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


METHODS
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).


CONCLUSIONS
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.
Fracasso
Paula M
PM
Department of Internal Medicine, Alvin J. Siteman Cancer Center and Washington University School of Medicine, St Louis, MO, USA. fracasso@virginia.edu
Williams
Kerry J
KJ
Chen
Ronald C
RC
Picus
Joel
J
Ma
Cynthia X
CX
Ellis
Matthew J
MJ
Tan
Benjamin R
BR
Pluard
Timothy J
TJ
Adkins
Douglas R
DR
Naughton
Michael J
MJ
Rader
Janet S
JS
Arquette
Matthew A
MA
Fleshman
James W
JW
Creekmore
Allison N
AN
Goodner
Sherry A
SA
Wright
Lisa P
LP
Guo
Zhanfang
Z
Ryan
Christine E
CE
Tao
Yu
Y
Soares
Eliane M
EM
Cai
Shi-Rong
SR
Lin
Li
L
Dancey
Janet
J
Rudek
Michelle A
MA
McLeod
Howard L
HL
Piwnica-Worms
Helen
H
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
D000077146:Irinotecan; C054852:7-hydroxystaurosporine; D019311:Staurosporine; D002166:Camptothecin