Neoplasms

All Conditions

Skin and Connective Tissue Diseases

Carcinoma

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Immunomodulating Agents

No intervention

Sylvie Giacchetti, Dr

Jérôme Lambert, Pr

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.

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

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

RCB is studied after neoadjuvant treatment (Symmans et al. 2007)

Measurement of immune adverse events according to CTC-CAE Toxicity Grading Scale for Determining The Severity of Adverse Events version 5

Complete response is defined as hCR or RCB 0 Invasive residual disease rate is defined as RCB 2-3

Association of RCB (class and continuous variable) with tumor-infiltrating lymphocyte (TIL) levels

Assistance Publique - Hôpitaux de Paris

Symptoms and General Pathology

Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Neoplasms, Second Primary

Liver Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Liver Diseases

Hematinics

Oxaliplatin

Fluorouracil

Irinotecan

Cetuximab

Liver Extracts

Antineoplastic Agents, Immunological

Topoisomerase I Inhibitors

Enzyme Inhibitors

Cetuximab is administered every two weeks at the dose of 500 mg/m² over 2h30 (150 minutes).

IV cetuximab

Irinotecan (180 mg/m²) on day 2 as a 6 hour infusion, starting at 2:00, with a peak at 5:00

Oxaliplatin (85 mg/m²) in split daily doses for 3 days, starting on day 2. Daily sinusoidal infusion duration will last from 10:15 to 21:45, with peak delivery rate at 16:00.

5-Fluorouracil (2800 mg/m²) in split daily doses for 3 days, alternating with oxaliplatin infusions, starting on day 2. Daily sinusoidal infusions will last from 22:15 to 9:45 , with peak delivery at 4:00.

Treatments will be repeated every 2 weeks.

HAI chronomodulated chemotherapy

Irinotecan (180 mg/m²) on day 1 as a one hour infusion, then

Oxaliplatin (85 mg/m²) on day 1 as a two hour infusion, then

5-Fluorouracil (2800 mg/m²) as a 48 h infusion starting on day 2, after completion of oxaliplatin delivery.

Treatments will be repeated every 2 weeks.

HAI conventional chemotherapy

Francis A. Lévi, M.D., Ph.D.

The primary objective of the study is to increase by 15% the complete macroscopic resection rate of predominantly liver metastases from metastatic colorectal cancer through combining systemic cetuximab and hepatic artery infusion of three-drug chemotherapy (irinotecan, oxaliplatin and 5-fluorouracil).

Primary end-point: incidence of complete macroscopic resections of liver metastases (R0+R1).

Secondary end-points:

* the rate of histologic complete responses,
* the individual rates of R0 and R1 resections,
* the rate and site(s) of relapse in the resected patients throughout the 3-year span that follows hepatectomy,,
* the relapse-free survival curve and median in the resected patients,
* the progression-free and the overall survival in the patients receiving at least 4 full courses of HAI therapy and in all the patients (intent to treat),
* the objective response rate,
* the rate of adverse events,
* the dose intensities over 3, 6 and 9 courses,
* the per-operative and post-operative complications associated to liver surgery.

The study also includes a pharmacokinetic analysis, a translational research and a rest/activity monitoring investigation.

Open, label, European, non randomized, multicenter, phase II study of intravenous cetuximab (ERBITUX®) and hepatic artery infusion of three-drug chemotherapy (irinotecan, 5-fluorouracil and oxaliplatin) using conventional or chronomodulated delivery (according to institution experience) in patients with liver metastases from colorectal cancer.

Patients undergo partial hepatectomy after 6 ± 3 courses of therapy whenever possible. The minimum of 3 and the maximum of 9 courses before liver surgery depend upon results from iterative onco-surgical evaluations. A minimum of 6 and up to 9 additional courses of therapy will be administered after surgery, depending upon results of liver surgery, pathology report and patient's status. Overall, the patients will receive 9 to 18 courses of protocol therapy.

The interval between the last course of cetuximab-HAI chemotherapy and surgery will be 2 to 4 weeks. Post operative treatment will be initiated 2 to 4 weeks after liver surgery.

TRANSLATIONAL RESEARCH:

1. Pharmacokinetics:

   For a subset of 16 patients (8 on conventional administration and 8 on chronotherapeutic delivery), plasma pharmacokinetics of irinotecan, 5-FU and oxaliplatin and main metabolites will be evaluated after the first course.
2. Rest-Activity monitoring:

   Rest-activity will be monitored with a wrist-worn actigraph (Ambulatory Monitoring, USA) for 1 week prior to treatment onset and during the 2 weeks following treatment onset (3 weeks). This evaluation will be repeated before, during and after the 4th treatment course and before during and after 7th treatment course. Participation of the centers to this investigation will be left optional.

