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A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in

Isa E L M Kuppens1, Els O Witteveen, Roxanne C Jewell

  • 1Division of Clinical Pharmacology, Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 5, 2007
PubMed
Abstract

Insights

Coadministering elacridar with oral topotecan significantly enhances topotecan

Area of Science:

  • Pharmacology
  • Oncology
  • Drug Metabolism

Background:

  • Breast cancer resistance protein (BCRP) significantly reduces oral topotecan bioavailability.
  • Elacridar, a BCRP inhibitor, can improve topotecan's oral absorption.

Purpose of the Study:

  • Determine the minimum effective elacridar dose for maximal topotecan oral bioavailability.
  • Establish the optimal coadministration schedule for oral topotecan and elacridar.
  • Define dose-limiting toxicities and maximum tolerated dose of oral topotecan with elacridar.

Main Methods:

  • Part I: Randomized trial of elacridar doses (100-1000 mg) with oral topotecan (2.0 mg) in 20 patients.
  • Part II: Daily oral topotecan with the determined lowest effective elacridar dose to assess MTD and DLT.
  • Pharmacokinetic sampling on specific days throughout both study parts.

Main Results:

  • Complete apparent oral bioavailability of topotecan (102 ± 7%) achieved with elacridar coadministration.
  • Two dose-limiting toxicities observed at the 2.5 mg oral topotecan dose level during escalation.

Conclusions:

  • The optimal regimen is 2.0 mg oral topotecan with 100 mg elacridar, given daily for five days every 21 days.
  • This combination enhances topotecan oral bioavailability and establishes safe dosing parameters.

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