Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with fluorouracil in patients with advanced solid tumors Journal Article

Authors: Kortmansky, J.; Shah, M. A.; Kaubisch, A.; Weyerbacher, A.; Yi, S.; Tong, W.; Sowers, R.; Gonen, M.; O'reilly, E.; Kemeny, N.; Ilson, D.; Saltz, L. B.; Maki, R. G.; Kelsen, D. P.; Schwartz, G. K.
Article Title: Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with fluorouracil in patients with advanced solid tumors
Abstract: Purpose: Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. Patients and Methods: FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m 2 over 72 hours in cycle 1 and 67.5 mg/m 2 over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. Results: We escalated the weekly FU dose to 2,600 mg/m 2 in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 μmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. Conclusion: The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m 2. © 2005 by American Society of Clinical Oncology.
Keywords: adult; clinical article; controlled study; protein expression; treatment response; aged; clinical trial; constipation; drug tolerability; fatigue; fluorouracil; advanced cancer; area under the curve; cancer combination chemotherapy; diarrhea; dose response; monotherapy; solid tumor; cancer patient; binding affinity; reverse transcription polymerase chain reaction; controlled clinical trial; multiple cycle treatment; sensory neuropathy; anemia; blood toxicity; stomatitis; myalgia; enzyme activity; abdominal pain; drug dose escalation; dyspnea; fever; hyperglycemia; syncope; heart palpitation; hypotension; drug clearance; nausea and vomiting; hyperbilirubinemia; headache; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; heart arrhythmia; thymidylate synthase; cyclin dependent kinase inhibitor; hypoxemia; heart atrium fibrillation; fluoropyrimidine derivative; abdominal cramp; drug binding; peripheral blood mononuclear cell; muscle cramp; protein kinase c inhibitor; pharyngitis; 7 hydroxystaurosporine; orosomucoid
Journal Title: Journal of Clinical Oncology
Volume: 23
Issue: 9
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2005-03-20
Start Page: 1875
End Page: 1884
Language: English
DOI: 10.1200/jco.2005.03.116
PROVIDER: scopus
PUBMED: 15699481
Notes: --- - "Cited By (since 1996): 67" - "Export Date: 24 October 2012" - "CODEN: JCOND" - "Source: Scopus"
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MSK Authors
  1. William Ping-Yiu Tong
    123 Tong
  2. Leonard B Saltz
    580 Saltz
  3. Gary Schwartz
    358 Schwartz
  4. Mithat Gonen
    701 Gonen
  5. Robert Maki
    211 Maki
  6. Manish Shah
    174 Shah
  7. David H Ilson
    269 Ilson
  8. Eileen O'Reilly
    316 O'Reilly
  9. San S Yi
    12 Yi
  10. David P Kelsen
    332 Kelsen
  11. Nancy Kemeny
    347 Kemeny
  12. Rebecca S Sowers
    32 Sowers
  13. William Yuwa Tong
    5 Tong