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/m(2) 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 (C(ss)) was a significant determinant of antitumor activity; mean C(ss) 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 C(ss) 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 C(ss).
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/m(2) 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 (C(ss)) was a significant determinant of antitumor activity; mean C(ss) 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 C(ss) 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 C(ss).
Authors: Leena Gandhi; D Ross Camidge; Moacyr Ribeiro de Oliveira; Philip Bonomi; David Gandara; Divis Khaira; Christine L Hann; Evelyn M McKeegan; Elizabeth Litvinovich; Philip M Hemken; Caroline Dive; Sari H Enschede; Cathy Nolan; Yi-Lin Chiu; Todd Busman; Hao Xiong; Andrew P Krivoshik; Rod Humerickhouse; Geoffrey I Shapiro; Charles M Rudin Journal: J Clin Oncol Date: 2011-01-31 Impact factor: 44.544
Authors: Carolyn A Kitchens; Peter R McDonald; Tong Ying Shun; Ian F Pollack; John S Lazo Journal: J Pharmacol Exp Ther Date: 2011-08-31 Impact factor: 4.030
Authors: Meir Wetzler; Kathleen A Donohue; Olatoyosi M Odenike; Eric J Feldman; David D Hurd; Richard M Stone; Peter Westerfelt; Clara D Bloomfield; Richard A Larson Journal: Leuk Lymphoma Date: 2008-07