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

Jeremy Kortmansky, Manish A. Shah, Andreas Kaubisch, Amanda Weyerbacher, Sandy Yi, William Tong, Rebecca Sowers, Mithat Gonen, Eileen O'Reilly, Nancy Kemeny, David I. Ilson, Leonard B. Saltz, Robert G. Maki, David P. Kelsen, Gary K. Schwartz

Research output: Contribution to journalArticle

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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/m2 over 72 hours in cycle 1 and 67.5 mg/m2 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/m2 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/m2.

Original languageEnglish (US)
Pages (from-to)1875-1884
Number of pages10
JournalJournal of Clinical Oncology
Volume23
Issue number9
DOIs
StatePublished - 2005
Externally publishedYes

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Cyclin-Dependent Kinase Inhibitor Proteins
Protein C Inhibitor
Protein Kinase Inhibitors
Fluorouracil
Protein Kinase C
Neoplasms
Thymidylate Synthase
Blood Cells
7-hydroxystaurosporine
Orosomucoid
Clinical Trials, Phase I
Cyclin-Dependent Kinases
Syncope
Reverse Transcriptase Polymerase Chain Reaction
Hyperglycemia
Nausea
Area Under Curve
Vomiting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Kortmansky, Jeremy; Shah, Manish A.; Kaubisch, Andreas; Weyerbacher, Amanda; Yi, Sandy; Tong, William; Sowers, Rebecca; Gonen, Mithat; O'Reilly, Eileen; Kemeny, Nancy; Ilson, David I.; Saltz, Leonard B.; Maki, Robert G.; Kelsen, David P.; Schwartz, Gary K.

In: Journal of Clinical Oncology, Vol. 23, No. 9, 2005, p. 1875-1884.

Research output: Contribution to journalArticle

Kortmansky, J, Shah, MA, Kaubisch, A, Weyerbacher, A, Yi, S, Tong, W, Sowers, R, Gonen, M, O'Reilly, E, Kemeny, N, Ilson, DI, Saltz, LB, Maki, RG, Kelsen, DP & Schwartz, GK 2005, '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 of Clinical Oncology, vol. 23, no. 9, pp. 1875-1884. https://doi.org/10.1200/JCO.2005.03.116
Kortmansky, Jeremy ; Shah, Manish A. ; Kaubisch, Andreas ; Weyerbacher, Amanda ; Yi, Sandy ; Tong, William ; Sowers, Rebecca ; Gonen, Mithat ; O'Reilly, Eileen ; Kemeny, Nancy ; Ilson, David I. ; Saltz, Leonard B. ; Maki, Robert G. ; Kelsen, David P. ; Schwartz, Gary K. / 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. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 9. pp. 1875-1884.
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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/m2 over 72 hours in cycle 1 and 67.5 mg/m2 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/m2 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/m2.",
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T1 - 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

AU - Kortmansky, Jeremy

AU - Shah, Manish A.

AU - Kaubisch, Andreas

AU - Weyerbacher, Amanda

AU - Yi, Sandy

AU - Tong, William

AU - Sowers, Rebecca

AU - Gonen, Mithat

AU - O'Reilly, Eileen

AU - Kemeny, Nancy

AU - Ilson, David I.

AU - Saltz, Leonard B.

AU - Maki, Robert G.

AU - Kelsen, David P.

AU - Schwartz, Gary K.

PY - 2005

Y1 - 2005

N2 - 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/m2 over 72 hours in cycle 1 and 67.5 mg/m2 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/m2 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/m2.

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