A phase II study of ADI-PEG 20 and FOLFOX6 in patients (pts) with advanced hepatocellular carcinoma (HCC).

Abstract

TPS477 Background: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways, and preclinical data indicate that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in HCC models. A prior phase 1 study of FOLFOX6 and ADI-PEG 20 established the safety and recommended phase 2 dose of the combination in pts with advanced gastrointestinal tumors (Harding et al. CCP 2018). For 23 treatment-refractory HCC pts who were treated at the recommended phase 2 dose on an expansion cohort of the phase 1, the objective response rate (ORR) was 21% (95% CI 7.5-43.7) and median progression-free survival (PFS) was 7.3 months. These data were favorable when compared to historic data for FOLFOX alone where the ORR was ~8% and PFS was 2.93 months and suggest greater clinical activity of the combination (Qin et al. JCO 2013). Prospective confirmation of these results is required. Methods: This is an international, multicenter, single-arm, open-label phase 2 trial of ADI-PEG 20 and FOLFOX6 for advanced HCC pts with Child-Pugh A liver function who progressed on ≥ 2 prior lines of prior systemic therapy (NCT02102022). The primary objective is to define the ORR by RECIST 1.1 as assessed by blinded independent central review. Secondary objectives include determination of safety, disease control rate (DCR), duration of response (DOR), PFS, overall survival (OS), serum arginine, citrulline and anti-ADI-PEG 20 levels over 24 weeks, and alpha-fetoprotein response. Eligible pts receive intravenous FOLFOX6 biweekly at standard doses and ADI-PEG 20 intramuscularly weekly at 36 mg/m.2 Cross-sectional imaging will be completed every 8 weeks until progression of disease. Based on a two-sided exact test of a one-sample proportion with an alpha of 0.05, under a presumed ORR of 22%, there is 80% power to yield 95% confidence interval of 15-26%, which will require 46 objective responses in 225 subjects. Futility will be assessed three times during the study based on having ORR data available for 56, 110, and 166 patients. This Phase 2 will be stopped for futility if the conditional power drops below 20% at any of these time points. Clinical trial information: NCT02102022.