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A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies

PURPOSE: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pha...

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Detalles Bibliográficos
Autores principales: Fracasso, Paula M., Williams, Kerry J., Chen, Ronald C., Picus, Joel, Ma, Cynthia X., Ellis, Matthew J., Tan, Benjamin R., Pluard, Timothy J., Adkins, Douglas R., Naughton, Michael J., Rader, Janet S., Arquette, Matthew A., Fleshman, James W., Creekmore, Allison N., Goodner, Sherry A., Wright, Lisa P., Guo, Zhanfang, Ryan, Christine E., Tao, Yu, Soares, Eliane M., Cai, Shi-rong, Lin, Li, Dancey, Janet, Rudek, Michelle A., McLeod, Howard L., Piwnica-Worms, Helen
Formato: Texto
Lenguaje:English
Publicado: Springer-Verlag 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102212/
https://www.ncbi.nlm.nih.gov/pubmed/20694727
http://dx.doi.org/10.1007/s00280-010-1410-1
Descripción
Sumario:PURPOSE: UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors. EXPERIMENTAL DESIGN: Patients received irinotecan (75–125 mg/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50–90 mg/m(2) IV on day 2 and 25–45 mg/m(2) on day 23 and subsequent doses) every 42 days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained. RESULTS: Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125 mg/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 mg/m(2) on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C(max) and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24 h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18 weeks, range 7–30 weeks). CONCLUSION: UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00280-010-1410-1) contains supplementary material, which is available to authorized users.