A phase I and Pharmacologic trial of weekly epothilone B in patients with advanced malignancies

Li Liu, MD

University of Pennsylvania Cancer
Last Modified: May 13, 2001

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Presenter: E.H.Rubin
Affiliation: The Cancer Institute of New Jersey, New Brunswick, NJ

Background:

    The epothilones are equipotent and exhibit kinetics similar to taxol in inducing tubulin polymerization into microtubules in vitro and in producing enhanced microtubule stability and bundling in cultured cells. Epothilones also cause cell cycle arrest at the G2-M transition leading to cytotoxicity, similar to taxol.

Materials and Methods:

  • A total of 54 patients were included in this phase I trial
  • Patients were treated with weekly epothilone B infusion
  • Doses ranged from 0.3 mg/m2 to 3.6 mg/m2

Results:

  • 4/6 patients treated at 3.6 mg/m2 developed dose- limiting diarrhea
  • 1/12 patients experienced dose-limiting diarrhea at dose level of 2.5 mg/m2
  • Two patients achieved partial responses
  • Tumor dose levels were approximately 10 to 15 fold higher than blood levels in one patient
  • Blood levels were not predictive of efficacy or toxicity

Authors' Conclusions

  • Epothilone appeared to have some antitumor activity in patients who were heavily treated with other chemotherapeutic agents
  • The dose-limiting toxicity was diarrhea
  • No correlation can be drawn between toxicity and activity

Clinical/Scientific Implications:

  • Epothilones represent a novel structural class of compounds since the original discovery of taxol
  • The clinical antitumor activity and optimal dosing schedule will be evaluated in phase II trials

ASCO Abstract 270

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OncoLink ASCO 2001 coverage is provided by an unrestricted educational grant from Amgen



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