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- Title
A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer.
- Authors
LoConte, Noelle K.; Thomas, James P.; Alberti, Dona; Heideman, Jennifer; Binger, Kimberly; Marnocha, Rebecca; Utecht, Kyle; Geiger, Peter; Eickhoff, Jens; Wilding, George; Kolesar, Jill
- Abstract
This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies. Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m2 of bortezomib with 15 mg/m2 of doxorubicin to 1.5 mg/m2 of bortezomib with 20 mg/m2 of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates. The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m2 bortezomib, 20 mg/m2 doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m2 bortezomib, 15 mg/m2 doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients. Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m2 intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease.
- Subjects
PHARMACODYNAMICS; CANCER patients; DOXORUBICIN; NEUROPATHY; PROSTATE cancer
- Publication
Cancer Chemotherapy & Pharmacology, 2008, Vol 63, Issue 1, p109
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-008-0719-5