A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin

Gary K. Schwartz, David Ward, Leonard Saltz, Ephraim S. Casper, Tara Spiess, Eillen Mullen, Jim Woodworth, Robert Venuti, Peter Zervos, Anna Maria Storniolo, David P. Kelsen

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Abstract

We performed a pilot clinical trial with safingol (L-threo-dihydrosphingosine), a protein kinase C-specific inhibitor that potentiates the effect of doxorubicin (DOX) in tumor-bearing animals. Safingol was initially administered as a 1-h infusion at escalating doses. Fourteen days later, patients received the same dose of safingol in combination with a fixed dose of DOX. The combination was repeated at 3-week intervals. Safingol dose levels ranged from 15 to 120 mg/m2. The plasma levels achieved at the final dose level were comparable to those associated with potentiation of DOX in animals. The mean C(max) and area under the curve for safingol at the 120 mg/m2 dose level were 1040 ± 196 ng/ml and 1251 ± 317 mg x h/ml, respectively. The mean plasma half-life for safingol was 3.97 ± 2.51 h, the mean estimated clearance was 3140 ± 765 ml/min, and the mean volume of distribution was of 995 ± 421 liters. Coadministration of a fixed dose of DOX did not significantly change the pharmacokinetics of safingol, nor did increasing doses of safingol significantly affect the pharmacokinetics of DOX. Minor responses were observed in three patients with pancreatic cancer and one patient with angiosarcoma of the scalp. This pilot phase I study indicates that the protein kinase C inhibitor safingol can be given safely with 45 mg/m2 of DOX at a dose that is potentially pharmacologically active without dose-limiting toxicity.

Original languageEnglish (US)
Pages (from-to)537-543
Number of pages7
JournalClinical Cancer Research
Volume3
Issue number4
StatePublished - 1997

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Doxorubicin
Protein Kinase C
Pharmacology
Pharmacokinetics
Clinical Studies
safingol
Hemangiosarcoma
Protein C Inhibitor
Protein Kinase Inhibitors
Scalp
Pancreatic Neoplasms
Area Under Curve
Half-Life
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Schwartz, G. K., Ward, D., Saltz, L., Casper, E. S., Spiess, T., Mullen, E., ... Kelsen, D. P. (1997). A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. Clinical Cancer Research, 3(4), 537-543.

A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. / Schwartz, Gary K.; Ward, David; Saltz, Leonard; Casper, Ephraim S.; Spiess, Tara; Mullen, Eillen; Woodworth, Jim; Venuti, Robert; Zervos, Peter; Storniolo, Anna Maria; Kelsen, David P.

In: Clinical Cancer Research, Vol. 3, No. 4, 1997, p. 537-543.

Research output: Contribution to journalArticle

Schwartz, GK, Ward, D, Saltz, L, Casper, ES, Spiess, T, Mullen, E, Woodworth, J, Venuti, R, Zervos, P, Storniolo, AM & Kelsen, DP 1997, 'A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin', Clinical Cancer Research, vol. 3, no. 4, pp. 537-543.
Schwartz, Gary K. ; Ward, David ; Saltz, Leonard ; Casper, Ephraim S. ; Spiess, Tara ; Mullen, Eillen ; Woodworth, Jim ; Venuti, Robert ; Zervos, Peter ; Storniolo, Anna Maria ; Kelsen, David P. / A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin. In: Clinical Cancer Research. 1997 ; Vol. 3, No. 4. pp. 537-543.
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