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Early Trial Discontinuation in Toxicity-Driven, Dose-Escalating, Phase I Cancer Trials: Occurrence, Outcomes and Predictive Factors

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Abstract

Introduction

The selection of patients for phase I cancer trials remains challenging. Patients who dropout of the trial before completion need to be replaced and this can result in significant delays to trial completion.

Objective

The objective of this study was to identify patients enrolled in phase I oncology trials who were unable to complete the minimum evaluation period of the trial, and to use these data to develop a predictive model of risk factors for patient replacement.

Patients and Methods

We retrospectively reviewed all consecutive patients who were enrolled in dose-escalating phase I cancer trials at four medical centers in France between May 2003 and May 2013. Replacement was defined as trial discontinuation before 6 weeks, without the occurrence of dose-limiting toxicity. Using logistic regression and decision-tree analyses, we developed a predictive model to identify patients who were at high risk for replacement, and also their common risk factors. This model was designed to provide maximum specificity and a negative predictive value.

Results

Of 332 patients enrolled in the study, 16 had to be replaced (4.8 %). The median overall survival time was 45 days for the patients who were replaced versus 480 days for the patients who were not replaced (p < 0.0001). In the univariate analysis, the risk factors for replacement included Eastern Cooperative Oncology Group performance status (ECOG-PS) = 2 [odds ratio (OR) 11], Royal Marsden Score (RMS) = 3 (OR 29), and enrollment in a study investigating multiple agents (OR 7). Multivariate analysis retained PS ≥2 and RMS = 3 as independent predictive factors for replacement. The following two patient subgroups were identified: low risk of replacement (RMS ≤2 and PS ≤1) and high risk of replacement (RMS = 3 or PS ≥2). The rates of replacement were 8/312 (2.5 %) and 8/20 (40.0 %) for low- and high-risk patients, respectively, and the specificity and negative predictive values of our model were 96.2 and 97.5 %, respectively.

Conclusions

Approximately 5 % of enrolled patients were replaced, and these patients experienced very poor outcomes. To minimize trial delays, enrolling patients who have an RMS = 3 or PS ≥2 should be avoided.

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Authors and Affiliations

  1. Medical Oncology Department, Centre Oscar Lambret, 3, rue F Combemale, 59020, Lille Cedex, France

    Sophie Cousin, Nuria Kotecki-Borghesi & Nicolas Penel

  2. Medical Oncology Department, Centre Léon Bérard, Lyon, France

    Philippe A. Cassier, Louis Tassy & Catherine Terret

  3. Medical Oncology Department, Institut Claudius Regaud, Toulouse, France

    Carlos Gomez-Roca, Eleonora De Maio, Juliette Bouchet & Jean-Pierre Delord

  4. Medical Oncology Department, Centre Georges-François Leclerc, Dijon, France

    Nicolas Isambert, Sylvie Zanetta & Anne-Laure Simonet-Lamm

  5. Clinical Research and Methodological Platform of SIRIC OncoLille Consortium, Research Unit EA2694, Lille-Nord-de-France University, Medical School, Lille, France

    Nicolas Penel

Authors
  1. Sophie Cousin
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  2. Philippe A. Cassier
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  3. Carlos Gomez-Roca
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  4. Nicolas Isambert
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  6. Sylvie Zanetta
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  7. Louis Tassy
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  8. Anne-Laure Simonet-Lamm
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  9. Eleonora De Maio
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  10. Catherine Terret
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  11. Juliette Bouchet
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  12. Jean-Pierre Delord
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  13. Nicolas Penel
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Corresponding author

Correspondence to Nicolas Penel.

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Funding

No specific funding was used for this retrospective study.

Conflict of interest

The authors declare no competing interests for this work. Drs. Cousin, Cassier, Gomez-Rocca, Isamert, Kotecki-Borghesi, Zanetta, Bouchet, Tassy, Simonet-Lamm, De Maio, Terret, Delord and Penel have completed the Unified Competing Interest form and declare the following: no support was received from any organization for the submitted work; no financial relationships were initiated with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities were undertaken that could appear to have influenced the submitted work.

Ethical approval

All data were collected by the coordination center (Centre Oscar Lambret) after approval from the Clinical Trial Review Committee and the French Data Protection Authority (CNIL). Some patients in this study were treated in the context of phase I clinical trials by the different authors.

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Cousin, S., Cassier, P.A., Gomez-Roca, C. et al. Early Trial Discontinuation in Toxicity-Driven, Dose-Escalating, Phase I Cancer Trials: Occurrence, Outcomes and Predictive Factors. Pharm Med 30, 49–55 (2016). https://doi.org/10.1007/s40290-015-0120-8

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  • DOI: https://doi.org/10.1007/s40290-015-0120-8

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