Faculty Collaboration Database

A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies. Cancer Chemother Pharmacol 2011 Jun;67(6):1225-37

Date

08/10/2010

Pubmed ID

20694727

Pubmed Central ID

PMC3102212

DOI

10.1007/s00280-010-1410-1

Scopus ID

2-s2.0-79959604565 (requires institutional sign-in at Scopus site)   53 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/m(2) IV on days 1, 8, 15, 22) and UCN-01 (50-90 mg/m(2) IV on day 2 and 25-45 mg/m(2) 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/m(2) on days 1, 8, 15, 22 and UCN-01 70 mg/m(2) on day 2 and 35 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 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.

Author List

Fracasso PM, Williams KJ, Chen RC, Picus J, Ma CX, Ellis MJ, Tan BR, Pluard TJ, Adkins DR, Naughton MJ, Rader JS, Arquette MA, Fleshman JW, Creekmore AN, Goodner SA, Wright LP, Guo Z, Ryan CE, Tao Y, Soares EM, Cai SR, Lin L, Dancey J, Rudek MA, McLeod HL, Piwnica-Worms H

Author

Janet Sue Rader MD Chair, Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Camptothecin
Drug Resistance, Neoplasm
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Staurosporine
Young Adult