A phase I study of OGX-011, a 2'-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

• Authors: Kim N Chi, Lillian L Siu, Hal Hirte, Sebastien J Hotte, Jennifer Knox, Christian Kollmansberger, Martin Gleave, Emma Guns, Jean Powers, Wendy Walsh, Dongsheng Tu, Elizabeth Eisenhauer
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 3 Pg. 833-9 (Feb 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18245546 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Clusterin
• OGX-011
• Oligonucleotides, Antisense
• Taxoids
• Thionucleotides
• Docetaxel

Topics

• Antineoplastic Agents (therapeutic use, toxicity)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Clinical Trials, Phase II as Topic
• Clusterin (genetics)
• Docetaxel
• Humans
• Neoplasms (drug therapy)
• Oligonucleotides, Antisense (toxicity)
• Taxoids (pharmacokinetics, therapeutic use)
• Thionucleotides (toxicity)