicity, best overall response rate, and overall survival. Early and late molecular events associated with disease progression will also be assessed using serial biopsies in a subset of patients in each arm. Support: NIH/NCI/NCTN grants CA180888, CA180819, CA180820 Clinical trial information: NCT02196181