An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma.
OBJECTIVE
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.
Kim
George P
GP
Mayo Clinic Florida, Jacksonville, FL, USA. kim.george@mayo.edu
Mahoney
Michelle R
MR
Szydlo
Daniel
D
Mok
Tony S K
TS
Marshke
Robert
R
Holen
Kyle
K
Picus
Joel
J
Boyer
Michael
M
Pitot
Henry C
HC
Rubin
Joseph
J
Philip
Philip A
PA
Nowak
Anna
A
Wright
John J
JJ
Erlichman
Charles
C
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009656:North America; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease