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

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.

Safety, PK/PD and preliminary anti-tumor activities of pegylated recombinant human arginase 1 (BCT-100) in patients with advanced arginine auxotrophic tumors

“…In vitro and in vivo, BCT-100 synergizes with a number of chemotherapeutic agents in different arginine auxotrophic cancer models [3]. In our previous Phase II HCC study, BCT-100 in combination with oxaliplatin-based chemotherapy led to a significant improvement in OS for patients with ASS1 deficient HCC tumours [20]. We plan to test the efficacy of BCT-100 in combination with oxaliplatin-based chemotherapy in ASS1 deficient HCC patients.…”

PEG-BCT-100 in Combination With Capecitabine and Oxaliplatin (PACOX) in Patients With Advanced Hepatocellular Carcinoma: A Phase I Study Results

“…This PACOX study was one of the two clinical studies launched in 2014 to test the potential clinical efficacy of PEG-BCT-100 in combination with chemotherapy in HCC and as monotherapy to test if clinical outcomes were influenced by the tumor expression of the arginine regeneration enzyme Argininosuccinate synthetase1 (ASS1). The ASS1 study showed that OS was significantly longer in patients with HCC that under-expressed ASS1 (7). Therefore, it would be logical use ASS1 as a biomarker selection in our future PACOX study, which is now been actively planned.…”

“…Depletion of arginine in vitro and in vivo lead to rapid cell death of this type of cancer, which are termed as arginine auxotrophic cancer (6). Tumor ASS negativity could also be used as a biomarker predicting anti-tumor response (7). Currently there are two main arginine depleting agents in clinical phase development in HCC:…”

Personalized treatment for hepatocellular carcinoma: Current status and future perspectives

“…Total 27 patients with prior treatment of sorafenib were recruited, and final results showed that the median PFS and OS were 6.0 weeks and 23.7 weeks, respectively. 25 Biomarker analyses showed that ASS-negativity was associated with a trend of better OS (35 weeks) as compared with ASS-positive HCC (15.1 weeks), but OTC expression was not associated with treatment outcome. 25 Finally, ramucirumab is monoclonal antibody against the VEGFR2, which was found by the REACH study to be associated with better median OS in HCC patients with prior sorafenib and baseline serum alpha-fetoprotein (AFP) of 400 ng/mL or higher.…”

“…In this study, all patients were required to undergo liver biopsy to obtain tissue for IHC assessment of ASS and OTC. Total 27 patients with prior treatment of sorafenib were recruited, and final results showed that the median PFS and OS were 6.0 weeks and 23.7 weeks, respectively 25 . Biomarker analyses showed that ASS‐negativity was associated with a trend of better OS (35 weeks) as compared with ASS‐positive HCC (15.1 weeks), but OTC expression was not associated with treatment outcome 25 …”