Summary
Introduction. We investigated the safety and efficacy of a pegylated arginase (PEG-BCT-100) in combination with chemotherapy (oxaliplatin and capecitabine) [PACOX] in advanced HCC patients. Methods. This was a single centre phase 1 trial to assess the safety and tolerability of PACOX. All the enrolled subjects received treatment in 3-weekly cycles: intravenous PEG-BCT-100 2.7 mg/kg on days 1, 8 and 15 of each cycle; oral capecitabine 1000 mg/m2 twice daily on day 1–14 of each cycle and intravenous oxaliplatin on day 1. Three dose levels of oxaliplatin (85 mg/m2, 100 mg/m2 or 130 mg/m2) were studied to define the maximum tolerated dose (MTD). Adverse events (AEs), efficacy by RECIST v1.1, time to progression (TTP), progression-free survival (PFS) and overall survival (OS) were studied. Results. Seventeen patients were enrolled at 3 dose levels of oxaliplatin: 85 mg/m2 (8 patients), 100 mg/m2 (3 patients), and 130 mg/m2 (6 patients). The median age was 55 years; all had had locoregional chemotherapy or targeted therapy such as sorafenib, but no systemic chemotherapy. The most common AEs were nausea (82%), injection site reaction (76%), palmar-plantar erythrodysesthesia (59%), oral mucositis (53%) and vomiting (53%). There was no dose-limiting toxicity (DLT). Median duration on study was 8 weeks overall. In 14 evaluable cases, one achieved partial response (PR), 4 had stable disease (SD); disease control rate was 36%; most responses were observed in the 130 mg/m2 cohort with 1 PR and 2 SDs. Median TTP and PFS were both 7.0 weeks. Overall median OS was 10.7 months; the median OS was not reached at 19.4 months of follow-up in the 130 mg/m2 cohort. Conclusion. The PACOX regimen demonstrated good anti-cancer activity and survival advantage in advanced pre-treated HCC with favourable safety profile. It warrants further phase II/III studies.
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References
Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J et al (2013) Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol 31:3501–3508
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390
Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, Qin S, Kim JS et al (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10:25–34
Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M et al (2020) REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol 55:113–122
Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y et al (2021) IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). JCO Wolters Kluwer 39:267–267
Scott L, Lamb J, Smith S, Wheatley DN (2000) Single amino acid (arginine) deprivation: rapid and selective death of cultured transformed and malignant cells. Br J Cancer 83:800–810
Chan SL, Cheng PNM, Liu AM, Chan LL, Li L, Chu CM et al (2021) A phase II clinical study on the efficacy and predictive biomarker of pegylated recombinant arginase on hepatocellular carcinoma. Invest New Drugs [Internet]. 2021 [cited 2021 Jun 8]; Available from: https://link.springer.com/https://doi.org/10.1007/s10637-021-01111-8
Yang T-S, Lu S-N, Chao Y, Sheen I-S, Lin C-C, Wang T-E et al (2010) A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br J Cancer 103:954–960
Abou-Alfa GK, Qin S, Ryoo B-Y, Lu S-N, Yen C-J, Feng Y-H et al (2018) Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma. Ann Oncol 29:1402–1408
Yau T, Cheng PN, Chan P, Chan W, Chen L, Yuen J et al (2013) A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma. Invest New Drugs 31:99–107
Yau T, Cheng PN, Chan P, Chen L, Yuen J, Pang R et al (2015) Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma. Invest New Drugs 33:496–504
De Santo C, Cheng P, Beggs A, Egan S, Bessudo A, Mussai F (2018) Metabolic therapy with PEG-arginase induces a sustained complete remission in immunotherapy-resistant melanoma. J Hematol Oncol 11:68
Cheng PN-M, Lam T-L, Lam W-M, Tsui S-M, Cheng AW-M, Lo W-H et al (2007) Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Res 67:309–17
Szlosarek PW, Steele JP, Nolan L, Gilligan D, Taylor P, Spicer J et al (2017) Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial. JAMA Oncol 3:58–66
Beddowes E, Spicer J, Chan PY, Khadeir R, Corbacho JG, Repana D et al (2017) Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers. J Clin Oncol 35:1778–1785
Hall PE, Lewis R, Syed N, Shaffer R, Evanson J, Ellis S et al (2019) A Phase I Study of Pegylated Arginine Deiminase (Pegargiminase), Cisplatin, and Pemetrexed in Argininosuccinate Synthetase 1-Deficient Recurrent High-grade Glioma. Clin Cancer Res 25:2708–2716
Yau T, Kang Y-K, Kim T-Y, El-Khoueiry AB, Santoro A, Sangro B et al (2020) Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol
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TY and PC designed the study, performed the research, and wrote the manuscript. AL wrote the manuscript. All authors read and approved the final manuscript.
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Yau, T., Cheng, P.N.M., Chiu, J. et al. A phase 1 study of pegylated recombinant arginase (PEG-BCT-100) in combination with systemic chemotherapy (capecitabine and oxaliplatin)[PACOX] in advanced hepatocellular carcinoma patients. Invest New Drugs 40, 314–321 (2022). https://doi.org/10.1007/s10637-021-01178-3
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DOI: https://doi.org/10.1007/s10637-021-01178-3