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 (75โ125ย mg/m^2^ IV on days 1, 8, 15, 22) and UCN-01 (50โ90ย mg/m^2^ IV on day 2 and 25โ45ย mg/m^2^ on day 23 and subsequent doses) every 42ย 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 125ย mg/m^2^ on days 1, 8, 15, 22 and UCN-01 70ย mg/m^2^ on day 2 and 35ย 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 24ย 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 18ย weeks, range 7โ30ย 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.