Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer

Christos N. Papandreou, Danai D. Daliani, Darrell Nix, Hong Yang, Timothy Madden, Xuemei Wang, Christine S. Pien, Randall E. Millikan, Shi Ming Tu, Lance Pagliaro, Jeri Kim, Julian Adams, Peter Elliott, Dixie Esseltine, Alexandria Petrusich, Pauline Dieringer, Cherie Perez, Christopher J. Logothetis

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410 Scopus citations

Abstract

Purpose: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). Patients and Methods: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m2/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m 2). Results: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m2 (diarrhea, hypotension) occurring at an average 1-hour post-dose of ≥ 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at & 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes. Conclusion: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m 2. Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)2108-2121
Number of pages14
JournalJournal of Clinical Oncology
Volume22
Issue number11
DOIs
StatePublished - Dec 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Papandreou, C. N., Daliani, D. D., Nix, D., Yang, H., Madden, T., Wang, X., Pien, C. S., Millikan, R. E., Tu, S. M., Pagliaro, L., Kim, J., Adams, J., Elliott, P., Esseltine, D., Petrusich, A., Dieringer, P., Perez, C., & Logothetis, C. J. (2004). Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. Journal of Clinical Oncology, 22(11), 2108-2121. https://doi.org/10.1200/JCO.2004.02.106