RT Journal Article
SR Electronic
T1 A Phase II, Pharmacokinetic, and Biological Correlative Study of Oblimersen Sodium and Docetaxel in Patients with Hormone-Refractory Prostate Cancer
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 3854
OP 3861
DO 10.1158/1078-0432.CCR-04-2145
VO 11
IS 10
A1 Tolcher, Anthony W.
A1 Chi, Kim
A1 Kuhn, John
A1 Gleave, Martin
A1 Patnaik, Amita
A1 Takimoto, Chris
A1 Schwartz, Garry
A1 Thompson, Ian
A1 Berg, Kristin
A1 D'Aloisio, Susan
A1 Murray, Nevin
A1 Frankel, Stanley R.
A1 Izbicka, Elzbieta
A1 Rowinsky, Eric
YR 2005
UL http://clincancerres.aacrjournals.org/content/11/10/3854.abstract
AB Purpose: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy. Experimental Design: Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment. Results: Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m2 i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration (Css) was a significant determinant of antitumor activity; mean Css values were higher in responders compared with nonresponders (6.24 ± 1.68 versus 4.27 ± 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen Css or response. Conclusions: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize oblimersen Css.