   Time series will be analyzed before, during and after chemotherapy course, with the time courses of the following parameters:
   * Autocorrelation coefficient at 24 h (r24)
   * Dichotomy index I\<O
   * Wavelet-based model function at baseline, and deviation from this model function during and after treatment course delivery.
3. Predictive molecular factors:

In primary tumor and/or in metastases obtained any time prior to inclusion and in resected metastases and non tumoral liver:

* EGFR immunohistochemistry and gene expression or amplification and polymorphism.
* K-ras mutations.
* Clock genes polymorphism or mRNA or protein expression.
* Gene polymorphisms or expression for main pharmacology determinants of irinotecan, 5- FU and oxaliplatin efficacy.
* Inflammatory and immune cell subsets infiltration. Whenever possible, a biopsy of a liver metastasis will also be obtained before treatment onset for documenting these translational endpoints.

In serum, upon inclusion and after 3 courses:

· Determination of serum levels of TGFa, EGF, VEGF, IL-6, IL-8, amphiregulin and epiregulin.

In blood cells upon inclusion:

· Constitutive polymorphisms for ADCC (FCII and FCIII), circadian clock and EGFR.

STATISTICAL METHODS AND SAMPLE SIZE:

The main endpoint will be the incidence of macroscopically complete resections of liver metastases (R0+R1). The confidence intervals (CI) for the response rate will be based on the exact binomial distribution.

For the secondary endpoints, rate of histologic complete responses, rate of R0 resections, rate of R1 resections, rate of relapses, rate of objective responses, the results will be estimated with CI based on the exact binomial distribution. Overall survival time (OS) and progression free survival (PFS) will be analyzed by Kaplan Meier curve. Multivariate analysis will be performed using the Cox proportional hazard model. This analysis will include the following factors: center, performance status, gender, liver disease characteristics, leucocyte count and alkaline phosphatases upon inclusion and treatment delivery schedule, Relapse incidence (RI) is defined as the probability of having had a relapse before time t. Death without experiencing a relapse is a competing event. The method of analysis will be therefore the estimation of Cumulative Incidence curve in a competing risk setting. Multivariate analysis will be performed by the Fine \& Gray model. All patients achieving complete remission will be analyzed.

The goal is to increase the rate of complete resections (R0+R1) by 15%, i.e. from 15% (p0=0.15) to 30% (p1=0.30). According to the exact single-stage phase II design method, the trial for accepting that p1 is to be preferred to p0 (with a=5% and b=20%) requires 48 patients assessable for response. To obtain 48 patients assessable for response, 60 patients will be included in the trial.

A major additional effect expected further from this combined treatment modality is the increase of complete histologic responses, a secondary endpoint in this trial, from 5% (with systemic chemotherapy) to 20% with combined cetuximab and 3-drug HAI. This improvement should further reduce the risk of relapse in the liver or outside the liver by 15 %, i.e. from 80% to 65%.

Therefore, the total number of patients will be 60 patients, including 48 assessable and 12 estimated as unassessable for technical reasons (i.e. HAI catheter dysfunction within the first 2 months).

Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy

Optimal Control of Liver Metastases With Intravenous Cetuximab and Hepatic Artery Infusion of Three-drug Chemotherapy in Patients With Liver-only Metastases From Colorectal Cancer. A European Multicenter Phase II Trial

Gustave Roussy, Cancer Campus, Grand Paris

Merck Serono International SA

Pfizer

CRESGE

Association pour la Recherche sur le Temps Biologique et la Chronothérapie

Administration of endocrine therapy defined as, within one hour of the patient wake up time

Administration of endocrine therapy defined as, within one hour of the patient bed time

Endocrine therapy administered within one hour of patient wake up time

Morning administration of endocrine therapy

Endocrine therapy administered within one hour of the patient bed time

Evening administration of endocrine therapy

Marie-France Savard, MD

Endocrine therapy is an established treatment for hormone receptor-positive breast cancer, but can cause significant side effects with deterioration in quality of life. The side effects of all forms of endocrine therapy are well recognized and can lead to treatment non-persistence or non-compliance. Chronotherapy, also called chronotherapeutics, is defined as the administration of a medication in coordination with circadian rhythm in order to minimize side effects and yield a greater efficacy. The investigators propose to perform a pragmatic, multi-centre, open-label, randomized clinical trial to establish the optimal timing (morning vs. evening) of administering endocrine therapy based on side effects and benefits in early stage breast cancer patients.

Endocrine therapy is an established treatment for hormone receptor-positive breast cancer, but can cause significant side effects with deterioration in quality of life. The side effects of all forms of endocrine therapy are well recognized and can lead to treatment non-persistence or non-compliance. Compliance is defined as the degree or extent of conformity to the recommended administration by the provider, whereas persistence refers to the act of continuing treatment for a certain prescribed duration. Treatment adherence is especially important in breast cancer, as early cessation or reduced compliance to hormonal therapy are associated with reduced disease-free survival and increased mortality. Chronotherapy, also called chronotherapeutics, is defined as the administration of a medication in coordination with circadian rhythm in order to minimize side effects and yield a greater efficacy. The investigators propose to perform a pragmatic, multi-centre, open-label, randomized clinical trial to establish the optimal timing (morning vs. evening) of administering endocrine therapy based on side effects and benefits in early stage breast cancer patients.

