Background: The overexpression of hypoxia induced factor (HIF) 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with the standard dose of axitinib to patients with metastatic RCC. Primary endpoint is safety, secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 9 patients with metastatic RCC; who failed one or more prior lines of treatment; are enrolled. The first 3 patients were treated at 4000 µg, the second and third 3 patients were treated at 2500 and 3000 µg respectively. No dose limiting toxicity (DLT) is encountered. Six patients are evaluable to date. Of the 4000 µg cohort, 2 patients achieved complete remission (CR) at 18 and 20 months, 1 patient with partial response (PR) at 19 month. Of the 2500 µg cohort, one patient achieved PR at 9 months, 1 patient had stable disease for 9 months before progression, and 1 patient had disease progression at 4 months. The 3000 µg cohort is too early to evaluate for efficacy. Of interest the 4000μg SLM dose yielded a plasma selenium concentration of 40-50μM which is comparable with SLM dose determined synergistic with anti-cancer drugs in preclinical models. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT02535533