Faculty Collaboration Database

A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer. Cancer Chemother Pharmacol 2008 Dec;63(1):109-15

Date

03/07/2008

Pubmed ID

18322686

DOI

10.1007/s00280-008-0719-5

Scopus ID

2-s2.0-53149091626 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

PURPOSE: 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.

PATIENTS AND METHODS: 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/m(2) of bortezomib with 15 mg/m(2) of doxorubicin to 1.5 mg/m(2) of bortezomib with 20 mg/m(2) of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates.

RESULTS: The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m(2) bortezomib, 20 mg/m(2) doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m(2) bortezomib, 15 mg/m(2) 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.

CONCLUSIONS: Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m(2 )intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m(2) 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.

Author List

LoConte NK, Thomas JP, Alberti D, Heideman J, Binger K, Marnocha R, Utecht K, Geiger P, Eickhoff J, Wilding G, Kolesar J

Author

James P. Thomas MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Boronic Acids
Bortezomib
Combined Modality Therapy
Dose-Response Relationship, Drug
Doxorubicin
Fatigue
Female
Gastrointestinal Diseases
Hematologic Diseases
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Proteins
Neoplasms
Proteasome Inhibitors
Protein Processing, Post-Translational
Pyrazines
Salvage Therapy
Treatment Outcome
Ubiquitination