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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2011

Open Access 01-06-2011 | Original Article

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

Authors: Paula M. Fracasso, Kerry J. Williams, Ronald C. Chen, Joel Picus, Cynthia X. Ma, Matthew J. Ellis, Benjamin R. Tan, Timothy J. Pluard, Douglas R. Adkins, Michael J. Naughton, Janet S. Rader, Matthew A. Arquette, James W. Fleshman, Allison N. Creekmore, Sherry A. Goodner, Lisa P. Wright, Zhanfang Guo, Christine E. Ryan, Yu Tao, Eliane M. Soares, Shi-rong Cai, Li Lin, Janet Dancey, Michelle A. Rudek, Howard L. McLeod, Helen Piwnica-Worms

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2011

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Abstract

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/m2 IV on days 1, 8, 15, 22) and UCN-01 (50–90 mg/m2 IV on day 2 and 25–45 mg/m2 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/m2 on days 1, 8, 15, 22 and UCN-01 70 mg/m2 on day 2 and 35 mg/m2 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 Cmax 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.
Appendix
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Metadata
Title
A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies
Authors
Paula M. Fracasso
Kerry J. Williams
Ronald C. Chen
Joel Picus
Cynthia X. Ma
Matthew J. Ellis
Benjamin R. Tan
Timothy J. Pluard
Douglas R. Adkins
Michael J. Naughton
Janet S. Rader
Matthew A. Arquette
James W. Fleshman
Allison N. Creekmore
Sherry A. Goodner
Lisa P. Wright
Zhanfang Guo
Christine E. Ryan
Yu Tao
Eliane M. Soares
Shi-rong Cai
Li Lin
Janet Dancey
Michelle A. Rudek
Howard L. McLeod
Helen Piwnica-Worms
Publication date
01-06-2011
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-010-1410-1

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