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Breast Cancer Research and Treatment

, Volume 156, Issue 2, pp 331–341 | Cite as

Revisiting dosing regimen using PK/PD modeling: the MODEL1 phase I/II trial of docetaxel plus epirubicin in metastatic breast cancer patients

  • Emilie Hénin
  • Christophe Meille
  • Dominique Barbolosi
  • Benoit You
  • Jérôme Guitton
  • Athanassios Iliadis
  • Gilles Freyer
Clinical trial

Abstract

The MODEL1 trial is the first model-driven phase I/II dose-escalation study of densified docetaxel plus epirubicin administration in metastatic breast cancer patients, a regimen previously known to induce unacceptable life-threatening toxicities. The primary objective was to determine the maximum tolerated dose of this densified regimen. Study of the efficacy was a secondary objective. Her2-negative, hormone-resistant metastatic breast cancer patients were treated with escalating doses of docetaxel plus epirubicin every 2 weeks for six cycles with granulocyte colony stimulating factor support. A total of 16 patients were treated with total doses ranging from 85 to 110 mg of docetaxel plus epirubicin per cycle. Dose escalation was controlled by a non-hematological toxicity model. Dose densification was guided by a model of neutrophil kinetics, able to optimize docetaxel plus epirubicin dosing with respect to pre-defined acceptable levels of hematological toxicity while ensuring maximal efficacy. The densified treatment was safe since hematological toxicity was much lower compared to previous findings, and other adverse events were consistent with those observed with this regimen. The maximal tolerated dose was 100 mg given every 2 weeks. The response rate was 45 %; median progression-free survival was 10.4 months, whereas 54.6 months of median overall survival was achieved. The optimized docetaxel plus epirubicin dosing regimen led to fewer toxicities associated with higher efficacy as compared with standard or empirical densified dosing. This study suggests that model-driven dosage adjustment can lead to improved efficacy-toxicity balance in patients with cancer when several anticancer drugs are combined.

Keywords

Intensification Densification Drug combination Dosing regimen optimization PK/PD modeling 

Abbreviations

PKs

Pharmacokinetics

PDs

Pharmacodynamics

PK/PD

Pharmacokinetic/pharmacodynamic

BSA

Body surface area

G-CSF

Granulocyte colony stimulating factors

DTX

Docetaxel

EPI

Epirubicin

MTD

Maximum tolerated dose

DLT

Dose-limiting toxicity

HFS

Hand-foot syndrome

AE

Adverse event

SAE

Severe adverse event

Notes

Acknowledgments

The authors would like to thank R. Maraval-Gaget, study coordinator at Centre Hospitalier Lyon Sud, and Dr. B. Tranchand for their involvement in the MODEL1 study. We also extend kind thanks to Dr. J. Ciccolini for helping in the preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Emilie Hénin
    • 1
    • 2
  • Christophe Meille
    • 3
    • 6
  • Dominique Barbolosi
    • 3
  • Benoit You
    • 1
    • 2
    • 4
  • Jérôme Guitton
    • 1
    • 2
    • 5
  • Athanassios Iliadis
    • 3
  • Gilles Freyer
    • 1
    • 2
    • 4
  1. 1.EMR3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon Sud Charles Mérieux, Université Claude BernardOullinsFrance
  2. 2.Université de LyonLyonFrance
  3. 3.Pharmacokinetics Unit, Aix-Marseille University, SMARTc, Inserm CRO2 UMR_S 911MarseilleFrance
  4. 4.Institut de Cancérologie des HCL, Service d’Oncologie MédicaleCentre Hospitalier Lyon Sud69495France
  5. 5.Département de PharmacologieCentre Hospitalo-Universitaire Lyon SudPierre BéniteFrance
  6. 6.OCP-TCO, Novartis Pharma AG, WSJ-340.5.25.27BaselSwitzerland

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