Background: The combination of gemcitabine (G) and docetaxel (D) is a standard second line therapy for soft tissue sarcoma (STS) with a modest response rate. Recent studies have looked to add agents to enhance response. We have shown that argininosuccinate synthase 1 (ASS1) expression is silenced in 88% of all sarcomas (n = 708) (Bean et al., 2016, Cell Death and Disease), and that this loss is associated with a reliance on extracellular sources of the amino acid arginine. The arginine depleting enzyme PEGylated arginine deiminase (ADI-PEG 20) depletes extracellular arginine. Preclinical studies have demonstrated that arginine starvation and D administration induce c-Myc-driven hENT1 surface expression overcoming intrinsic cell surface G transporter related resistance. To test this hypothesis, we opened this multi-institutional randomized phase II trial examining the safety and efficacy of ADI-PEG 20 with G + D in STS (NCT03449901) in July of 2018. Methods: Eligible patients are adults with metastatic or unresectable histologically or cytologically confirmed FNCLCC grade 2 or 3 STS that would be standardly treated with G and/or D. Patients are treated with ADI-PEG 20 at a dose of 36 mg/m2 via intramuscular injection on Day -7 of Cycle 1 and then on Days 1, 8, and 15 of each subsequent cycle. G will be given intravenously at a dose of 750 mg/m2 over 90 minutes on Days 1 and 8 and D will be given intravenously at a dose of 75 mg/m2 over 60 minutes on Day 8 of each cycle. The median PFS of metastatic sarcoma patients receiving the standard G + D treatment was estimated to be 6.2 months in a randomized phase II study (Maki et. al., 2007, JCO). With the addition of ADI-PEG 20, we target to improve the median PFS to 9 months, a 45.2% (2.8 months or 12 weeks) improvement in patients treated on G + D + ADI-PEG 20 against the null hypothesis median PFS of 6.2 months to achieve 80% power to detect the improvement in PFS at a 5% alpha level. Tumor specimens (pre- and post-ADI-PEG 20 during week -1) and blood are collected for correlative studies including metabolomics, pharmacodynamics, immunogenicity and ASS1 biomarkers. Quality of life will be measured using FACT-G7. Clinical trial information: NCT03449901