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.
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.
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Oblimersen 钠（genasense，g3139）（一种 bcl-2 mRNA 的反义寡核苷酸）和多西紫杉醇在激素难治性前列腺癌患者中的 I 期药代动力学和生物相关性研究。
DOI：
10.1158/1078-0432.ccr-03-0701
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Rowinsky,EricK
中科院分区：
文献类型：
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作者：
Tolcher,AnthonyW;Kuhn,John;Schwartz,Garry;Patnaik,Amita;Hammond,LisaA;Thompson,Ian;Fingert,Howard;Bushnell,David;Malik,Shazli;Kreisberg,Jeffrey;Izbicka,Elzbieta;Smetzer,Leslie;Rowinsky,EricK
目的：评估奥立默森钠（一种针对Bcl-2 mRNA的硫代磷酸反义寡核苷酸）与多西他赛联合治疗难治性前列腺癌患者的可行性;表征相关的药代动力学参数、外周血单核细胞（PBMC）和肿瘤中Bcl-2蛋白抑制;并寻求抗肿瘤活性的初步证据。患者在第1 - 6天通过连续静脉输注给予递增剂量的奥贝默森钠，并在第6天每隔1小时静脉给予多西他赛。3周血浆采样，以表征两个oblimersen和多西他赛的药代动力学参数，和Bcl-2蛋白表达测定从配对的PBMC的收集预处理和post-treatment.Results：20例患者接受了124个疗程的oblimersen和多西他赛的组合，剂量范围从5至7 mg/kg/天oblimersen和60至100 mg/m2多西他赛。当剂量超过7 mg/kg/天的oblimersen和75 mg/m2多西他赛时，重度疲乏伴重度中性粒细胞减少的发生率高得不可接受。恶心、呕吐和发烧很常见，但很少严重。在5和7 mg/kg剂量水平下，Oblimersen平均稳态浓度分别为3.44 ± 1.31和5.32 ± 2.34。前列腺特异性抗原反应在7/12例紫杉烷初治患者中观察到，但在紫杉烷难治患者中未观察到反应。Bcl-2的表达在诊断肿瘤标本中的初步评价是不预测的反应，以这种therapeutic.Conclusions：推荐的第二阶段剂量为oblimersen和多西他赛在此时间表是7毫克/公斤/天连续静脉输注第1至6天，和75毫克/m2静脉第6天，分别每3周一次。在该推荐剂量下没有严重毒性，PBMC和肿瘤组织中Bcl-2蛋白抑制的证据，以及在HPRC患者中令人鼓舞的抗肿瘤活性，证明了该组合的进一步临床评价。
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/m2docetaxel. The rate of severe fatigue accompanied by severe neutropenia was unacceptably high at doses exceeding 7 mg/kg/day oblimersen and 75 mg/m2docetaxel. 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/m2i.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.