A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (Bortezomib, Velcade), in patients with advanced cancer

Grace K. Dy, James P. Thomas, George Wilding, Laura Bruzek, Sumithra Mandrekar, Charles Erlichman, Dona Alberti, Kim Binger, Henry C. Pitot, Steven R. Alberts, Lorelei J. Hanson, Rebecca Marnocha, Kendra Tutsch, Scott H. Kaufmann, Alex A. Adjei

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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 female) received PS-341 twice vveekly 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 thiobocytopenia, 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 1. Grade ≥ 3 toxicities for schedule I were constipation, fatigue, myalgia, and sensory neuropathy. Grade ≥ 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.

Original languageEnglish (US)
Pages (from-to)3410-3416
Number of pages7
JournalClinical Cancer Research
Volume11
Issue number9
DOIs
StatePublished - May 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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