A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma
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Officially Accepted for Publication


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AbstractBackground: 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.
Acceptance Date28/03/2021
All Author(s) ListStephen L. Chan, Paul N.M. Cheng, Angela M. Liu, Landon L. Chan, Leung Li, Cheuk M. Chu, Charing C.N. Chong, Yat M. Lau, Winnie Yeo, Kelvin K.C. Ng, Simon C.H. Yu, Tony S.K. Mok, Anthony W.H. Chan
Journal nameInvestigational New Drugs
Year2021
PublisherSpringer
ISSN0167-6997
eISSN1573-0646
LanguagesEnglish-United States
KeywordsLiver cancer, Arginine deprivation, Biomarkers, PEG-BCT-100, Second line

Last updated on 2021-13-06 at 00:59