Faculty Collaboration Database

A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer. Clin Cancer Res 2005 May 01;11(9):3410-6

Date

05/04/2005

Pubmed ID

15867242

DOI

10.1158/1078-0432.CCR-04-2068

Scopus ID

2-s2.0-20944450476 (requires institutional sign-in at Scopus site)   66 Citations

Abstract

PURPOSE: To define the toxicities, pharmacodynamics, and clinical activity of the proteasome inhibitor, PS-341 (bortezomib), in patients with advanced malignancies.

PATIENTS AND METHODS: Twenty-eight patients (14 male and 14 female) received PS-341 twice weekly for 4 of 6 weeks (schedule I). Because toxicity necessitated dose omissions on this schedule, 16 additional patients (12 male and 4 female) received PS-341 twice weekly for 2 of every 3 weeks (schedule II). A total of 73 courses of treatment was given (median, 2; range, 1-4). Inhibition of 20S proteasome activity in peripheral blood mononuclear cells (PBMC) and accumulation of proteasome-targeted polypeptides in tumor tissue were evaluated as pharmacodynamic markers of PS-341 activity.

RESULTS: The most common toxicity was thrombocytopenia, which was dose limiting at 1.7 mg/m2 (schedule I) and 1.6 mg/m2 (schedule II), respectively. Sensory neuropathy was dose-limiting in a patient in schedule I. Grade > or =3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade > or =3 toxicities for schedule II were dehydration resulting from diarrhea, nausea and vomiting, fatigue, hypoglycemia, and hypotension. The maximum tolerated dose was 1.5 mg/m2 for both schedules. Reversible dose-dependent decreases in 20S proteasome activity in PBMCs were observed, with 36% inhibition at 0.5 mg/m2, 52% at 0.9 mg/m2, and 75% at 1.25 mg/m2. Accumulation of proteasome-targeted polypeptides was detected in tumor samples after treatment with PS-341. A patient with multiple myeloma had a partial response.

CONCLUSION: PS-341 given 1.5 mg/m2 twice weekly for 2 of every 3 weeks is well tolerated and should be further studied.

Author List

Dy GK, Thomas JP, Wilding G, Bruzek L, Mandrekar S, Erlichman C, Alberti D, Binger K, Pitot HC, Alberts SR, Hanson LJ, Marnocha R, Tutsch K, Kaufmann SH, Adjei AA

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
Anemia
Antineoplastic Agents
Blotting, Western
Boronic Acids
Bortezomib
Cell Cycle Proteins
Cell Line, Tumor
Cyclin E
Cyclin-Dependent Kinase Inhibitor p27
Diarrhea
Dose-Response Relationship, Drug
Drug Administration Schedule
Fatigue
Female
Humans
I-kappa B Proteins
Male
Middle Aged
NF-kappa B
Nausea
Neoplasms
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Proto-Oncogene Proteins c-bcl-2
Pyrazines
Thrombocytopenia
Treatment Outcome
Tumor Suppressor Proteins
Vomiting
bcl-2-Associated X Protein