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A loading dose is an essential pharmacological strategy to rapidly achieve the target plasma drug concentration necessary for an immediate therapeutic effect. This approach is especially critical for drugs characterized by slow absorption or extended half-lives, where delaying therapeutic plasma levels could compromise treatment outcomes. By administering a loading dose, clinicians ensure a prompt onset of drug action, even for agents with complex pharmacokinetic profiles.Achieving steady-state...
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Implementing the EffTox dose-finding design in the Matchpoint trial.

Kristian Brock1, Lucinda Billingham2, Mhairi Copland3

  • 1Cancer Research UK Clinical Trials Unit, Institute of Cancer & Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK. k.brock@bham.ac.uk.

BMC Medical Research Methodology
|July 22, 2017
PubMed
Summary

The Matchpoint trial used the EffTox adaptive design to find the optimal ponatinib dose for chronic myeloid leukaemia patients. This Bayesian approach efficiently balances efficacy and toxicity in dose-finding studies.

Keywords:
CMLDose-findingEffToxEfficacyPhase I/IIToxicity

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Area of Science:

  • Clinical Oncology
  • Biostatistics
  • Pharmacology

Background:

  • The Matchpoint trial investigates optimal ponatinib dosing with chemotherapy for chronic myeloid leukaemia in blastic transformation.
  • The study focuses on achieving both tolerable and efficacious dose levels.

Purpose of the Study:

  • To describe the implementation experience of the EffTox adaptive dose-finding design within the Matchpoint trial.
  • To evaluate the effectiveness and challenges of using EffTox for joint efficacy and toxicity assessment.

Main Methods:

  • Utilized EffTox, a Bayesian adaptive design, for joint analysis of binary efficacy and toxicity outcomes.
  • Employed dose-transition pathways to guide dose selection for future cohorts based on observed outcomes.
  • Addressed challenges such as dose ambivalence and outcome ambiguity within the trial design.

Main Results:

  • Developed an EffTox parameterization demonstrating strong simulated performance across various scenarios.
  • Successfully navigated dose ambivalence using dose-transition pathways, aiding in planning and decision-making.
  • Overcame short-term outcome ambiguity, ensuring trial progression.

Conclusions:

  • EffTox is an efficient and powerful design for joint phase I/II clinical trials, despite implementation challenges.
  • The experience provides practical insights for others implementing adaptive dose-finding designs.
  • Joint phase I/II designs are crucial for future drug development, especially for non-cytotoxic treatments.