A phase I pharmacokinetic and pharmacodynamic study of OGX-011, a 2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer.
BACKGROUND
Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA and has been reported to inhibit clusterin expression and enhance drug efficacy in xenograft models. The primary objective of this clinical study was to determine a biologically effective dose of OGX-011 that would inhibit clusterin expression in human cancer.


METHODS
Subjects (n = 25) with localized prostate cancer with high-risk features who were candidates for prostatectomy were treated with OGX-011 by 2-hour intravenous infusion on days 1, 3, and 5 and then weekly from days 8-29 combined with androgen blockade starting on day 1; prostatectomy was performed on days 30-36. Six different doses were tested, from 40 to 640 mg. OGX-011 plasma and prostate tissue concentrations were measured by an enzyme-linked immunosorbent assay method, and the pharmacokinetics of OGX-011 were determined from these data. Prostate cancer tissue, lymph nodes, and serial samples of peripheral blood mononuclear cells were assessed for clusterin expression using quantitative real-time polymerase chain reaction and immunohistochemistry. All statistical tests were two-sided.


RESULTS
Only grade 1 and 2 toxicities were observed. The plasma half-life of OGX-011 was approximately 2-3 hours, and the area under the concentration versus time curve and CMAX (peak plasma concentration) increased proportionally with dose (Ptrend < .001). OGX-011 in prostate tissue increased with dose (Ptrend < .001). Dose-dependent decreases in prostate cancer and lymph node clusterin expression were observed by polymerase chain reaction of greater than 90% (Ptrend = .008 and Ptrend < .001, respectively) and by immunohistochemistry (Ptrend < .001 and Ptrend = .01, respectively).


CONCLUSIONS
OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors. The optimal biologic dose for OGX-011 at the schedule used is 640 mg.
Chi
Kim N
KN
Vancouver Cancer Centre, BC Cancer Agency, Vancouver, British Columbia, V5Z 4E6, Canada. kchi@bccancer.bc.ca
Eisenhauer
Elizabeth
E
Fazli
Ladan
L
Jones
Edward C
EC
Goldenberg
S Larry
SL
Powers
Jean
J
Tu
Dongsheng
D
Gleave
Martin E
ME
D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D051152:Clusterin; D003169:Complement Inactivator Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007262:Infusions, Intravenous; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D013873:Thionucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; C495242:CLU protein, human; D051152:Clusterin; D003169:Complement Inactivator Proteins; D006023:Glycoproteins; D018832:Molecular Chaperones; C503781:OGX-011; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides