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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
Affiliation:1. Department of Internal Medicine, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St. Louis, MO, USA
8. Department of Medicine, University of Virginia, P.O. Box 800716, Charlottesville, VA, 22908, USA
10. Department of Radiation Oncology, University of North Carolina, Chapel Hill, NC, USA
2. Department of Obstetrics and Gynecology, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St. Louis, MO, USA
3. Department of Surgery, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St. Louis, MO, USA
4. Department of Cell Biology and Physiology, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St. Louis, MO, USA
5. Howard Hughes Medical Institute, Bethesda, MD, USA
11. High Impact Clinical Trials, The Ontario Institute for Cancer Research, Toronto, ON, Canada
6. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA
7. Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
9. Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA
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?C125?mg/m2 IV on days 1, 8, 15, 22) and UCN-01 (50?C90?mg/m2 IV on day 2 and 25?C45?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?C30?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.
Keywords:
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