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Breast Cancer Res Treat. 2016 Apr;156(2):331-41. doi: 10.1007/s10549-016-3760-9. Epub 2016 Mar 22.

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

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EMR3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon Sud Charles Mérieux, Université Claude Bernard, Oullins, France.
Université de Lyon, Lyon, France.
Pharmacokinetics Unit, Aix-Marseille University, SMARTc, Inserm CRO2 UMR_S 911, 13375, Marseille, France.
OCP-TCO, Novartis Pharma AG, WSJ-340.5.25.27, 4002, Basel, Switzerland.
Institut de Cancérologie des HCL, Service d'Oncologie Médicale, Centre Hospitalier Lyon Sud, 69495, Lyon, France.
Département de Pharmacologie, Centre Hospitalo-Universitaire Lyon Sud, Pierre Bénite, France.
Pharmacokinetics Unit, Aix-Marseille University, SMARTc, Inserm CRO2 UMR_S 911, 13375, Marseille, France.


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.


Densification; Dosing regimen optimization; Drug combination; Intensification; PK/PD modeling

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