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:
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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.)
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Chemical References |
- Antineoplastic Agents
- Boronic Acids
- Proteasome Inhibitors
- Pyrazines
- Bortezomib
- Proteasome Endopeptidase Complex
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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
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