Evaluating the Dose Timing (Morning vs Evening) of Endocrine Therapy and Its Effects on Tolerability and Compliance

A Pragmatic Randomised, Multicentre Trial Evaluating the Dose Timing (Morning vs Evening) of Endocrine Therapy and Its Effects on Tolerability and Compliance (REaCT-CHRONO)

Comparing rates of non-compliance and non-persistence to endocrine therapy with patient age, turmour stage, chemotherapy use and type of endocrine therapy. The rates of non-compliance and rates of non-persistence will be tracked throughout the duration of the study and then compared to patient age, tumour stage, chemotherapy use and the type of endocrine therapy used.

Measured by the change in total Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaire from baseline to 12 weeks following the beginning of endocrine therapy. FACT-ES is a validated sub scale of the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. FACT-ES consists of 46 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much). It is designed to measure five domains of health related quality of life in breast cancer patients receiving endocrine therapy: physical, social, emotional, functional well-being as well as an endocrine symptom sub-scale (ESS).

Measured by the change in total score and individual Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) questionnaires from baseline to 4, 8, 12 and 52 weeks following the beginning of endocrine therapy. FACT-ES consists of 46 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much). It is designed to measure five domains of health related quality of life in breast cancer patients receiving endocrine therapy: physical, social, emotional, functional well-being as well as an endocrine symptom sub-scale (ESS).

Measured by the change in the total score and individual sub scales of the validated Functional Assessment of Cancer Therapy for patients with Breast cancer (FACT-B) questionnaire from baseline to 4, 8, 12 and 52 weeks following the beginning of endocrine therapy. The FACT-B consists of 37 items on a 5 point Likert type scale ranging from 0 (not at all) to 4 (very much). It is designed to measure five domains of health related quality of life in breast cancer patients: physical, social, emotional, functional well-being as well as a breast-cancer sub-scale (BCS).

Rates of non-persistence or non-compliance with initially prescribed endocrine therapy

Incremental cost-effectiveness rations (cost per one quality-adjusted life year (QALY) gained).

Ottawa Hospital Research Institute

Patients with metastatic colorectal cancer treated with chemotherapy

Francis Lévi, MD PhD

Observational, non randomized study aimed at measuring the effect of chemotherapy in the urinary concentrations of physiological modified nucleosides in 30 patients with metastatic colorectal cancer.

"Cancersensor" Chemotherapy

Molecularly Imprinted Polymer Sensors of Modified Nucleosides for Non-invasive Monitoring of Cancer Therapy : Effect of Chemotherapy on Cancerous Proliferation Based on the Dynamic Excretion of Urinary Nucleosides.

Measurement of modified nucleosides, cortisol and 6-sulfatoxymelatonin concentration in urine samples before and after chemotherapy

1 saliva sample Measurement of Clock genes polymorphisms expression

1 urine sample per day 3 days before and 14 days after beginning of chemotherapy Measurement of modified nucleosides, cortisol and 6-sulfatoxymelatonin concentration

1 saliva sample : Measurement of Clock genes polymorphisms expression

Institut National de la Santé Et de la Recherche Médicale, France

Gland and Hormone Related Diseases

Rare Diseases

Behaviors and Mental Disorders

Emergencies

Pancreatic Neoplasms

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Quality of Life

Gastrointestinal Agents

Pancrelipase

Pancreatin

All the patients undergo multidimensional tele monitoring for 7 weeks using an upgraded version of the Picado internet platform

The system will monitor the circadian rhythms, physical activity, sleep, symptoms and body weight of patients with advanced pancreatic cancer during one week before (baseline) and six weeks after the 1st course of standard mFOLFIRINOX. The reach of preset thresholds for several parameters that are automatically computed will trigger alerts toward approved health professionals, and their responses will be traced.

