Phase I/II trial of bortezomib in patients with unresectable hepatocellular carcinoma (HCC)

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4089 Background: Bortezomib (Velcade) is a potent and reversible inhibitor of the proteasome and causes apoptotic cell death in a dose dependent matter in the human malignant hepatoma cell line HepG2. Available chemotherapeutic agents offer limited benefit to patients (pts) with HCC. The primary objective of this phase I/II study was to assess the dose limiting (DLT) and maximum tolerated dose (MTD) of bortezomib given as an iv bolus on days 1, 4, 8 and 11 of a 3 week cycle. Secondary objectives included response assessment, safety and pharmacodynamics of bortezomib. Methods: Eligibility criteria included histologically documented or diagnostic evidence of diagnosis of hepatocellular carcinoma and measurable surgically unresectable disease. So far 18 pts have been accrued to the study (17 male/1 female; Child-Pugh score A/B - 13/5 pts), median age 62 (range 33–82), a median KPS 80% (range 70–100). A prior history of hepatitis B and/or C or alcoholic cirrhosis was present in 39% and 17%, respectively.The DLT was defined on toxicities which occurred in cycle 1. Responses were evaluated every 4 cycles by CT scan using RECIST criteria. Results: A mean of 4.5 cycles (range 1–12) has been administered to these pts, 28 cycles at dose level 1 (1 mg/m2, 6 pts) and 54 cycles at dose level 2 (1.3 mg/m2, 12 pts).No grade III/IV DLTs in cycle 1 occurred. Grade II/III toxicities per pt included thrombocytopenia (7/3, respectively), fatigue (5/3), neuropathy (2/1), loss of appetite (6/2), hypotension (0/2), and abdominal cramps (2/1). 1 grade IV thrombocytopenia was observed. 5 pts required dose reduction. Based on observed toxicities in all cycles 1.3 mg/m2 was considered the MTD. SD has been observed in 7/15 evaluable pts lasting for 21, 14, 36+, 22+, 16+, 12+ and 9+ weeks, 8 pts progressed. Pharmacodynamics of bortezomib were similar to findings in pts without compromised liver function. Conclusions: Bortezomib appeared to be well tolerated in pts with HCC. Doxorubicin is considered standard treatment in HCC. Since proteasome inhibitors attenuate certain pathways implicated in resistance to anthracyclines further study of bortezomib in combination with doxorubicin may be warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millenium Pharmaceuticals Millenium Pharmaceuticals Millenium Pharmaceuticals Millennium Pharmaceuticals