Influence of patient’s morphological characteristics on pharmacokinetic and toxicity of trastuzumab-deruxtecan administered for metastatic breast cancers (TDXdose)

The primary objective is to compare plasma exposition of the payload (free-DXd) between overweight or obese patients with body mass index greater than 25 and normal weight patients with body mass index of 25 or less during the first three cycles of trastuzumab-deruxtecan treatment in metastatic breast cancer. This comparison is clinically relevant to determine whether body composition influences drug exposure, which may impact dosing strategies and treatment outcomes in patients with different weight categories.

The secondary objectives include:

• To compare the frequency and intensity of adverse effects between overweight or obese patients and normal weight patients.

• To evaluate the relationship between pharmacokinetic parameters, specifically plasma concentration or exposition of trastuzumab-deruxtecan or free-DXd, and toxicity of the treatment.

• To evaluate the relationship between pharmacokinetic parameters and treatment efficacy measured by progression-free survival.

• To develop a population pharmacokinetic model of trastuzumab-deruxtecan and evaluate the impact of various covariates including morphologic parameters such as alternative body composition measurements, demographic factors, and biological parameters on pharmacokinetic parameters.

• To evaluate the association between sarcopenia, both initial status and its evolution during treatment, and the effects of trastuzumab-deruxtecan regarding adverse effects and efficacy.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes **adult** women and men aged 18 years or older diagnosed with histologically proven **breast cancer**. Participants present with **metastatic** or locally advanced disease characterized by **HER2 overexpression/amplification** (IHC +++ or ++ with positive in situ hybridization), low HER2 expression (IHC + or ++ with negative in situ hybridization), or potentially ultra-low HER2 expression in first-line treatment settings, subject to regulatory approval. The trial population was selected based on eligibility for **Trastuzumab-Deruxtecan** (T-DXd) therapy, with particular focus on comparing plasma exposure of the drug payload between overweight or obese patients (BMI>25) and normal weight patients (BMI≤25) during the initial three treatment cycles. Female participants of childbearing potential are required to have negative **pregnancy** tests and must utilize contraception methods for the study duration and seven months post-treatment, while male participants must employ contraception for four months following the last dose. All participants must be affiliated with Social Health Insurance in France and provide signed informed consent demonstrating their ability and willingness to comply with study protocol requirements.

This is a phase IV, low-intervention clinical trial investigating the influence of patient morphological characteristics on the pharmacokinetics and toxicity of **trastuzumab deruxtecan** in patients with **metastatic breast cancer**. The study is designed as a prospective observational trial comparing plasma exposure of the active payload (free-DXd) between overweight or obese patients (BMI greater than 25) and normal weight patients (BMI 25 or less) during the first three treatment cycles. The investigational medicinal product, **Enhertu** 100 mg powder for concentrate for **solution for infusion**, contains trastuzumab deruxtecan as the active substance and will be administered via **intravenous use** according to the approved marketing authorization. The maximum daily dose is 1 mg/kg with a maximum total dose of 36 mg, and the maximum treatment period is 24 months. The trial will employ a **non-linear mixed-effects approach** with **Bayesian estimation** to determine the area under the concentration versus time curve over the first three cycles or until an event such as treatment interruption or dose modification due to toxicity occurs.

Eligible participants include women or men aged 18 years or older with histologically proven breast cancer that is metastatic or locally advanced with **HER2 overexpression/amplification** (IHC +++ or ++ with positive in situ hybridization), low HER2 expression (IHC + or ++ with negative in situ hybridization), or potentially ultra-low expression in first-line treatment pending approval. Patients must be eligible for trastuzumab deruxtecan treatment, and concomitant administration of **pertuzumab** may be permitted in first-line treatment for HER2-overexpressed/amplified disease if approved. Female participants of childbearing potential must have a negative pregnancy test within 72 hours prior to the first dose and must use at least one method of contraception or abstain from heterosexual activity for the duration of the study and until seven months after the last dose. Male participants must use contraception for the duration of the study and until four months after the last dose. All participants must provide signed written informed consent and be affiliated with Social Health Insurance in France.

The primary endpoint is plasma exposure of free-DXd measured by cumulative area under the curve over the first three cycles or until an event, divided by the number of corresponding cycles, with differences between the two BMI groups assessed using Student's test or Mann-Whitney test if applicable. Secondary endpoints include safety assessment through adverse event recording using **NCI-CTCAE** toxicity classification version 5.0, with descriptive statistics and between-group comparisons using Chi-squared or Fisher's exact test. Efficacy will be evaluated using the **Kaplan-Meier approach** to estimate **progression-free survival** rates for each group, with the association between plasma exposure and progression-free survival assessed using a **Cox proportional hazards model** with time-dependent variables adjusted for clinicopathological variables of interest. Additional analyses will include Landmark approach at different time points, assessment of the association between progression-free survival and body composition, and evaluation of the relationship between plasma exposure and safety using **logistic regression models** with reporting of odds ratios and corresponding confidence intervals.

The estimated recruitment start date is September 2025, with an estimated trial end date of September 2029, indicating an overall trial duration of approximately four years. The expected length of participant involvement extends up to the maximum treatment period of 24 months or until treatment discontinuation. Conditions that may lead to early termination from the study include treatment interruption or dose modification due to toxicity, disease progression, withdrawal of consent, or other safety concerns as determined by the investigator or protocol requirements.

The experimental medication utilized in this clinical trial is **Enhertu** 100 mg powder for concentrate for **solution for infusion**. The **active substance** is **trastuzumab deruxtecan**, also known by its synonyms DS-8201 and DS-8201A. Trastuzumab deruxtecan is classified as a protein-based therapeutic agent. The pharmaceutical form consists of a powder for concentrate that is reconstituted to prepare a solution for infusion. The product is authorized within the European Union under the marketing authorization number EU/1/20/1508/001 and is manufactured by Daiichi Sankyo Europe GmbH.

The **route of administration** for trastuzumab deruxtecan is **intravenous use**. The **dosage** is calculated based on body weight, with a maximum daily dose of 1 **mg/kg**. The maximum total dose per administration is 36 **mg**. The treatment period extends up to **24 months**. The medication is administered during consecutive treatment cycles, with pharmacokinetic monitoring conducted during the first three cycles to assess plasma exposition of the payload component, specifically free-DXd, in relation to patient morphological characteristics including **body mass index**.

Efficacy will be assessed through the evaluation of Progression Free Survival (PFS). The Kaplan-Meier approach will be used to estimate PFS rates for each group. To consider immortal time bias, the association between plasma exposure or plasma concentration and PFS will be assessed using a Cox proportional hazards model with time-dependent variable. The Cox model will be adjusted on clinico-pathological variables of interest. A complementary analysis will be conducted using Landmark approach at different time points. The association between PFS and body composition will be assessed using a similar approach to the one used for association with plasma exposure.