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 (MODEL1)

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

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Combination of Docetaxel (DTX) and Epirubicin (EPI)

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Combination of Docetaxel (DTX) and Epirubicin (EPI)	Drug: Combination of Docetaxel (DTX) and Epirubicin (EPI); Six cycles of densified DTX+EPI chemotherapy (2 weeks per cycle) for each patient

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Gilles FREYER, Professor, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud - Service d'oncologie médicale

Study record dates

Study Major Dates

• Study Start: June 1, 2005
• Primary Completion (ACTUAL): March 1, 2009
• Study Completion (ACTUAL): March 1, 2009

Study Registration Dates

• First Submitted: March 3, 2015
• First Submitted That Met QC Criteria: March 13, 2015
• First Posted (ESTIMATE): March 19, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): March 19, 2015
• Last Update Submitted That Met QC Criteria: March 13, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Drug combination; Accelerated chemotherapy; Mathematical model; Hematotoxicity; Individualized dosage
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Docetaxel; Epirubicin
• Other Study ID Numbers: 2004.356