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

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. SoaresShi Rong Cai, Li Lin, Janet Dancey, Michelle A. Rudek, Howard L. McLeod, Helen Piwnica-Worms

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish
Pages (from-to)1225-1237
Number of pages13
JournalCancer Chemotherapy and Pharmacology
Volume67
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • Chk1
  • Irinotecan
  • Phase 1
  • Ribosomal protein S6
  • UCN-01

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