Picado system internet platform and connected objects

JEAN FRANÇOIS OUDET

Marie Barba

Jean Francois OUDET

Mohamed BOUCHAHDA, Dr

Francis LEVI, Pr

Pancreatic cancer is a rapidly developing cancer with a poor prognosis. The mFOLFIRINOX protocol has become the standard medical treatment for this pathology. However, mFOLFIRINOX is the cause of severe toxicities including leukoneutropenia, thrombocytopenia, diarrhea, nausea-vomiting, anorexia, asthenia, weight loss and peripheral sensory neuropathy. Therefore, its indication is limited to patients in good general condition. In practice, it is often interrupted upon the occurrence of hematological and/or clinical grade 3-4 toxicities, Remote patient tele-monitoring of symptoms (Patient Reported Outcomes), body weight, circadian rhythms, sleep and activity would allow the identification of early warning signals reflecting deterioration or improvement in the health of these fragile patients, and trigger proactive interventions, while they are outside the hospital. Thus, the MultiDom study proposes a comprehensive tele-monitoring and telecare strategy that would complement standard of care over a 7-weeks period to 42 consenting patients. The patients receive neoadjuvant or first line chemotherapy with mFOLFIRINOX for advanced or metastatic pancreatic cancer at one of four centres in Ile-de-France region (France).

MultiDom stands up among the very first prospective patient-entered and multidimensional, multiactor and multicenter study, that assesses the qualitative and quantitative impact of mFOLFIRINOX on the daily life of patients with pancreatic cancer in real time. Main endpoint is the rate of patients undergoing toxicity-related emergency hospitalisations, and the objective is to reduce it to \<10%. Telemonitored data-based proactive interventions will expectedly prevent worsening of patients 'health, and maintain their chances of disease control on effective mFOLFIRINOX chemotherapy.

Participating patients have usual follow up and treatments for their disease, but also: wear a chest sensor that measures and teletransmits accelerometry, surface temperature and 3D-orientation every min, weigh themselves daily on a BLE-balance, with immediate weight tele transmission, and fill out electronic PRO questionnaires daily using a telecommunicating tablet.

All data are tele transmitted to an approved health data hub, and automatically analysed for physical activity, sleep, circadian rhythms, symptoms scores trends in real time. Visualization screens and alerts are generated according to preset thresholds, and medical team responses are traced.

Currently recruiting centres:

1. Clinique du Mousseau, Evry, France
2. Hospital Paul Brousse (Assistance Publique-Hôpitaux de Paris), Villejuif, France
3. Clinique St-Jean L'Ermitage, Melun, France
4. Private Hospital of Antony, Antony, France

Multidom Remote Monitoring of Patient With Advanced Pancreatic Cancer Treated With Florinox Using the PiCaDo Plateform

Multidom Remote Monitoring of Patient With Advanced Pancreatic Cancer Treated With Florinox Using the PiCaDo Domomedecine Plateform

Individual participant data that underlie the results reported in the original trial report manuscripts will be shared after deidentification. Supportive information will consist in the study protocol.

The main objective is to assess the toxicities occurring during the 6 weeks following the start of the 1st cycle of FOLFIRINOX in conventional administration in patients benefiting from the PiCADo telemonitoring system.

Secondary objectives include rates and grades of toxicity and early tumor responses, as well as PiCADo platform performances and users perceptions.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Association of Pembrolizumab Infusion Time and Efficacy in Patients With Non-metastatic Triple-negative Breast Cancer (TNBC) Treated With Neoadjuvant Chemotherapy and Immunotherapy	NCT06418139	Non-Metastatic ...	No intervention	18 Years - 100 Years	Assistance Publique - Hôpitaux de Paris
Optimal Control of Liver Metastases From Colorectal Cancer With Cetuximab and Hepatic Artery Infusion of Chemotherapy	NCT00852228	Metastatic Colo... Liver Metastase... Hepatic Lesions	IV cetuximab HAI chronomodul... HAI conventiona...	18 Years -	Association pour la Recherche sur le Temps Biologique et la Chronothérapie
Association of Pembrolizumab Infusion Time and Efficacy in Patients With Non-metastatic Triple-negative Breast Cancer (TNBC) Treated With Neoadjuvant Chemotherapy and Immunotherapy	NCT06418139	Non-Metastatic ...	No intervention	18 Years - 100 Years	Assistance Publique - Hôpitaux de Paris
Evaluating the Dose Timing (Morning vs Evening) of Endocrine Therapy and Its Effects on Tolerability and Compliance	NCT04864405	Breast Cancer	Morning adminis... Evening adminis...	18 Years -	Ottawa Hospital Research Institute
"Cancersensor" Chemotherapy	NCT01693861	Metastatic Colo...		18 Years -	Institut National de la Santé Et de la Recherche Médicale, France
"Cancersensor" Chemotherapy	NCT01693861	Metastatic Colo...		18 Years -	Institut National de la Santé Et de la Recherche Médicale, France
Multidom Remote Monitoring of Patient With Advanced Pancreatic Cancer Treated With Florinox Using the PiCaDo Plateform	NCT04263948	Pancreas Cancer	Picado system i...	18 Years - 85 Years	Ramsay Générale de Santé
Evaluating the Dose Timing (Morning vs Evening) of Endocrine Therapy and Its Effects on Tolerability and Compliance	NCT04864405	Breast Cancer	Morning adminis... Evening adminis...	18 Years -	Ottawa Hospital Research Institute

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