Abstract
Background: Pegylated recombinant human arginase (PEG-BCT-100) is an arginine depleting drug. Preclinical studies showed that HCC is reliant on exogenous arginine for growth due to the under-expression of the arginine regenerating enzymes argininosuccinate synthetase (ASS) and ornithine transcarbamylase (OTC). Methods: This is a single arm open-label Phase II trial to assess the potential clinical efficacy of PEG-BCT-100 in chemo naïve sorafenib-failure HCC patients. Pre-treatment tumour biopsy was mandated for ASS and OTC expression by immunohistochemistry (IHC). Weekly intravenous PEG-BCT-100 at 2.7 mg/kg was given. Primary endpoint was time to progression (TTP); secondary endpoints included radiological response as per RECIST1.1, progression free survival (PFS) and overall survival (OS). Treatment outcomes were correlated with tumour immunohistochemical expressions of ASS and OTC. Results: In total 27 patients were recruited. The median TTP and PFS were both 6 weeks (95% CI, 5.9–6.0 weeks). The disease control rate (DCR) was 21.7% (5 stable disease). The drug was well tolerated. Post hoc analysis showed that duration of arginine depletion correlated with OS. For patients with available IHC results, 10 patients with ASS-negative tumour had OS of 35 weeks (95% CI: 8.3–78.0 weeks) vs. 15.14 weeks (95% CI: 13.4–15.1 weeks) in 3 with ASS-positive tumour; expression of OTC did not correlate with treatment outcomes. Conclusions: PEG-BCT-100 in chemo naïve post-sorafenib HCC is well tolerated with moderate DCR. ASS-negative confers OS advantage over ASS-positive HCC. ASS-negativity is a potential biomarker for OS in HCC and possibly for other ASS-negative arginine auxotrophic cancers. Trial registration number: NCT01092091. Date of registration: March 23, 2010.
Highlights
Arginine is a conditional/semi-essential amino acid involved in the synthesis of a wide range of proteins, a myriad of metabolic pathways as well as being a signing molecule in various cellular pathways [1]
Arginine deprivation could induce tumour regression in a group of cancers designated as arginine auxotrophic cancers which include melanoma, prostate cancer, acute myeloid leukaemia and hepatocellular carcinoma (HCC) [3, 4]
For selection of cancers for arginine deprivation therapy, it has been postulated that tumours with absent or low expression of arginine regeneration enzymes, argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC), are reliant on exogenous source of arginine for growth and more sensitive to arginine deprivation [3, 5]
Summary
Arginine is a conditional/semi-essential amino acid involved in the synthesis of a wide range of proteins, a myriad of metabolic pathways as well as being a signing molecule in various cellular pathways [1]. Regarding evaluation of predictive biomarker for PEG-BCT-100, patients were not mandated to have pretreatment tumour tissues in previous clinical trials evaluations of ASS and OTC were not available to correlate with treatment outcomes [8]. We set to evaluate in a phase II setting the treatment efficacy of PEG-BCT100 in post sorafenib HCC and to correlate treatment outcomes with tumour expression of ASS and OTC (NCT02089763).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
