A Pilot Dose Escalation Trial of a Densified Chemotherapy Association of Docetaxel and Epirubicin Driven by Mathematical Modeling in Metastatic Breast Cancer Patients: The MODEL1 Study

Study Overview
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Brief Summary
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To determine the maximum tolerated dose of a densified regimen of the association of docetaxel (DTX) and epirubicin (EPI), supported by the concomitant administration of hematopoietic growth factors in patients with metastatic breast cancer in first-line, optimizing in each patient the administration schedule using a formal procedure based on mathematical models in order to manage the severity of induced neutropenia. The models used in this project allow: an optimal administration schedule of the planned total dose per cycle (number of infusions and calculating their rates and durations) an individualization of the administration schedule from the second cycle (based on observations from the first cycle), and an assessment of the risk of a dose-limiting toxicity event combining several severe non-hematological toxicities (conditioning the decision for dose escalation). Using formal mathematical models the investigators expect controlling the hematological and non-hematological toxicities in order to realize the full series of six cycles of densified DTX+EPI chemotherapy (2 weeks per cycle) for each patient. For each patient, chemotherapy is considered feasible if it is possible, in the absence of tumor progression, to consider 6 cycles of treatment without observing any serious adverse events and without: patient death that may be related to the treatments; decision of the patient to interrupt treatment for physical or psychological tolerance reasons; decision of the investigator to discontinue treatment, in the absence of disease progression.

Official Title
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A Pilot Dose Escalation Phase I Trial of a Densified Chemotherapy Association of Docetaxel and Epirubicin Driven by Mathematical Modeling in Metastatic Breast Cancer Patients: The MODEL1 Study

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Combination of Docetaxel (DTX) and Epirubicin (EPI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years, ECOG performance status ≤ 2 Diagnosed with metastatic HER2-negative hormone-resistant chemotherapy-naive breast cancers, previous adjuvant chemotherapy treatment are allowed. Histologically or cytologically proven breast cancer metastases or associated with CA 15-3 levels 50% above the normal value Hormone resistance defined by the presence of negative hormone receptors or disease progression within 6 months of the initiation of hormone therapy. Adequate renal and liver function (ASAT and ALAT < twice the upper limit normal value (ULN) if no liver metastases, or < 4×ULN if liver metastases; total bilirubin < 2×ULN), Adequate cardiac function (left ventricular ejection fraction (LVEF) > 50%), Neutrophils ≥ 1200/mm3 Platelets ≥ 105/mm3 Exclusion Criteria: Cerebral metastases and meningeal involvement, Other malignant diseases, Significant comorbidities, Previous chemotherapy for metastatic disease, or previous chemotherapy with a total cumulative dose greater than 600 mg/m² for EPI or greater than 450 mg/m² for DTX

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination of Docetaxel (DTX) and Epirubicin (EPI)<br> | Drug: Combination of Docetaxel (DTX) and Epirubicin (EPI)<br>* Six cycles of densified DTX+EPI chemotherapy (2 weeks per cycle) for each patient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the risk of Dose-limiting Toxicities | DLTs were defined as ≥ grade 3 vomiting, ≥ grade 3 mucositis,≥ grade 3 hand-foot syndrome (HFS), grade 2 vomiting plus grade 2 mucositis, or grade 2 vomiting plus grade 2 HFS | 84 days (6 treatment cycles x 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration of Docetaxel and Epirubicin after administration | Assessment of the pharmacokinetics of Docetaxel and Epirubicin | 84 days (6 treatment cycles x 14 days) | 
| Tumor response for each patient with one or more measurable lesions | Measurement of tumor response by MRI for each patient with one or more measurable lesions, classified according to RECIST criteria | after 28 days (2 treatment cycles x 14 days) and 84 days (6 treatment cycles x 14 days) | 
| Progression-free survival |  | 115 days (study duration (6 treatment cycles x 14 days) + follow-up (31 days) when available) | 
| Overall survival |  | 115 days (study duration (6 treatment cycles x 14 days) + follow-up (31 days) when available) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug combination, Accelerated chemotherapy, Mathematical model, Hematotoxicity, Individualized dosage