Phase I Trial of the Proteasome Inhibitor Bortezomib in Patients With Advanced Solid Tumors With Observations in Androgen-Independent Prostate Cancer

• Published in: Journal of clinical oncology Vol. 22; no. 11; pp. 2108 - 2121
• Main Authors: PAPANDREOU, Christos N, DALIANI, Danai D, KIM, Jeri, ADAMS, Julian, ELLIOTT, Peter, ESSELTINE, Dixie, PETRUSICH, Alexandria, DIERINGER, Pauline, PEREZ, Cherie, LOGOTHETIS, Christopher J, NIX, Darrell, HONG YANG, MADDEN, Timothy, XUEMEI WANG, PIEN, Christine S, MILLIKAN, Randall E, TU, Shi-Ming, PAGLIARO, Lance
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 01.06.2004; Lippincott Williams & Wilkins
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological and medical sciences; Boronic Acids - administration & dosage; Boronic Acids - pharmacokinetics; Boronic Acids - pharmacology; Bortezomib; Cysteine Endopeptidases - blood; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Gynecology. Andrology. Obstetrics; Humans; Male; Male genital diseases; Maximum Tolerated Dose; Medical sciences; Middle Aged; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - blood; Neoplasms - drug therapy; Neoplasms, Hormone-Dependent - drug therapy; Nephrology. Urinary tract diseases; Prostatic Neoplasms - drug therapy; Protease Inhibitors - administration & dosage; Protease Inhibitors - pharmacokinetics; Protease Inhibitors - pharmacology; Proteasome Endopeptidase Complex; Pyrazines - administration & dosage; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Statistics, Nonparametric; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Antineoplastic agent; Human; Multicatalytic endopeptidase complex; Solid tumor; Urinary system disease; Bortezomib; Prostate disease; Androgen; Enzyme; Malignant tumor; Peptidases; Phase I trial; Hydrolases; Advanced stage; Inhibitor; Sex steroid hormone; Male genital diseases; Prostate cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2004.02.106

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). Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/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)). A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (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. 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.