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
| العنوان: | 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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| المؤلفون: | Shazli N. Malik, Lisa A. Hammond, Leslie Smetzer, Elzbieta Izbicka, Anthony W. Tolcher, Amita Patnaik, Jeffrey I. Kreisberg, Eric K. Rowinsky, David Bushnell, Howard Fingert, Garry Schwartz, Ian M. Thompson, John G. Kuhn |
| المصدر: | Clinical Cancer Research. 10:5048-5057 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Male, Cancer Research, medicine.medical_specialty, Time Factors, Nausea, Biopsy, Antineoplastic Agents, Docetaxel, Pharmacology, Peripheral blood mononuclear cell, Prostate cancer, Pharmacokinetics, Internal medicine, medicine, Humans, RNA, Messenger, Phosphorylation, Infusions, Intravenous, Aged, Dose-Response Relationship, Drug, business.industry, Oblimersen, Prostatic Neoplasms, Middle Aged, Oligonucleotides, Antisense, Prostate-Specific Antigen, Thionucleotides, medicine.disease, Immunohistochemistry, Dose–response relationship, Endocrinology, Proto-Oncogene Proteins c-bcl-2, Oncology, Drug Resistance, Neoplasm, Area Under Curve, Leukocytes, Mononuclear, Vomiting, Taxoids, medicine.symptom, business, medicine.drug |
| الوصف: | 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/m2 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. |
| تدمد: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-03-0701 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5f0dce4835a12df7f0dc138d9ff8fd4c https://doi.org/10.1158/1078-0432.ccr-03-0701 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5f0dce4835a12df7f0dc138d9ff8fd4c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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| DOI: | 10.1158/1078-0432.ccr-03-0701 |