Journal article
A Phase I pharmacokinetic and biological correlative study of oblimersen sodium (Genasense, G3139), an antisense oligonucleotide to the Bcl-2 mRNA, and of docetaxel in Patients with hormone-refractory prostate cancer
Clinical cancer research, Vol.10(15), pp.5048-5057
2004
DOI: 10.1158/1078-0432.CCR-03-0701
PMID: 15297406
Abstract
Purpose: To assess the feasibility of administering oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the Bcl-2 mRNA, with docetaxel to patients with hormone-refractory prostate cancer; to characterize the pertinent pharmacokinetic parameters, Bcl-2 protein inhibition in peripheral blood mononuclear cell(s) (PBMC) and tumor; and to seek preliminary evidence of antitumor activity. Experimental Design: Patients were treated with increasing doses of oblimersen sodium administered by continuous i.v. infusion on days 1 to 6 and docetaxel administered i.v. over 1 h on day 6 every 3 weeks. Plasma was sampled to characterize the pharmacokinetic parameters of both oblimersen and docetaxel, and Bcl-2 protein expression was measured from paired collections of PBMCs pretreatment and post-treatment. Results: Twenty patients received 124 courses of the oblimersen and docetaxel combination at doses ranging from 5 to 7 mg/kg/day oblimersen and 60 to 100 mg/m2 docetaxel. The rate of severe fatigue accompanied by severe neutropenia was unacceptably high at doses exceeding 7 mg/kg/day oblimersen and 75 mg/m2 docetaxel. Nausea, vomiting, and fever were common, but rarely severe. Oblimersen mean steady-state concentrations were 3.44 ± 1.31 and 5.32 ± 2.34 at the 5- and 7-mg/kg dose levels, respectively. Prostate-specific antigen responses were observed in 7 of 12 taxane-naïve patients, but in taxane-refractory patients no responses were observed. Preliminary evaluation of Bcl-2 expression in diagnostic tumor specimens was not predictive of response to this therapy. Conclusions: The recommended Phase II doses for oblimersen and docetaxel on this schedule are 7 mg/kg/day continuous i.v. infusion days 1 to 6, and 75 mg/m 2 i.v. day 6, respectively, once every 3 weeks. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition in PBMC and tumor tissue, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination.
Details
- Title: Subtitle
- A Phase I pharmacokinetic and biological correlative study of oblimersen sodium (Genasense, G3139), an antisense oligonucleotide to the Bcl-2 mRNA, and of docetaxel in Patients with hormone-refractory prostate cancer
- Creators
- Anthony W Tolcher - Inst. Drug Devmt./Cancer Ther./R. C.John Kuhn - The University of Texas Health Science Center at San AntonioElzbieta Izbicka - Inst. Drug Devmt./Cancer Ther./R. C.Leslie Smetzer - Inst. Drug Devmt./Cancer Ther./R. C.Eric K Rowinsky - Inst. Drug Devmt./Cancer Ther./R. C.Garry Schwartz - Brooke Army Medical CenterAmita Patnaik - Inst. Drug Devmt./Cancer Ther./R. C.Lisa A Hammond - Inst. Drug Devmt./Cancer Ther./R. C.Ian Thompson - The University of Texas Health Science Center at San AntonioHoward Fingert - GenedataDavid Bushnell - SanofiShazli Malik - The University of Texas Health Science Center at San AntonioJeffrey Kreisberg - The University of Texas Health Science Center at San Antonio
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.10(15), pp.5048-5057
- Publisher
- American Association for Cancer Research
- DOI
- 10.1158/1078-0432.CCR-03-0701
- PMID
- 15297406
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 2004
- Academic Unit
- Radiology
- Record Identifier
- 9984318805602771
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