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A Phase I Trial of Daily Oral 4'- N -Benzoyl-Staurosporine in Combination With Protracted Continuous Infusion 5-fluorouracil in Patients With Advanced Solid Malignancies

A Phase I Trial of Daily Oral 4'- N -Benzoyl-Staurosporine in Combination With Protracted Continuous Infusion 5-fluorouracil in Patients With Advanced Solid Malignancies

Joseph P Eder Jr, Rocio Garcia-Carbonero, Jeffrey W Clark, Jeffrey G Supko, Thomas A Puchalski, David P Ryan, Pamela Deluca, Antoinette Wozniak, Angela Campbell, John Rothermel, Patricia LoRusso

Invest New Drugs. 2004 Apr;22(2):139-50.

PMID: 14739662

Abstract:

Purpose:
4'- N -Benzoyl-staurosporine (PKC412) is an orally available staurosporine derivative that inhibits protein kinase C. The objectives of this phase I trial were to determine the maximum tolerated dose (MTD), the dose limiting toxicities (DLTs), and the pharmacokinetics of PKC412 when co-administered with 5-Fluorouracil (5-FU).
Experimental design:
PKC412 was given daily with a 21-day continuous i.v. infusion of 5-FU 200 mg/m2/day, repeated every 4 weeks. The PKC412 dose was escalated by a modified continual reassessment method. The steady-state plasma pharmacokinetics of 5-FU, PKC412, and two of its circulating metabolites were determined during the first cycle of therapy.
Results:
A total of 33 patients were treated with 70 cycles (median: 2, range: 1-4) of PKC412 at doses ranging from 25 to 225 mg/day. No significant toxicities were encountered with doses up to 150 mg/day. Among nine patients treated with 225 mg/day of PKC412, one experienced grade 3 fatigue and nausea, another developed grade 3 hyperglycemia, and three had grade 2 emesis and stomatitis, leading to early treatment discontinuation. Minor responses consisting of a 40-45% tumor reduction were observed in two patients, one with gall bladder carcinoma and one with breast cancer. Mean values of steady-state pharmacokinetic variables for both PKC412 and 5-FU were comparable to single agent studies.
Conclusions:
The recommended phase II dose of PKC412 is 150 mg/day when combined with a continuous infusion of 200 mg/m2/day 5-FU. The dose limiting toxicity was grade 2 emesis and stomatitis and the regimen showed indications of activity. There was no evidence of a pharmacokinetic interaction between the two drugs.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP120685112	Staurosporine, N-Benzoyl		120685-11-2	Price

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