Investigational New Drugs

, Volume 30, Issue 1, pp 387–394 | Cite as

An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma

  • George P. Kim
  • Michelle R. Mahoney
  • Daniel Szydlo
  • Tony S. K. Mok
  • Robert Marshke
  • Kyle Holen
  • Joel Picus
  • Michael Boyer
  • Henry C. Pitot
  • Joseph Rubin
  • Philip A. Philip
  • Anna Nowak
  • John J. Wright
  • Charles Erlichman
PHASE II STUDIES

Summary

Background and Rationale Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin-proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. Methods The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Results Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1–12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. Conclusions This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.

Keywords

Boronic acids Antineoplastic agents Biologic agents Treatment outcome 

Abbreviations

HCC

Hepatocellular carcinoma

RR

Response rate

AEs

Adverse events

VEGF

Vascular endothelial growth factor

UNL

Upper normal limit

CTCAE

Common terminology criteria for adverse events

CBCs

Complete blood cell counts

CR

Complete response

PR

Partial response

PD

Progressive disease

SD

Stable disease

CIs

Confidence intervals

SHARP

Sorafenib hepatocellular carcinoma assessment randomized protocol

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedCrossRefGoogle Scholar
  2. 2.
    El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the united states. N Engl J Med 340(10):745–750. doi:10.1056/nejm199903113401001 PubMedCrossRefGoogle Scholar
  3. 3.
    El-Serag HB (2007) Epidemiology of hepatocellular carcinoma in USA. Hepatol Res 37(Suppl 2):S88–94PubMedCrossRefGoogle Scholar
  4. 4.
    Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB (2006) Phase ii study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(26):4293–4300PubMedCrossRefGoogle Scholar
  5. 5.
    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):378–390PubMedCrossRefGoogle Scholar
  6. 6.
    Cheng A, Kang Y, Chen Z, Tsao C, Qin S, Kim J, Burock K, Zou J, Voliotis D, Guan ZZ (2008) Randomized phase iii trial of sorafenib versus placebo in asian patients with advanced hepatocellular carcinoma. J Clin Oncol (Meeting Abstracts) 26 (15_suppl):4509Google Scholar
  7. 7.
    Teicher BA, Ara G, Herbst R, Palombella VJ, Adams J (1999) The proteasome inhibitor ps-341 in cancer therapy. Clin Cancer Res 5(9):2638–2645PubMedGoogle Scholar
  8. 8.
    Rolfe M, Chiu MI, Pagano M (1997) The ubiquitin-mediated proteolytic pathway as a therapeutic area. J Mol Med 75(1):5–17PubMedCrossRefGoogle Scholar
  9. 9.
    Ciechanover A, Orian A, Schwartz AL (2000) Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays 22(5):442–451PubMedCrossRefGoogle Scholar
  10. 10.
    Ozturk M (1999) Genetic aspects of hepatocellular carcinogenesis. Semin Liver Dis 19(3):235–242PubMedCrossRefGoogle Scholar
  11. 11.
    Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC (1994) Hepatitis b virus x protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ercc3. Proc Natl Acad Sci USA 91(6):2230–2234PubMedCrossRefGoogle Scholar
  12. 12.
    Ray RB, Steele R, Meyer K, Ray R (1997) Transcriptional repression of p53 promoter by hepatitis c virus core protein. J Biol Chem 272(17):10983–10986PubMedCrossRefGoogle Scholar
  13. 13.
    Frankel A, Man S, Elliott P, Adams J, Kerbel RS (2000) Lack of multicellular drug resistance observed in human ovarian and prostate carcinoma treated with the proteasome inhibitor ps-341. Clin Cancer Res 6(9):3719–3728PubMedGoogle Scholar
  14. 14.
    Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C, Sausville E, Adams J, Elliott P, Van Waes C (2001) Novel proteasome inhibitor ps-341 inhibits activation of nuclear factor-kappa b, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7(5):1419–1428PubMedGoogle Scholar
  15. 15.
    Cusack JC Jr, Liu R, Houston M, Abendroth K, Elliott PJ, Adams J, Baldwin AS Jr (2001) Enhanced chemosensitivity to cpt-11 with proteasome inhibitor ps-341: Implications for systemic nuclear factor-kappab inhibition. Cancer Res 61(9):3535–3540PubMedGoogle Scholar
  16. 16.
    Bold RJ, Virudachalam S, McConkey DJ (2001) Chemosensitization of pancreatic cancer by inhibition of the 26s proteasome. J Surg Res 100(1):11–17PubMedCrossRefGoogle Scholar
  17. 17.
    San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos M-V, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG, The VTI (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–917. doi:10.1056/NEJMoa0801479 PubMedCrossRefGoogle Scholar
