Clinical trial NCT06418139: Association of Pembrolizumab Infusion Time and Efficacy in Patients With Non-metastatic Triple-negative Breast Cancer (TNBC) Treated With Neoadjuvant Chemotherapy and Immunotherapy
Official title: Etude de l'Effet de l'Horaire de Perfusion de l'immunothérapie Sur la réponse et la toxicité Des Traitements Chez Les Patientes Atteintes de Cancer du Sein Triple négatif à Haut Risque traité Par chimiothérapie néoadjuvante et Pembrolizumab
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Non-Metastatic Breast Carcinoma
Keywords: Non metastatic Triple-negative breast cancer
Triple-negative breast cancer
Chronotherapy
Immunotherapy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2024-05-16
Enrollment: 450
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Female with high-risk early triple-negative breast cancer treated with neoadjuvant chemotherapy combined with pembrolizumab

Brief summary: Background: Triple negative breast cancer (TNBC) is characterized by an aggressive biological behaviour responsible for higher risk of recurrence and shorter median survival. Pembrolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death (PD-1), in association to chemotherapy showed improvement of event-free survival in patients with previously untreated stage II or III TNBC and has been approved in Europe since March 2022 for this indication (KEYNOTE-522). Circadian timing system controls many various biological functions in humans including xenobiotic metabolism and elimination, immune functions, cell cycle event and apoptosis. Thus, chronotherapeutic approaches have shown improved efficacy and tolerability in the treatment of different types of cancer, notably in colorectal cancer. Pronounced circadian rhythms in immune functions are generated by cell-autonomous molecular clocks in T and B lymphocytes, macrophages, neutrophils, and dendritic cells. Recently, first evidence of the effect of timing infusion of immune checkpoint inhibitors on prognosis of patients with cancer has been reported in several retrospective trials. Landre et al.'s meta-analysis of 7 retrospective studies including 1019 patients who had metastatic cancer was presented at the American Society of Clinical Oncology (ASCO) meeting in 2023. An early time-of-day ICI infusions was associated with an increase overall survival (HR: 0.49, \[95% CI: 0.36-0.69\] p \< 0.0001).

Objectives: The aim is to analyze immunotherapy infusion timing impact on histological response, toxicity and Event Free-Survival (EFS) in patients with TNBC treated with Neo-Adjuvant Chemotherapy (NAC) associated with pembroluzimab. Measure of histological response is the primary objective determined by Residual Cancer Burden (RCB). Secondary endpoints are Event free Survival (EFS), calculated from the date of diagnosis to invasive local, regional, or metastatic relapse, contralateral breast cancer, or death from any cause), toxicity which is assessed by recording adverse events (CT-CAE v5) occurring from start of treatment to last course.

Methods: Data from patients with histologically proven early TNBC treated from July 2021 to May 2023 with the association of Pembrolizumab, Paclitaxel Carboplatine followed with Pembrolizumab Cyclophosphamide Epirubicine (according to KEYNOTE 522 study) will be collected. Dosing times of each Pembrolizumab and chemotherapy infusions given to consecutive patients as a neoadjuvant standard treatment, associated with chemotherapy, for early TNBC are retrieved from hospital records. Adjuvant Pembrolizumab timing intake will be also recorded as EFS is a secondary endpoint.

Statistics: First, median clock hour of all infusions of Pembrolizumab will be determined. Then, patients will be dichotomized between "morning' and 'afternoon' groups using 2 cut-offs: 1/ median clock of all infusions of pembrolizumab ('morning group' will include the patients who receive the majority of Pembrolizumab infusions before this median clock hour and 'afternoon group', patients who receive the majority of Pembrolizumab infusions after this median clock hour) and 2/ cut-off optimizing differences of RCB between two groups.

Patient's characteristics, toxicities, tumor response and EFS will be compared.


Eligibility criteria: Inclusion Criteria:

* Female sex
* Age ≥ 18 years-old
* Previously untreated histologically proven triple-negative breast cancer (RE \< 10%, RP \< 10%, Her-2 negative)
* No metastatic
* Having at least one injection of pembrolizumab associated with chemotherapy
* Pembrolizumab injection schedule correctly reported by the nurse in charge of the patient

Exclusion Criteria:

• Metastatic disease

Primary outcomes:
measure: Residual cancer burden class (RCB)
timeFrame: Up to 36 months
Secondary outcomes:
measure: Number of immune adverse events
timeFrame: Up to 36 months
measure: Histological Complete Response (hCR) rate versus invasive residual disease rate
timeFrame: Up to 36 months
measure: Tumor-infiltrating lymphocyte (TIL) levels
timeFrame: Up to 36 months
measure: Progression-free survival
timeFrame: At 2 years
measure: Number of Pembrolizumab infusions performed
timeFrame: Up to 36 months
measure: Tumor cellularity
timeFrame: Up to 36 months
measure: Size of residual breast tumor
timeFrame: Up to 36 months
measure: Number of invaded nodes
timeFrame: Up to 36 months
measure: Diameter of largest lymph node metastasis if lymph node invaded
timeFrame: Up to 36 months
Other outcomes:
Locations:
Study officials:
References: