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.

Abstract

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.

• Authors: A L Hamilton, J P Eder, A C Pavlick, J W Clark, L Liebes, R Garcia-Carbonero, A Chachoua, D P Ryan, V Soma, K Farrell, N Kinchla, J Boyden, H Yee, A Zeleniuch-Jacquotte, J Wright, P Elliott, J Adams, F M Muggia
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 25 Pg. 6107-16 (Sep 01 2005) ISSN: 0732-183X [Print] United States
• PMID: 16135477 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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