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An NCIC CTG phase I/pharmacokinetic study of the matrix metalloproteinase and angiogenesis inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin

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Abstract

Background: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin in patients with advanced solid tumours, and to identify the maximum tolerated dose and the dose for use in future studies. Patients and methods: BAY 12-9566 and 5-fluorouracil/leucovorin were administered to 17 patients in 3 cohorts. Each patient served as his/her own control, with 5-fluorouracil being given alone on days 1–5 of cycle 1. In cohort 1, BAY 12-9566 at 800 mg p.o. b.i.d. was given with 350 mg/m2 5-fluorouracil/20 mg/m2 leucovorin × 5 days q28 days. In cohort 2, the BAY 12-9566 dose was reduced to 400 mg p.o. b.i.d., with the 5-fluorouracil/leucovorin doses remaining unchanged. Finally, in cohort 3, BAY 12-9566 400 mg bid was given with 5-fluorouracil 400 mg/m2/day. Patients were continued on therapy until unacceptable toxicity or tumour progression occurred. Pharmacokinetic analyses for both BAY 12-9566 and 5-fluorouracil were performed. Results: The maximum tolerated dose was 400 mg p.o. b.i.d. BAY 12-9566 plus 5-fluorouracil/leucovorin at 400 mg/m2/day and 20 mg/m2/day, respectively. Thrombocytopenia necessitated a decrease of the dose of BAY 12-9566 by 50% from cohort 1 to cohort 2. Two dose-limiting toxicities occurred in cohort 3 consisting of neutropenic fever, and ileitis, causing severe diarrhea. Of 17 patients treated on study, 7 of 14 patients evaluable for response achieved stable disease. Pharmacokinetic analysis suggested there was no interaction between BAY 12-9566 and 5-fluorouracil. Conclusions: BAY 12-9566 400 mg bid and 5-fluorouracil 350 mg/m2 plus leucovorin 20 mg/m2 can be co-administered. Although there is some evidence of a clinical interaction, there is no apparent pharmacokinetic interaction. Future studies with these 2 types of agents administered in combination are warranted.

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Authors and Affiliations

  1. Ottawa Regional Cancer Centre, Ottawa, Ontario, Canada

    R. Goel, D. J. Stewart, S. Huan, B. Waterfield & J. Roach

  2. Hamilton Regional Cancer Centre, Hamilton, Ontario, Canada

    E. Chouinard, H. Hirte & S. Stafford

  3. Bayer Inc., West Haven, USA

    C. Lathia, V. Agarwal & R. Humphrey

  4. National Cancer Institute of Canada—, Clinical Trials Group, Kingston, Ontario, Canada

    W. Walsh, S. Matthews & L. Seymour

Authors
  1. R. Goel
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  2. E. Chouinard
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  3. D. J. Stewart
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  4. S. Huan
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  5. H. Hirte
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  6. S. Stafford
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  7. B. Waterfield
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  8. J. Roach
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  9. C. Lathia
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  10. V. Agarwal
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  11. R. Humphrey
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  12. W. Walsh
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  13. S. Matthews
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  14. L. Seymour
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Goel, R., Chouinard, E., Stewart, D.J. et al. An NCIC CTG phase I/pharmacokinetic study of the matrix metalloproteinase and angiogenesis inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin. Invest New Drugs 23, 63–71 (2005). https://doi.org/10.1023/B:DRUG.0000047107.35764.d9

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  • DOI: https://doi.org/10.1023/B:DRUG.0000047107.35764.d9

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