  18. 18.
    Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617PubMedCrossRefGoogle Scholar
  19. 19.
    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):205–216PubMedCrossRefGoogle Scholar
  20. 20.
    Simon R (1989) Optimal two-stage designs for phase ii clinical trials. Control Clin Trials 10(1):1–10PubMedCrossRefGoogle Scholar
  21. 21.
    Duffy D, Santner T (1987) Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81–93CrossRefGoogle Scholar
  22. 22.
    Kaplan MP (1958) Nonparametirc estimation for incomplete observations. J Am Stat Assoc 53:457–481CrossRefGoogle Scholar
  23. 23.
    Chang L, Kamata H, Solinas G, Luo J-L, Maeda S, Venuprasad K, Liu Y-C, Karin M (2006) The e3 ubiquitin ligase itch couples jnk activation to tnf[alpha]-induced cell death by inducing c-flipl turnover. Cell 124(3):601–613PubMedCrossRefGoogle Scholar
  24. 24.
    Anan A, Baskin-Bey ES, Isomoto H, Mott JL, Bronk SF, Albrecht JH, Gores GJ (2006) Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse. Am J Physiol Gastrointest Liver Physiol 291(4):G709–716. doi:10.1152/ajpgi.00126.2006 PubMedCrossRefGoogle Scholar
  25. 25.
    Davis NB, Taber DA, Ansari RH, Ryan CW, George C, Vokes EE, Vogelzang NJ, Stadler WM (2004) Phase ii trial of ps-341 in patients with renal cell cancer: a university of chicago phase ii consortium study. J Clin Oncol 22(1):115–119. doi:10.1200/jco.2004.07.165 PubMedCrossRefGoogle Scholar
  26. 26.
    Engel RH, Brown JA, Von Roenn JH, O’Regan RM, Bergan R, Badve S, Rademaker A, Gradishar WJ (2007) A phase ii study of single agent bortezomib in patients with metastatic breast cancer: a single institution experience. Cancer Investig 25(8):733–737CrossRefGoogle Scholar
  27. 27.
    Mackay H, Hedley D, Major P, Townsley C, Mackenzie M, Vincent M, Degendorfer P, Tsao M-S, Nicklee T, Birle D, Wright J, Siu L, Moore M, Oza A (2005) A phase ii trial with pharmacodynamic endpoints of the proteasome inhibitor bortezomib in patients with metastatic colorectal cancer. Clin Cancer Res 11(15):5526–5533. doi:10.1158/1078-0432.ccr-05-0081 PubMedCrossRefGoogle Scholar
  28. 28.
    Kozuch PS, Rocha-Lima CM, Dragovich T, Hochster H, O’Neil BH, Atiq OT, Pipas JM, Ryan DP, Lenz H-J (2008) Bortezomib with or without irinotecan in relapsed or refractory colorectal cancer: results from a randomized phase ii study. J Clin Oncol 26(14):2320–2326. doi:10.1200/jco.2007.14.0152 PubMedCrossRefGoogle Scholar
  29. 29.
    Alberts SR, Foster NR, Morton RF, Kugler J, Schaefer P, Wiesenfeld M, Fitch TR, Steen P, Kim GP, Gill S (2005) Ps-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a north central cancer treatment group (ncctg) randomized phase ii study. Ann Oncol 16(10):1654–1661PubMedCrossRefGoogle Scholar
  30. 30.
    Hegewisch-Becker S, Sterneck M, Schubert U, Rogiers X, Guerciolini R, Pierce JE, Hossfeld DK (2004) Phase i/ii trial of bortezomib in patients with unresectable hepatocellular carcinoma (hcc). J Clin Oncol (Meeting Abstracts) 22 (14_suppl):4089Google Scholar
  31. 31.
    Berlin JD, Powell ME, Su Y, Horton L, Short S, Richmond A, Kauh JS, Staley CA, Mulcahy M, Benson AB, III (2008) Bortezomib (b) and doxorubicin (dox) in patients (pts) with hepatocellular cancer (hcc): A phase ii trial of the eastern cooperative oncology group (ecog 6202) with laboratory correlates. J Clin Oncol (Meeting Abstracts) 26 (15_suppl):4592Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • George P. Kim
    • 1
  • Michelle R. Mahoney
    • 2
  • Daniel Szydlo
    • 2
  • Tony S. K. Mok
    • 3
  • Robert Marshke
    • 4
  • Kyle Holen
    • 5
  • Joel Picus
    • 6
  • Michael Boyer
    • 7
  • Henry C. Pitot
    • 2
  • Joseph Rubin
    • 2
  • Philip A. Philip
    • 8
  • Anna Nowak
    • 9
  • John J. Wright
    • 10
  • Charles Erlichman
    • 2
  1. 1.Mayo Clinic FloridaJacksonvilleUSA
  2. 2.Mayo Clinic RochesterRochesterUSA
  3. 3.National University HospitalSingaporeSingapore
  4. 4.Mayo Clinic ArizonaScottsdaleUSA
  5. 5.University of Wisconsin Carbone Cancer CenterMadisonUSA
  6. 6.Washington UniversitySt. LouisUSA
  7. 7.Royal Prince Alfred HospitalCamperdownAustralia
  8. 8.Karmanos Cancer InstituteDetroitUSA
  9. 9.Sir Charles Gairdner HospitalPerthAustralia
  10. 10.National Cancer InstituteRockvilleUSA

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