CLINICAL RESEARCH: Observational Studies, Interventional Studies, Clinical Trials

PICASSO

Prospective randomised trial evaluating the safety and efficacy of fecal transplantation in melanoma patients treated with anti PD-1

This research evaluates the safety and efficacy of treating melanoma with faecal microbiota transplantation in addition to the usual treatment of melanoma, which consists of immunotherapy with ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor).
Fecal microbiota transplantation is routinely used to treat recurrences of Clostridioides difficile intestinal infection (gut bacteria), which causes inflammation of the colon.
It involves the rectal introduction (enema) of intestinal microbiota into the digestive tract of a recipient patient.

Several recent studies suggest that metastatic melanoma patients whose gut microbiome is colonised by eubiotic bacteria have a stronger anti-cancer response to ipilimumab and nivolumab.

Two recent studies have been performed in patients with metastatic melanoma refractory to anti PD1 immunotherapy. These patients received a faecal transplant (from the stool of melanoma patients who had responded to anti PD1) in conjunction with continued anti PD1 therapy. The results of these studies are promising: some patients who were refractory to immunotherapy responded to immunotherapy after receiving the faecal transplant.

To answer the research question, it is planned to include 60 people with melanoma requiring treatment with ipilimumab and nivolumab, in care facilities in France.

Coordinating investigator: CARBONNEL Franck

Coordinating centre: Greater Paris University Hospitals - AP-HP - Hôpital Bicêtre

Coordinating Clinical Research Unit: URC Paris Sud (HUPS)

Institution(s):

• Greater Paris University Hospitals - AP-HP - Ambroise Paré Hospital
• Greater Paris University Hospitals - AP-HP - Saint Louis Hospital
• CHU Lille - Hôpital Claude Huriez
• CHU Nantes - Hôtel-Dieu - Hôpital Mère-Enfant
• Gustave Roussy - Villejuif site

PREMIS

Predictive markers for immunological adverse events (IrAE) in patients treated with immunostimulant drugs

In oncology, immunostimulatory drugs, in particular immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA4, are revolutionising the treatment of many cancers. The number of patients treated with these molecules is increasing remarkably, with the granting of numerous marketing authorisations and the setting up of numerous clinical trials, particularly with combinations, in many indications.

These new treatments are generating a new type of inflammatory or autoimmune adverse event (AEI), which can affect all organs and can be severe or even fatal if not detected quickly and managed adequately. The risk of developing irAE is greater when patients are treated with combinations of immunotherapies than with monotherapy.

There is currently no way to predict the occurrence of irAE in patients treated with immunotherapy. The induction of immunity depends on the immune status of the host and differs from patient to patient. The mechanisms responsible for the occurrence of irAE have not yet been elucidated. Their understanding is necessary to identify patients at risk and to manage these toxicities more specifically.

The PREMIS study - Predictive markers of immunological adverse events (IrAE) in patients treated with immunostimulatory drugs - is a low-risk, low-constraint interventional research study promoted by Gustave Roussy, whose main objective is to identify non-invasive predictive biomarkers of irAE in patients treated with immunotherapy.

The study will include 1000 patients treated for cancer with a monoclonal antibody targeting immune checkpoints (mainly anti-PD1, anti-PD-L1, anti-CTLA4 and combination immunotherapies), regardless of indication and line of treatment.

The study was set up at Gustave Roussy at the end of September 2018.

Clinical data and biological samples are being collected from all patients just prior to the start of immunotherapy treatment and at 6 weeks of treatment initiation and from patients with irAE, at the time of irAE occurrence.

The data from the samples will allow the identification of immune and biological biomarkers, either pre-existing to the treatment or appearing shortly after the initiation of the treatment, predisposing the patients to develop irAE.

The results will allow us to propose appropriate strategies for the prevention and management of irAE, to make the use of immunotherapy safer and improve the prognosis of treated patients.

They will also contribute to the development of personalised medicine in the field of immunotherapy.

TNF Sen

Opposite mechanisms: Senescent T cells in cancer and in AID

Professor Chaput and Dr. Nocturne are presenting a collaborative project exploring cell senescence and its implication in autoimmune diseases, cancer and chronic viral infections.

The objective of this project is to understand the potential common and opposing mechanisms leading to T cell senescence and the means to control it in autoimmunity, cancer and chronic viral infections.

In this context, Professor Franck Carbonnel suggested exploring Crohn's disease as part of this project.

Professor Mariette noted that this collaborative work perfectly embodies the spirit of the FHU, which aims to create synergies between teams.

REISAMIC

Registry of Severe Adverse Reactions to Immunomodulatory Monoclonal Antibodies in Cancer

Immunotherapies, particularly anti-PD1 and anti PD-L1, are revolutionising the treatment of certain cancers. Their use in current practice is becoming a reality as these molecules obtain marketing authorisations in several indications. However, they expose patients to new complications in oncology: adverse effects related to immunity. These effects require specific management, different from the toxicities observed with chemotherapy or targeted therapies.

Gustave Roussy has set up a unique organisation for the management of immune toxicities, based on 4 axes:

• a network of referral specialists
• institutional recommendations for management
• a specific pharmacovigilance register (REISAMIC)
• a dedicated multidisciplinary consultation meeting (RCP): Organised on the first and third Wednesday of each month at Gustave Roussy, it is also open by webconference to external doctors who wish to discuss a case. This RCP brings together the toxicity referents and the REISAMIC pharmacovigilance team with prescribing physicians confronted with unusual, recurrent toxicities or those occurring in a particular field.

What is REISAMIC?
REISAMIC is a multicentre, national registry, accessible via a web platform, smartphones and tablets, which collects and analyses data concerning suspected immunological and/or severe adverse events occurring in patients treated with immunomodulating monoclonal antibodies (mAbs) used in cancerology.

What is collected?
The data collected in this registry are data on all suspected immunological adverse events of CTCAE grade ≥ 2 and non-immunological adverse events of CTCAE grade ≥ 3, occurring in patients treated with any immunomodulatory mAb, used alone or in combination, in the context of a marketing authorisation, a TUE or a clinical trial (subject to the prior formal agreement of the trial sponsor), regardless of the indication.

What use is made of these data?
The safety data collected are reviewed by the network of immunoTox referents, which includes recognised experts in drug and autoimmune toxicities. They are then discussed during multidisciplinary consultation meetings (RCP) organised every first Wednesday of the month. The establishment of this network and the Immunotox RCP has made it possible to draft and regularly update specific institutional recommendations* for the management of immunotherapy-related toxicities.

How to connect to REISAMIC?
To access the web portal of the registry, you need a login and a password which are provided by the Pharmacovigilance Functional Unit of Gustave Roussy. Once you have obtained your login, type