TPS679 Background: AA has re-emerged as a promising anti-cancer agent based on recent knowledge of pharmacokinetics, discovery of unexpected mechanisms of action, and early phase trials with IV AA.(Shenoy et al, Cancer Cell 34: 2018, in press) We hypothesized that ccRCC would be particularly susceptible to anti-cancer effects of IV AA due to: a. TET dependent demethylation of the hypermethylated genome of ccRCC causing re-expression of tumor suppressors (Shenoy et al, AACR 2018 Targeting DNA methylation conf. A11; Hu et al, Clin Cancer Res 20:4349-60, 2014) b. H2O2 production causing intra-tumoral oxidative damage, hypothesized to be enhanced by high iron content in RCC microenvironment c. Intracellular accumulation of dehydroascorbic acid secondary to high HIF activity in ccRCC. Animal data and case reports support the hypothesis. Methods: Trial design: Patients (pts) with newly diagnosed metastatic/ unresectable ccRCC are randomized 1:1 to arm A (pazopanib 800 mg/d plus IV AA 1g/kg 3 times/week) or arm B (pazopanib 800 mg/d). Protocol treatment is for 10 cycles (unless PD, unacceptable AE, alternative therapy, or pt refusal), each cycle being 28 days. Primary endpoint is Treatment Failure-Free rate at 40 weeks (TFF40). Treatment Failure is defined as: Radiographic disease progression, off-protocol treatment due to AE, alternative therapy initiation (except metastasectomy post clinical benefit), or death. Secondary endpoints include OS, PFS, ORR and AE. Statistical methods: 82 eligible pts (41 in each in arm) will provide 81% power to detect a 19% increase of TFF40 from 45% in arm B to 64% in arm A assuming a one-sided type I error rate of 0.19 (EAST 6.4). Correlatives: Epigenetic mechanism: 5mC, 5hmC and H3K27me3 IHC, MeDIP/ hMeDIP seq, RNA seq. H2O2 mechanism: tumor microenvironment iron, tumor catalase IHC. Dehydroascorbic acid mechanism: HIF-1 alpha, HIF-2 alpha, GLUT-1 IHC. Key exclusion criteria: G6PD deficiency, renal disease (Cockcroft Gault CrCl < 55 ml/min). ClinicalTrials.gov Identifier: NCT03334409 Status: Open for accrual in 9/10 planned sites. Funding Source: Foundation. Clinical trial information: NCT03334409.