Advertisement

Investigational New Drugs

, Volume 33, Issue 2, pp 496–504 | Cite as

Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma

  • Thomas YauEmail author
  • Paul N. Cheng
  • Pierre Chan
  • Li Chen
  • Jimmy Yuen
  • Roberta Pang
  • Sheung Tat Fan
  • Denys N. Wheatley
  • Ronnie T. Poon
PHASE II STUDIES

Summary

This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90 %) were hepatitis B carriers. Median age was 61.5 (range 30–75). Overall disease control rate was 13 %, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95 % CI: 1.67–1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95 % CI: 3.3–12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25 %) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.

Keywords

Advanced HCC Arginine Arginase Peg-rhArg1 

Notes

Financial Support

Bio-Cancer Treatment International Limited and the University of Hong Kong Hepatocellular Carcinoma Research Grant.

Potential conflicts of interest

Drs Thomas Yau, Pierre Chan, Jimmy Yuen, Roberta Pang, Professor Sheung Tat Fan and Professor Ronnie Poon report no potential conflict of interest.

Dr Paul Cheng is the chief executive officer of Bio-Cancer Treatment International Limited. Dr Li Chen is the chief technical officer of Bio-Cancer Treatment International Limited. Professor Denys Wheatley is the chief scientific officer of Bio-Cancer Treatment International Limited.

