Association of Pembrolizumab Infusion Time and Efficacy in Patients With Non-metastatic Triple-negative Breast Cancer (TNBC) Treated With Neoadjuvant Chemotherapy and Immunotherapy (PEMCLOCK)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Metastatic Breast Carcinoma
• Intervention / Treatment: Other: No intervention

• Study Type: Observational
• Enrollment (Estimated): 450

Contacts and Locations

• Study Contact: Name: Jérôme Lambert, Pr; Phone Number: +33142499742; Email: jerome.lambert@u-paris.fr
• Study Contact Backup: Name: Sylvie Giacchetti, Dr; Phone Number: +33142499785; Email: sylvie.giacchetti@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Female with high-risk early triple-negative breast cancer treated with neoadjuvant chemotherapy combined with pembrolizumab

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Morning group	Other: No intervention; No intervention added by the study
Afternoon group	Other: No intervention; No intervention added by the study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Residual cancer burden class (RCB)	RCB is studied after neoadjuvant treatment (Symmans et al. 2007)	Up to 36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival		At 2 years
Number of immune adverse events	Measurement of immune adverse events according to CTC-CAE Toxicity Grading Scale for Determining The Severity of Adverse Events version 5	Up to 36 months
Histological Complete Response (hCR) rate versus invasive residual disease rate	Complete response is defined as hCR or RCB 0 Invasive residual disease rate is defined as RCB 2-3	Up to 36 months
Tumor-infiltrating lymphocyte (TIL) levels	Association of RCB (class and continuous variable) with tumor-infiltrating lymphocyte (TIL) levels	Up to 36 months
Number of Pembrolizumab infusions performed		Up to 36 months
Tumor cellularity	in %	Up to 36 months
Size of residual breast tumor	mm x mm	Up to 36 months
Number of invaded nodes		Up to 36 months
Diameter of largest lymph node metastasis if lymph node invaded		Up to 36 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: April 19, 2024
• First Submitted That Met QC Criteria: May 13, 2024
• First Posted (Actual): May 16, 2024

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 13, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Immunotherapy; Triple-negative breast cancer; Chronotherapy; Non metastatic Triple-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms
• Other Study ID Numbers: APHP240393

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No