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.
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.
Authors: D Fabbro; E Buchdunger; J Wood; J Mestan; F Hofmann; S Ferrari; H Mett; T O'Reilly; T Meyer Journal: Pharmacol Ther Date: 1999 May-Jun Impact factor: 12.310
Authors: H Kiyoi; T Naoe; Y Nakano; S Yokota; S Minami; S Miyawaki; N Asou; K Kuriyama; I Jinnai; C Shimazaki; H Akiyama; K Saito; H Oh; T Motoji; E Omoto; H Saito; R Ohno; R Ueda Journal: Blood Date: 1999-05-01 Impact factor: 22.113
Authors: S Omura; Y Iwai; A Hirano; A Nakagawa; J Awaya; H Tsuchya; Y Takahashi; R Masuma Journal: J Antibiot (Tokyo) Date: 1977-04 Impact factor: 2.649
Authors: C J van Groeningen; H M Pinedo; J Heddes; R M Kok; A P de Jong; E Wattel; G J Peters; J Lankelma Journal: Cancer Res Date: 1988-12-01 Impact factor: 12.701
Authors: J L Grem; N McAtee; F Balis; R Murphy; D Venzon; B Kramer; B Goldspiel; M Begley; C J Allegra Journal: Cancer Date: 1993-08-01 Impact factor: 6.860
Authors: E Fuse; H Tanii; N Kurata; H Kobayashi; Y Shimada; T Tamura; Y Sasaki; Y Tanigawara; R D Lush; D Headlee; W D Figg; S G Arbuck; A M Senderowicz; E A Sausville; S Akinaga; T Kuwabara; S Kobayashi Journal: Cancer Res Date: 1998-08-01 Impact factor: 12.701