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

Paula M Fracasso1, Kerry J Williams, Ronald C Chen

  • 1Department of Internal Medicine, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St Louis, MO, USA. fracasso@virginia.edu

Cancer Chemotherapy and Pharmacology
|August 10, 2010
PubMed
Abstract

Insights

The combination of UCN-01 (7-hydroxystaurosporine) and irinotecan showed acceptable toxicity and target inhibition in patients with resistant solid tumors. Anti-tumor activity was observed, particularly in triple-negative breast cancers.

Area of Science:

  • Oncology
  • Pharmacology
  • Cancer Therapeutics

Background:

  • UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor with synergistic potential alongside DNA-damaging agents.
  • Preclinical studies indicated that UCN-01 enhances the efficacy of DNA-damaging agents.

Purpose of the Study:

  • To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic/pharmacodynamic profiles of UCN-01 combined with irinotecan.
  • To evaluate the safety and preliminary efficacy of this combination in patients with resistant solid tumors.

Main Methods:

  • A Phase I clinical trial involving 25 patients with resistant solid tumors.
  • Dose escalation of irinotecan (75-125 mg/m(2)) and UCN-01 (50-90 mg/m(2)) administered on a specific schedule every 42 days.
  • Pharmacokinetic and pharmacodynamic analyses of UCN-01 and irinotecan, including assessments of phosphorylated ribosomal protein S6.

Main Results:

  • The MTD was established at irinotecan 125 mg/m(2) and UCN-01 70 mg/m(2) (day 2) / 35 mg/m(2) (day 23).
  • DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 exhibited a prolonged half-life and low clearance.
  • Pharmacodynamic effects included reduced phosphorylated ribosomal protein S6 in blood, rectal mucosa, and tumor biopsies. Two partial responses were noted in triple-negative breast cancers (TNBC).

Conclusions:

  • The combination of UCN-01 and irinotecan demonstrated acceptable toxicity and achieved target inhibition in patients with resistant solid tumors.
  • Observed anti-tumor activity supports further investigation, with a specific study in women with TNBC currently underway.

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