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

被引:61
作者
Tolcher, AW
Kuhn, J
Schwartz, G
Patnaik, A
Hammond, LA
Thompson, I
Fingert, H
Bushnell, D
Malik, S
Kreisberg, J
Izbicka, E
Smetzer, L
Rowinsky, EK
机构
[1] Canc Therapy & Res Ctr S Texas, Inst Drug Dev, San Antonio, TX 78229 USA
[2] Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78285 USA
[3] Univ Texas, Hlth Sci Ctr, Dept Surg, San Antonio, TX 78285 USA
[4] Brooke Army Med Ctr, San Antonio, TX USA
[5] Genta Inc, Berkeley Hts, NJ USA
[6] Aventis Pharmaceut, Bridgewater, NJ USA
关键词
D O I
10.1158/1078-0432.CCR-03-0701
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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/m(2) docetaxel. The rate of severe fatigue accompanied by severe neutropenia was unacceptably high at doses exceeding 7 mg/kg/day oblimersen and 75 mg/m(2) 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-naive 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.
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页码:5048 / 5057
页数:10
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