TY - JOUR
T1 - A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies
AU - Fracasso, Paula M.
AU - Williams, Kerry J.
AU - Chen, Ronald C.
AU - Picus, Joel
AU - Ma, Cynthia X.
AU - Ellis, Matthew J.
AU - Tan, Benjamin R.
AU - Pluard, Timothy J.
AU - Adkins, Douglas R.
AU - Naughton, Michael J.
AU - Rader, Janet S.
AU - Arquette, Matthew A.
AU - Fleshman, James W.
AU - Creekmore, Allison N.
AU - Goodner, Sherry A.
AU - Wright, Lisa P.
AU - Guo, Zhanfang
AU - Ryan, Christine E.
AU - Tao, Yu
AU - Soares, Eliane M.
AU - Cai, Shi Rong
AU - Lin, Li
AU - Dancey, Janet
AU - Rudek, Michelle A.
AU - McLeod, Howard L.
AU - Piwnica-Worms, Helen
N1 - Funding Information:
Acknowledgments We wish to thank the patients and their families for participation in this study. We also thank the nurses, clinical research and regulatory coordinators at the Siteman Cancer Center for their care of the patients on this study. Dr. Mark A. Watson, Director, Tissue Procurement Core, Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital is thanked for tissue acquisition, storage, and processing, and Dr. Katherine Deschryver is thanked for IHC scoring. Grant support: St. Louis Men’s Group Against Cancer and NCI Translational Research Initiative Subcontract 22XS046 (P. M. Fracasso), P30 CA091842 (Pharmacology Core, Alvin J. Siteman Cancer Center), Doris Duke Charitable Foundation (R.C. Chen), P30 CA069773 (Analytical Pharmacology Core, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins), Howard Hughes Medical Institute, Komen Foundation, UL1 RR024992.
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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.
KW - Chk1
KW - Irinotecan
KW - Phase 1
KW - Ribosomal protein S6
KW - UCN-01
UR - https://www.scopus.com/pages/publications/79959604565
U2 - 10.1007/s00280-010-1410-1
DO - 10.1007/s00280-010-1410-1
M3 - Article
C2 - 20694727
AN - SCOPUS:79959604565
SN - 0344-5704
VL - 67
SP - 1225
EP - 1237
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -