Abstract
<title>Abstract</title> <p>Background Arginine deprivation with pegylated arginine deiminase (ADI-PEG 20, pegargiminase) may enhance chemotherapy efficacy in soft tissue sarcomas (STS). We conducted a phase II trial (NCT03449901) evaluating ADI-PEG20 plus gemcitabine/docetaxel in advanced STS. Methods Seventy-five evaluable patients received ADI-PEG20 with gemcitabine/docetaxel across three dose cohorts. Correlative analyses included immunogenicity, transcriptomics, and metabolomics for a subset of patients. Results Median PFS was 4.03 months and OS was 18.83 months, with a clinical benefit rate of 66.2%. Clinical benefit was preserved across gemcitabine/docetaxel dose cohorts, including the reduced-dose 600/60 mg/m² cohort selected after protocol-directed safety monitoring. Transcriptomics revealed MYC pathway enrichment in treated tumors. Metabolomics confirmed arginine depletion with compensatory glutamine anaplerosis and increased nucleotide turnover. Conclusions ADI-PEG20 plus gemcitabine/docetaxel demonstrates clinical activity in advanced STS. Correlative analyses provide the first clinical validation of arginine deprivation-induced metabolic reprogramming, supporting combination strategies targeting compensatory metabolic pathways.</p>