Investigational New Drugs

, Volume 30, Issue 1, pp 387-394

First online:

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

  • George P. KimAffiliated withMayo Clinic Florida Email author 
  • , Michelle R. MahoneyAffiliated withMayo Clinic Rochester
  • , Daniel SzydloAffiliated withMayo Clinic Rochester
  • , Tony S. K. MokAffiliated withNational University Hospital
  • , Robert MarshkeAffiliated withMayo Clinic Arizona
  • , Kyle HolenAffiliated withUniversity of Wisconsin Carbone Cancer Center
  • , Joel PicusAffiliated withWashington University
  • , Michael BoyerAffiliated withRoyal Prince Alfred Hospital
  • , Henry C. PitotAffiliated withMayo Clinic Rochester
    • , Joseph RubinAffiliated withMayo Clinic Rochester
    • , Philip A. PhilipAffiliated withKarmanos Cancer Institute
    • , Anna NowakAffiliated withSir Charles Gairdner Hospital
    • , John J. WrightAffiliated withNational Cancer Institute
    • , Charles ErlichmanAffiliated withMayo Clinic Rochester

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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