A phase I study of OGX-011, a 2'-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer.
OBJECTIVE
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, has a prolonged tissue half life, enhances drug efficacy in xenograft models, and reduces clusterin expression in humans with a biologically effective dose of 640 mg. The objective of this study was to determine a recommended phase II dose of OGX-011 in combination with docetaxel.


METHODS
Patients with cancers known from the literature to express clusterin were eligible. OGX-011 was given by 2-h i.v. infusion starting at 40 mg weekly after loading doses on days 1, 3, and 5. Docetaxel was given i.v. 30 mg/m(2) weekly for 5 of 6 weeks (schedule A) or 75 mg/m(2) every 3 weeks (schedule B). All patients had serial samples of peripheral blood mononuclear cells and serum assessed for clusterin expression.


RESULTS
Forty patients were enrolled to eight cohorts. OGX-011 could be given at the full biologically effective single-agent dose of 640 mg with both docetaxel schedules. Toxic effects were primarily myelosuppression, fatigue, hair loss, gastrointestinal effects (expected docetaxel effects), as well as dose-related chills and fever (expected OGX-011 effects). OGX-011 AUC and C(max) increased proportionally with no apparent effect on docetaxel pharmacokinetics. At the end of cycle 1, serum clusterin showed mean decreases of 34% and 38% (range, 15-99%) at the 640-mg dose levels.


CONCLUSIONS
OGX-011 can be given at a biologically effective dose with standard doses of docetaxel. Phase II trials of combined OGX-011 and chemotherapy are ongoing in patients with prostate, breast, and lung cancers.
Chi
Kim N
KN
British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia, Canada. kchi@bccancer.bc.ca
Siu
Lillian L
LL
Hirte
Hal
H
Hotte
Sebastien J
SJ
Knox
Jennifer
J
Kollmansberger
Christian
C
Gleave
Martin
M
Guns
Emma
E
Powers
Jean
J
Walsh
Wendy
W
Tu
Dongsheng
D
Eisenhauer
Elizabeth
E
D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D051152:Clusterin / Q000235:genetics*; D000077143:Docetaxel; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000633:toxicity*; D043823:Taxoids / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013873:Thionucleotides / Q000633:toxicity*
D000970:Antineoplastic Agents; D051152:Clusterin; C503781:OGX-011; D016376:Oligonucleotides, Antisense; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel