Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Gastrointestinal Agents

Nivolumab

Immunomodulating Agents

Ipilimumab

Laxatives

Cathartics

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Fecal microbiotherapy MaaT013 (actif arm) enemas will be administered by nurses, at the hospital, in the dermatology department in which the patients are treated for their melanoma. Nurses will be trained to administer enemas. The enema will be administered to the patient in the left lateral position with instructions to retain it for at least 20 minutes

Placebo fecal microbiotherapy will be administered by nurses, at the hospital, in the dermatology department in which the patients are treated for their melanoma. Nurses will be trained to administer enemas. The enema will be administered to the patient in the left lateral position with instructions to retain it for at least 20 minutes

study is an experimental drug , produced by MaaT Pharma, and composed of pooled-donor, full-ecosystem intestinal microbiome (455 species approximately against 274 on average)

MaaT013

Anti cytotoxicT-lymphocyte-associated protein 4 ( immunothérapy)

Osmotic laxative solution : patients take a single dose of two liters of Moviprep® or equivalent the night before the first administration of experimental treatment (Fecal microbiota transfer or placebo)

MoviPrep

Normacol

Placebo of Maat013

Franck CF CARBONNEL, Professor

Caroline CR ROBERT, Professor

Quereux Gaelle, PhD

CELESTE LEBBE, PHd

Robert Caroline

Recent studies suggest that patients with metastatic melanoma whose gut microbiome is colonized by eubiotic bacteria have a stronger anti-cancer response to anti CTLA-4 and anti PD1. The hypothesis of this research is that a pooled standardized fecal microbiome transfer (FMT) will shift melanoma patients' gut microbiome towards a composition close to that associated with a better response, and will therefore increase the response to a combination of anti CTLA-4 and anti PD1, without affecting the safety of these drugs. The present trial is the first randomized trial of FMT in patients with unresectable or metastatic melanoma. It will include patients who have neither been exposed to anti CTLA-4 nor anti PD1 or PDL-1, prior to inclusion in the study. The pooled standardized fecal microbiome transfer administered in this study is an experimental drug MaaT013, a microbiome restoration biotherapeutic, produced by MaaT Pharma, and composed of pooled-donor, full-ecosystem intestinal microbiome. The MaaT013 product has a standardized richness (in number of species present) higher than a product obtained from a mono donor (455 species approximately against 274 on average) and contains bacteria species (mentioned in the rationale) associated with better response to anti- CTLA-4 and anti PD1.

PICASSO is a prospective, randomized, proof of concept clinical trial. This trial is about assessing the tolerance and clinical benefit of fecal microbiome transfer in patients with melanoma in addition to the usual treatment with immunotherapy combining ipilimumab (CTLA-4 inhibitor) and nivolumab (PD-1 inhibitor).

In the proposed research, we will compare faecal transplantation using MaaT013 to placebo in 60 patients.

Patients not exposed to anti CTLA-4 and anti PD1 or PDL-1 patients before the trial will be randomized to receive either: ipilimumab + nivolumab + MaaT013 (n = 30) or ipilimumab + nivolumab + placebo (n = 30).

The estimated duration of the study is 37 months. Administration of MaaT013 or placebo will be performed every 3 weeks between baseline and week 9 then from week 15 to week 23 every 4 weeks. A total of 7 fecal microbiome transfer will be performed.

Prior to the first administration (the day before) an evacuating enema by (MOVIPREP or equivalent) will be done, For subsequent administrations, an evacuating enema (equivalent to the specialty Normacol®) will be administered rectally before the transplantation of fecal microbiota or the placebo.

Blood and stool samples will be collected as well as biopsies for the purposes of the study.

An evaluation of the patient's condition will be made at week 27, Unblinding will be performed for patients who have progressed. Patients with disease progression who received placebo will be considered for receiving MaaT013, in an open-label basis, concurrently with nivolumab infusions, at week 31, 35, 39, 43 and 47.

. The end-of-follow-up visit for all patients is scheduled for week 51. Patients who met the inclusion criteria, received Ipilimumab+Nivolumab, who consented to have a baseline stool microbiota analysis before starting treatment with ipilimumab + nivolumab. They will form a cohort of 50 patients.

Multi-center, prospective, randomized, double blinded, pilot, proof-of concept, clinical trial

At week 27, unblinding will be performed on patients who progressed. For those who received Placebo, Maat 013 will be administrated in open label.

Assessing the Tolerance and Clinical Benefit of feCAl tranSplantation in patientS With melanOma

Prospective randomIzed Clinical Trial Assessing the Tolerance and Clinical Benefit of feCAl tranSplantation in patientS With melanOma Treated With CTLA-4 and PD1 Inhibitors

Safety will be measured by the occurrence of Grade 3 and grade 4 adverse events (AE), as graded by the CTCAE v 5.0

The best overall response rate, rated by immunological Response Evaluation Criteria in Solid Tumors (iRECIST; 19) in the experimental and control arms and among them, within the subgroup of patients who carried the unfavourable baseline microbiota.

Changes in the tumor micro environment (TME) pre and post MaaT013 or placebo

Changes in plasma levels of proteins or metabolites that play a role in immune activity against cancer and/or are associated with gut microbiome composition, pre and post MaaT013 or placebo : IL-6, IL-8, MCP1, IL-1β, TNF α, sCD25, sCTLA-4, sPD-L1, short chain fatty acids (SCFA), all in micromol/L

Changes in peripheral blood immune cell subpopulations pre and post MaaT013 or placebo

Microbial composition will be described by 16S ribosomal RNA gene sequencing as follows:

* Microbial diversity indices (Shannon, Simpson, etc...)
* Proportions of each bacterial taxa in the microbiome of each volunteer

Microbial metagenomes will be described by shotgun sequencing as follows:

* Number of bacterial genes (richness)
* Proportions of each metagenomic unit (species) in the microbiome of each volunteer
* Proportions of Kegg Orthology functional categories in the microbiome of each volunteer

Microbial metabolomes will be described by global metabolomic Liquid Chromatography with tandem mass spectrometry as follows:

* proportions of metabolites in the microbiome of each volunteer
* proportions of specific pathways (KEGG) in the microbiome of each volunteer

Overall response rate, either complete or partial, rated by Response Evaluation Criteria in Solid Tumours in patients with a stable disease or disease progression who received MaaT013, in an open-label basis.

Spots Global Cancer Trial Database for efficacy and safety of maat013