This is a multicenter, prospective, non-randomized, open-label, pharmacokinetic study, aiming to compare the plasma exposure of the payload (free-DXd) in patients treated by T-DXd for locally advanced or metastatic breast cancer according to their BMI.
The primary objective is to compare plasma exposition of the payload (free-DXd) between overweight or obese (BMI\>25) and normal weight (BMI≤25) breast cancer patients during the first 3 cycles of Trastuzumab-Deruxtecan (T-DXd).
A total of 210 patients will have to be enrolled in this study with the following repartition:
N = 105 patients with a BMI ≤ 25 (normal weight patients). N = 105 patients with a BMI \> 25 (overweight or obese patients) with at least 30 obese patients (BMI\>30).
Women (or men) aged ≥ 18 years on the day of signing the informed consent with histologically proven breast cancer.
Metastatic or locally advanced breast cancer with overexpression/amplification HER2 (IHC +++ or ++ and positive-hybridation in situ) or low HER2 expression (IHC + or ++ and negative-hybridation in situ) and may be ultra-low (in first line, in case of approval).
Patient eligible for Trastuzumab-Deruxtecan (T-DXd).
Concomitant administration of pertuzumab may be accepted in case of approval in first line for HER2- overexpressed/amplified locally advanced or metastatic breast cancer.
Peripheral venous access making blood samples difficult.
Patients unable to receive T-DXd treatment at a dose of 5.4 mg/kg in cycle 1 (whatever the reason)
Patients with known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study.
Single group
Pharmacokinetics blood samples
Biological/VaccineBlood samples will be collected at different time points during the first four treatment cycles and at the end of T-DXd treatment or at 24 months after inclusion in case of T-DXd continuation beyond this time period.
Primary Outcome Measure
Plasma exposure of free-DXd (payload) will be measured by the cumulative AUC (Area under the concentration vs. time curve) over the first 3 cycles or until an event (interruption or dose concession for toxicity) divided by the number of corresponding cycles. These AUCs will be determined by Bayesian estimation (Posthoc values) using a non-linear mixed-effects approach.
Safety: toxicities will be assessed using the NCI-CTCAE Version 5.0.
Efficacy: Progression Free Survival (PFS)
Progression Free Survival (PFS) is defined as the time from inclusion until progression or death; patients alive and without documented progression at last follow-up news are censored at this date or at initiation of new anticancer treatment (if applicable).
Secondary pharmacokinetic criteria
A population PK model will be performed to quantify the impact of several patient characteristics: morphological data (weight, height, BMI, lean mass, etc.), biological data (inflammation markers, albuminemia, liver enzymes, etc.), demographic data (age), on the PK parameters (elimination clearance, volume of distribution) of T-DXd and free-DXd.
Body composition parameters
Skeletal muscle mass index or density and lean body mass before treatment initiation and during the active treatment phase (at 3 months tumor assessment before C5D1 and at 6 months; tumor assessment before C9D1) using the "Cassandra" algorithm.
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Institut Claudius Regaud
Lead sponsor
Ligue contre le cancer, France
Collaborator
