Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle

J Clin Oncol. 2005 Sep 1;23(25):6107-16. doi: 10.1200/JCO.2005.01.136.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Boronic Acids / administration & dosage
  • Boronic Acids / pharmacokinetics*
  • Boronic Acids / pharmacology*
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Drug Administration Schedule
  • Female
  • Humans
  • Infusions, Intravenous
  • Lymphoma / drug therapy
  • Male
  • Middle Aged
  • Neoplasms / drug therapy
  • Peripheral Nervous System / drug effects
  • Peripheral Nervous System / pathology
  • Proteasome Endopeptidase Complex / blood
  • Proteasome Inhibitors
  • Pyrazines / administration & dosage
  • Pyrazines / pharmacokinetics*
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use
  • Treatment Outcome


  • Antineoplastic Agents
  • Boronic Acids
  • Proteasome Inhibitors
  • Pyrazines
  • Bortezomib
  • Proteasome Endopeptidase Complex