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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2108-2121
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.02.106
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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

From The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Millennium Pharmaceuticals, Inc, Cambridge, MA.

Address reprint requests to Christopher J. Logothetis, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0427, Houston, TX 77030; e-mail: clogothe{at}mdanderson.org

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/m2).

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/m2. 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.

Supported in part by CaPCURE and Millennium Pharmaceuticals Inc.

Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.

Authors' disclosures of potential conflicts of interest are found at the end of this article.




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