PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib 
administration once every 2 weeks to determine the recommended phase II dose and 
toxicity profile, and the extent of 20S proteasome inhibition obtained.
PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with 
bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome 
levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in 
cycle 1.
RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) 
was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients 
receiving individual total doses > or = 3.0 mg. The main DLT was peripheral 
neuropathy evident at the higher doses and in patients previously exposed to 
neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 
thrombocytopenia was also noted. Reversible inhibition of 20S proteasome 
activity was dose dependent and best fit a total dose (mg) per fraction rather 
than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg 
given on D1 and on D4 every other week. Antitumor effects short of confirmed 
partial responses were observed in patients with melanoma, non-small-cell lung 
cancer, and renal cell carcinoma.
CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well 
tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on 
D1 and D4 every other week. This dose correlates with 70% inhibition of 20S 
proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.