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


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.


Boronic acids Antineoplastic agents Biologic agents Treatment outcome 



Hepatocellular carcinoma


Response rate


Adverse events


Vascular endothelial growth factor


Upper normal limit


Common terminology criteria for adverse events


Complete blood cell counts


Complete response


Partial response


Progressive disease


Stable disease


Confidence intervals


Sorafenib hepatocellular carcinoma assessment randomized protocol


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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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