Background: Hypoxia induced factor 1α/2α (HIFs) and vascular endothelial growth factor (VEGF) are overexpressed in ccRCC and associated with increased tumor angiogenesis, vascular instability and drug resistance. In xenografts, high dose SLM resulted in sustained down regulation of HIFs, normalization of tumor vasculature that resulted in increased drug delivery, and therapeutic synergy with anti-VEGF therapeutic. These effects were highly SLM dose, sequence, and schedule dependent. Methods: After completion of the escalating phase I (3+3) trial, the non-toxic SLM dose of 4000μg was administered orally twice daily (BID) for 14 days, followed by once daily in combination with axitinib 5 mg BID. The primary endpoint is safety and the secondary end point include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). To assess the potential effects of SLM on tumor vascular function, dual energy computed tomography (DECT) was conducted at baseline, day 14 of SLM, and at 3 months of SLM + axitinib. Results: Thirty subjects are screened. Of whom 25 have efficacy data (3 subjects screen failure, 1 withdrew, 1 taken off study prior to first scan due to progression with brain lesions likely present prior to study entry). 13/25 (52%) have confirmed response (CR/PR). Two subjects had CR lasting for at least 35 and 44 months, 6 subjects achieved stable disease (SD) lasting at least 6 months accounting for disease control rate (DCR) of 76%, mPFS is 9.5 months. 5/30 patients have sarcomatoid features, all of which are evaluable for efficacy with 1 PR achieved (20%). In the 20 patients without sarcomatoid features, 12/20 achieved PR (60%). The most prevalent adverse events (AE) included fatigue, diarrhea, anorexia, nausea, hoarseness, weight loss, and hypertension. No deaths nor grade 4 toxicities observed. The blood selenium concentrations achieved in the 4000μg SLM dose cohorts are similar to those determined molecularly and therapeutically synergistic with axitinib in xenografts and are being achieved clinically without significant toxicity. DECT data demonstrated increased iodine uptake by tumor lesions, but not in normal tissues, on day 14 SLM treatment and decreased in these same lesions at 3 months of SLM/axitinib. Conclusions: Blood selenium concentrations and duration of treatment seem to be critical determinants of response. Pre and concurrent treatment with SLM enhance the ORR and PFS of axitinib, with no additional toxicity. Currently documented responses are similar across IMDC risk groups. Clinical trial information: NCT02535533.