Neoadjuvant Cytoreductive Treatment of Regionally Advanced Melanoma With BRAF/MEK Inhibition: Study Protocol of the REDUCTOR (Cytoreductive Treatment of Dabrafenib Combined With Trametinib to Allow Complete Surgical Resection in Patients With BRAF Mutated, Prior Unresectable Stage III or IV Melanoma) Trial

Abstract

BackgroundLocally advanced (unresectable or high risk of R1 resection) regionally metastatic melanoma occurs in approximately 5% of patients with regionally metastatic disease. Cytoreductive treatment with sufficient downsizing of the tumor could enable radical resection in these patients. BRAF + MEK combination treatment has shown quick responses in most patients with BRAF-mutated melanoma. The aim of the present study, therefore, was to evaluate the ability of short-term cytoreductive neoadjuvant BRAF + MEK inhibition to allow for complete surgical resection in patients with BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma. Patients and MethodsThe REDUCTOR (cytoreductive treatment of dabrafenib combined with trametinib to allow complete surgical resection in patients with BRAF mutated, prior unresectable stage III or IV melanoma) trial is a phase II trial in which 25 patients with BRAF-mutated, locally advanced, stage III or oligometastatic stage IV melanoma (≤ 3 metastases) will receive neoadjuvant cytoreductive dabrafenib and trametinib combination therapy. The patients will be treated for 8 weeks. The positron emission tomography/computed tomography response evaluation will occur at 2 and 8 weeks. In the case of sufficient tumor downsizing, surgery will be performed. Biopsies for translational research purposes will occur at baseline and 2 weeks, and the dissection specimen will be stored at 8 weeks. ConclusionThe primary endpoint of the present trial is the percentage of patients in whom an R0 resection (microscopically radical) can be performed, as evaluated by pathologic examination. The secondary endpoints are recurrence-free survival, time to next treatment, and overall survival. Translational research will focus primarily on the assessment of treatment-induced changes in exome mutations within the tumor and changes in gene expression profiles.