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94(2):153–156. doi: 10.1002/ijc.1440 CrossRefPubMedGoogle Scholar
  2. 2.
    Poon RT, Fan ST, Tsang FH, Wong J (2002) Locoregional therapies for hepatocellular carcinoma: a critical review from the surgeon’s perspective. Ann Surg 235(4):466–486CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Wheatley DN (2004) Controlling cancer by restricting arginine availability–arginine-catabolizing enzymes as anticancer agents. Anti-Cancer Drugs 15(9):825–833CrossRefPubMedGoogle Scholar
  4. 4.
    Wheatley DN, Campbell E, Lai PB, Cheng PN (2005) A rational approach to the systemic treatment of cancer involving medium-term depletion of arginine. Gene Ther Mol Biol 9:33–40Google Scholar
  5. 5.
    Cheng PN, Lam TL, Lam WM, Tsui SM, Cheng AW, Lo WH, Leung YC (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(1):309–317. doi: 10.1158/0008-5472.CAN-06-1945 CrossRefPubMedGoogle Scholar
  6. 6.
    Izzo F, Marra P, Beneduce G, Castello G, Vallone P, De Rosa V, Cremona F, Ensor CM, Holtsberg FW, Bomalaski JS, Clark MA, Ng C, Curley SA (2004) Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J Clin Oncol 22(10):1815–1822. doi: 10.1200/JCO.2004.11.120 CrossRefPubMedGoogle Scholar
  7. 7.
    Yang TS, Lu SN, Chao Y, Sheen IS, Lin CC, Wang TE, Chen SC, Wang JH, Liao LY, Thomson JA, Wang-Peng J, Chen PJ, Chen LT (2010) A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br J Cancer 103(7):954–960. doi: 10.1038/sj.bjc.6605856 CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Yau T, Cheng PN, Chan P, Chan W, Chen L, Yuen J, Pang R, Fan ST, Poon RT (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(1):99–107. doi: 10.1007/s10637-012-9807-9 CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Chow AK, Ng L, Sing Li H, Cheng CW, Lam CS, Yau TC, Cheng PN, Fan ST, Poon RT, Pang RW (2012) Anti-tumor efficacy of a recombinant human arginase in human hepatocellular carcinoma. Curr Cancer Drug Targets 12(9):1233–1243PubMedGoogle Scholar
  10. 10.
    Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, Christensen E, Pagliaro L, Colombo M, Rodes J (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35(3):421–430CrossRefPubMedGoogle Scholar
  11. 11.
    Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13(3):176–181. doi: 10.1016/S1053-4296(03)00031-6 CrossRefPubMedGoogle Scholar
  12. 12.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216CrossRefPubMedGoogle Scholar
  13. 13.
    Cheng PN, Leung YC, Lo WH, Tsui SM, Lam KC (2005) Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: arginase as a potential drug candidate for hepatocellular carcinoma. Cancer Lett 224(1):67–80. doi: 10.1016/j.canlet.2004.10.050 CrossRefPubMedGoogle Scholar
  14. 14.
    Yau T, Yao TJ, Chan P, Ng K, Fan ST, Poon RT (2008) A new prognostic score system in patients with advanced hepatocellular carcinoma not amendable to locoregional therapy: implication for patient selection in systemic therapy trials. Cancer 113(10):2742–2751. doi: 10.1002/cncr.23878 CrossRefPubMedGoogle Scholar
  15. 15.
    Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z (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(1):25–34. doi: 10.1016/S1470-2045(08)70285-7 CrossRefPubMedGoogle Scholar
  16. 16.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390CrossRefPubMedGoogle Scholar
  17. 17.
    Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G, Omata M, Pitman Lowenthal S, Lanzalone S, Yang L, Lechuga MJ, Raymond E (2013) Sunitinib versus Sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 31(32):4067–4075. doi: 10.1200/JCO.2012.45.8372 CrossRefPubMedGoogle Scholar
  18. 18.
    Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y (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(28):3501–3508. doi: 10.1200/JCO.2012.44.5643 CrossRefPubMedGoogle Scholar
  19. 19.
    Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, Koh J, Mo FK, Yu SC, Chan AT, Hui P, Ma B, Lam KC, Ho WM, Wong HT, Tang A, Johnson PJ (2005) A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 97(20):1532–1538. doi: 10.1093/jnci/dji315 CrossRefPubMedGoogle Scholar
  20. 20.
    Leung TW, Patt YZ, Lau WY, Ho SK, Yu SC, Chan AT, Mok TS, Yeo W, Liew CT, Leung NW, Tang AM, Johnson PJ (1999) Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res 5(7):1676–1681Google Scholar
  21. 21.
    Wheatley DN (2012) Amino acid deprivation as the primary intervention in cancer therapy: cellular basis of effective combinatorial therapy with arginase as the platform. Biomed Res 23:149–154Google Scholar
  22. 22.
    Bowles TL, Kim R, Galante J, Parsons CM, Virudachalam S, Kung HJ, Bold RJ (2008) Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. Int J Cancer 123(8):1950–1955. doi: 10.1002/ijc.23723 CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Dillon BJ, Prieto VG, Curley SA, Ensor CM, Holtsberg FW, Bomalaski JS, Clark MA (2004) Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation. Cancer 100(4):826–833. doi: 10.1002/cncr.20057 CrossRefPubMedGoogle Scholar
  24. 24.
    Yoon CY, Shim YJ, Kim EH, Lee JH, Won NH, Kim JH, Park IS, Yoon DK, Min BH (2007) Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. Int J Cancer 120(4):897–905. doi: 10.1002/ijc.22322 CrossRefPubMedGoogle Scholar
  25. 25.
    Hsueh EC, Knebel SM, Lo WH, Leung YC, Cheng PN, Hsueh CT (2012) Deprivation of arginine by recombinant human arginase in prostate cancer cells. J Hematol Oncol 5:17. doi: 10.1186/1756-8722-5-17 CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Lam TL, Wong GK, Chong HC, Cheng PN, Choi SC, Chow TL, Kwok SY, Poon RT, Wheatley DN, Lo WH, Leung YC (2009) Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest. Cancer Lett 277(1):91–100. doi: 10.1016/j.canlet.2008.11.031 CrossRefPubMedGoogle Scholar
  27. 27.
    Lam TL, Wong GK, Chow HY, Chong HC, Chow TL, Kwok SY, Cheng PN, Wheatley DN, Lo WH, Leung YC (2011) Recombinant human arginase inhibits the in vitro and in vivo proliferation of human melanoma by inducing cell cycle arrest and apoptosis. Pigment Cell Melanoma Res 24(2):366–376. doi: 10.1111/j.1755-148X.2010.00798.x CrossRefPubMedGoogle Scholar
  28. 28.
    Sugimura K, Ohno T, Kusuyama T, Azuma I (1992) High sensitivity of human melanoma cell lines to the growth inhibitory activity of mycoplasmal arginine deiminase in vitro. Melanoma Res 2(3):191–196CrossRefPubMedGoogle Scholar
  29. 29.
    Takaku H, Takase M, Abe S, Hayashi H, Miyazaki K (1992) In vivo anti-tumor activity of arginine deiminase purified from Mycoplasma arginini. Int J Cancer 51(2):244–249CrossRefPubMedGoogle Scholar
  30. 30.
    Tsui SM, Lam WM, Lam TL, Chong HC, So PK, Kwok SY, Arnold S, Cheng PN, Wheatley DN, Lo WH, Leung YC (2009) Pegylated derivatives of recombinant human arginase (rhArg1) for sustained in vivo activity in cancer therapy: preparation, characterization and analysis of their pharmacodynamics in vivo and in vitro and action upon hepatocellular carcinoma cell (HCC). Cancer Cell Int 9:9. doi: 10.1186/1475-2867-9-9 CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Hernandez CP, Morrow K, Lopez-Barcons LA, Zabaleta J, Sierra R, Velasco C, Cole J, Rodriguez PC (2010) Pegylated arginase I: a potential therapeutic approach in T-ALL. Blood 115(25):5214–5221. doi: 10.1182/blood-2009-12-258822 CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Dillon BJ, Holtsberg FW, Ensor CM, Bomalaski JS, Clark MA (2002) Biochemical characterization of the arginine degrading enzymes arginase and arginine deiminase and their effect on nitric oxide production. Med Sci Monit: Int Med J Exp Clin Res 8(7):BR248–BR253Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Thomas Yau
    • 1
    • 2
    • 3
    Email author
  • Paul N. Cheng
    • 4
  • Pierre Chan
    • 5
  • Li Chen
    • 4
  • Jimmy Yuen
    • 6
  • Roberta Pang
    • 2
    • 7
  • Sheung Tat Fan
    • 2
    • 3
    • 7
  • Denys N. Wheatley
    • 4
  • Ronnie T. Poon
    • 2
    • 3
    • 7
  1. 1.Department of MedicineThe University of Hong KongHong KongChina
  2. 2.Centre for Cancer ResearchThe University of Hong KongHong KongChina
  3. 3.State Key Laboratory for Liver ResearchThe University of Hong KongHong KongChina
  4. 4.Bio-Cancer Treatment International LimitedHong KongChina
  5. 5.Department of MedicineRuttonjee HospitalHong KongChina
  6. 6.Hong Kong Sanatorium HospitalHong KongChina
  7. 7.Department of SurgeryThe University of Hong Kong, Queen Mary HospitalHong KongChina

Personalised recommendations