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Dose-Seeking Phase I Trials for Currently Approved Molecular-Targeted Therapies in the USA: The Dose-Limiting Toxicity Definition Issue

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Abstract

Background

There is substantial evidence that classically used toxicity-driven dose-escalating phase I trials are not optimal for defining the recommended phase II dose for molecular-targeted therapies.

Objective

This study aimed to assess the actual methodology used for phase I trials of approved molecular-targeted therapies for solid tumors in the USA.

Methods

We evaluated the designs and endpoints used in 53 single-agent dose-seeking phase I trials that were published between 2001 and November 2015, investigating US Food and Drug Administration (FDA)-approved molecular-targeted therapies for solid tumors (n = 28).

Results

In all but three cases, the trials used dose-escalating designs that were toxicity-driven (50 trials, 94 %). The “3+3 design” was used in 25 trials (47 %). In 47 trials (89 %), dose-limiting toxicities were assessed during the first 28 days; the definitions of dose-limiting toxicities were similar to those used in cytotoxic drug trials (Grade 4 neutropenia, febrile neutropenia, thrombocytopenia with hemorrhage).

Conclusions

In most trials, the dose-limiting toxicity definition did not specifically address the expected side effects related to the mechanisms of action of the molecular-targeted therapy, the expected side effects of which differ significantly from cytotoxic agents.

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Author information

Authors and Affiliations

  1. Medical Oncology Department, Centre Oscar Lambret, 3, rue F Combemale, 59000, Lille, France

    Nuria Kotecki, Jacques Bonneterre, Antoine Adenis, Sophie Cousin & Nicolas Penel

  2. Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

    Ahmad Awada

  3. Medical Oncology Department, Lille University Hospital, Lille, France

    Mohamed Hebbar

  4. Pneumology Department, Lille University Hospital, Lille, France

    Alexis B. Cortot

  5. Clinical Research Unit, Centre Oscar Lambret, Lille, France

    Stéphanie Clisant

  6. Research Unit (EA 2694: Epidemiology and Quality of Care), Lille University Hospital, Lille, France

    Alain Duhamel & Nicolas Penel

  7. Université Lille II, Lille, France

    Jacques Bonneterre, Mohamed Hebbar & Alexis B. Cortot

Authors
  1. Nuria Kotecki
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  2. Ahmad Awada
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  3. Jacques Bonneterre
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  4. Mohamed Hebbar
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  5. Antoine Adenis
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  6. Alexis B. Cortot
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  7. Sophie Cousin
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  8. Stéphanie Clisant
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  9. Alain Duhamel
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  10. Nicolas Penel
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Corresponding author

Correspondence to Nicolas Penel.

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Funding

No funding source to declare.

Conflict of Interest

Nuria Kotecki, Ahmad Awada, Jacques Bonneterre, Mohamed Hebbar, Antoine Adenis, Alexis B. Cortot, Sophie Cousin, Stéphanie Clisant, Alain Duhamel and Nicolas Penel declare that there are no conflicts of interest.

Ethical Approval

The manuscript does not contain patient data.

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Kotecki, N., Awada, A., Bonneterre, J. et al. Dose-Seeking Phase I Trials for Currently Approved Molecular-Targeted Therapies in the USA: The Dose-Limiting Toxicity Definition Issue. Pharm Med 30, 143–147 (2016). https://doi.org/10.1007/s40290-016-0138-6

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  • DOI: https://doi.org/10.1007/s40290-016-0138-6

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