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


METHODS
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)).


RESULTS
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.


CONCLUSIONS
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.
Papandreou
Christos N
CN
The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0427, Houston, TX 77030, USA.
Daliani
Danai D
DD
Nix
Darrell
D
Yang
Hong
H
Madden
Timothy
T
Wang
Xuemei
X
Pien
Christine S
CS
Millikan
Randall E
RE
Tu
Shi-Ming
SM
Pagliaro
Lance
L
Kim
Jeri
J
Adams
Julian
J
Elliott
Peter
P
Esseltine
Dixie
D
Petrusich
Alexandria
A
Dieringer
Pauline
P
Perez
Cherie
C
Logothetis
Christopher J
CJ
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069286:Bortezomib; D003546:Cysteine Endopeptidases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000097:blood; D009369:Neoplasms / Q000188:drug therapy*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D001897:Boronic Acids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex